NUCLEAR PROTEIN TARGETING DEUBIQUITINASES AND METHODS OF USE

1. FIELD

This disclosure relates to fusion proteins comprising an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a moiety that specifically binds a target nuclear protein. The disclosure further relates to therapeutic methods of using the same.

2. BACKGROUND

A subset of genetic diseases are associated with a decrease in the level of expression of a functional nuclear protein or a decrease in the stability of a nuclear protein. For example, haploinsufficiency genetic diseases are caused by the presence a single copy of a wild-type allele in heterozygous combination with a loss of function variant allele, wherein the level of functional protein expressed is insufficient to produce the standard phenotype. Haploinsufficiency can arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it produces little or no functional protein. Despite recent developments in gene therapy, there are still no curative treatments for these diseases, and treatment typically centers on the management of symptoms. Therefore, new treatments are needed for diseases, e.g., genetic diseases, that are associated with decreased functional nuclear protein expression or stability.

3. SUMMARY

Provided herein are, inter alia, engineered deubiquitinases (enDubs) that comprise a targeting moiety that specifically binds a nuclear target protein and a catalytic domain of a deubiquitinase. The targeting moiety directs that deubiquitinase catalytic domain to the specific target nuclear protein for deubiquitination. The fusion proteins described herein are particularly useful in methods of treating genetic diseases, particularly those associated with or caused by decreased expression or stability of a specific nuclear protein.

In one aspect, provided herein are fusion proteins comprising: an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein.

In some embodiments, the deubiquitinase is a cysteine protease or a metalloprotease.

In some embodiments, the deubiquitinase is a cysteine protease. In some embodiments, the cysteine protease is a ubiquitin-specific protease (USP), a ubiquitin C-terminal hydrolase (UCH), a Machado-Josephin domain protease (MJD), an ovarian tumour protease (OTU), a MINDY protease, or a ZUFSP protease.

In some embodiments, the cysteine protease is a USP. In some embodiments, the USP is USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, or USP46.

In some embodiments, the cysteine protease is a UCH. In some embodiments, the UCH is BAP1, UCHL1, UCHL3, or UCHL5.

In some embodiments, the cysteine protease is a MJD. In some embodiments, the MJD is ATXN3 or ATXN3L.

In some embodiments, the cysteine protease is a OTU. In some embodiments, the OTU is OTUB1 or OTUB2.

In some embodiments, the cysteine protease is a MINDY. In some embodiments, the MINDY is MINDY1, MINDY2, MINDY3, or MINDY4.

In some embodiments, the cysteine protease is a ZUFSP. In some embodiments, the ZUFSP is ZUP1.

In some embodiments, the deubiquitinase is a metalloprotease. In some embodiments, the metalloprotease is a Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain protease.

In some embodiments, the catalytic domain comprises a catalytic domain derived from a deubiquitinase at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 1-112.

In some embodiments, the moiety that specifically binds a nuclear protein comprises an antibody, or functional fragment or functional variant thereof. In some embodiments, the antibody, or functional fragment or functional variant thereof, comprises a full-length antibody, a single chain variable fragment (scFv), a scFv2, a scFv-Fc, a Fab, a Fab′, a F(ab′)2, a F(v), a VHH, a (VHH)₂. In some embodiments, the antibody, or functional fragment or functional variant thereof, comprises a VHH or (VHH)₂.

In some embodiments, the nuclear protein is a transcription factor. In some embodiments, the nuclear protein is chromodomain-helicase-DNA-binding protein 2 (CHD2), arginine-glutamic acid dipeptide repeats protein (RERE), cyclin-dependent kinase-like 5 (CDKL5), methyl-CpG-binding protein 2 (MECP2), histone-lysine N-methyltransferase 2D (KMT2D), histone-lysine N-methyltransferase SETD5 (SETD5), zinc finger E-box-binding homeobox 2 (ZEB2), calmodulin-binding transcription activator 1 (CAMTA1), synaptic functional regulator FMR1 (FMR1), pre-mRNA-processing-splicing factor 8 (PRPF8), retinoic acid-induced protein 1 (RAI1), CREB-binding protein (CREBBP), neurofibromin (NF1), and histone-lysine N-methyltransferase 2A (KMT2A), chromodomain-helicase-DNA-binding protein 4 (CHD4), histone-lysine N-methyltransferase, H3 lysine-36 specific (NSD1), mediator of RNA polymerase II transcription subunit 13-like (MED13L), structural maintenance of chromosomes protein 1A (SMC1A), probable global transcription activator SNF2L2 (SMARCA2), AT-rich interactive domain-containing protein 1B (ARID1B), pogo transposable element with ZNF domain (POGZ), histone acetyltransferase KAT6B (KAT6B), AT-hook DNA-binding motif-containing protein 1 (AHDC1), histone acetyltransferase p300 (EP300), IQ motif and SEC7 domain-containing protein 2 (IQSEC2), transcription factor 20 (TCF20), putative polycomb group protein ASXL3(ASXL3), histone acetyltransferase KAT6A (KAT6A), Small nuclear ribonucleoprotein G (SNRPG), U6 snRNA-associated Sm-like protein LSm2 (LSM2), or Nuclear protein 2 (NUPR2).

In some embodiments, the nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 221-248 or 424-426.

In some embodiments, the effector domain is directly operably connected to the targeting domain. In some embodiments, the effector domain is indirectly operably connected to the targeting domain. In some embodiments, the effector domain is indirectly operably connected to the targeting domain via a peptide linker. In some embodiments, the effector domain is indirectly fused to the targeting domain via a peptide linker of sufficient length such that the effector domain and the targeting domain can simultaneous bind the respective target proteins. In some embodiments, the peptide linker comprises the amino acid sequence of any one of SEQ ID NOS: 427-436 or 249-367, or the amino acid sequence of any one of SEQ ID NOS: 427-436 or 249-367 comprising 1, 2, or 3 amino acid modifications. In some embodiments, the peptide linker comprises the amino acid sequence of any one of SEQ ID NOS: 427-436, or the amino acid sequence of any one of SEQ ID NOS: 427-436 comprising 1, 2, or 3 amino acid modifications.

In some embodiments, the effector domain is operably connected either directly or indirectly to the C terminus of the targeting domain. In some embodiments, the effector moiety is operably connected either directly or indirectly to the N terminus of the targeting domain.

In some embodiments, the fusion protein further comprises a nuclear localization signal (NLS). In some embodiments, the NLS is a at the N terminus of the fusion protein. In some embodiments, the NLS comprises the amino acid sequence of any one of SEQ ID NOS: 249-367.

In one aspect, provided herein are vectors comprising a nucleic acid molecule described herein (e.g., a nucleic acid molecule encoding a fusion protein described herein). In some embodiments, the vector is a plasmid or a viral vector.

In one aspect, provided herein are viral particles comprising a nucleic acid molecule described herein (e.g., a nucleic acid molecule encoding a fusion protein described herein).

In one aspect, provided herein are in vitro cell or population of cells comprising a fusion protein described herein, a nucleic acid molecule described herein, or a vector described herein.

In one aspect, provided herein are pharmaceutical compositions comprising a fusion protein described herein, a nucleic acid described herein, a vector described herein, or a viral particle described herein, and an excipient.

In one aspect, provided herein are methods of making a fusion protein described herein, comprising introducing into an in vitro cell or population of cells a nucleic acid molecule described herein, a vector described herein, or a viral particle described herein; culturing the cell or population of cells in a culture medium under conditions suitable for expression of the fusion protein, isolating the fusion protein from the culture medium, and optionally purifying the fusion protein.

In one aspect, provided herein are methods of treating or preventing a disease in a subject comprising administering a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, a viral particle described herein, or a pharmaceutical composition described herein, to a subject in need thereof. In some embodiments, the subject is human.

In some embodiments, the disease is associated with decreased expression of a functional version of the nuclear protein relative to a non-diseased control. In some embodiments, the disease is associated with decreased stability of a functional version of the nuclear protein relative to a non-diseased control. In some embodiments, the disease is associated with increased ubiquitination of the nuclear protein relative to a non-diseased control. In some embodiments, the disease is associated with increased ubiquitination and degradation of the nuclear protein relative to a non-diseased control. In some embodiments, wherein the disease is a genetic disease.

In some embodiments, the disease is CHD2 encephalopathy, CDKL5 deficiency disorder, SETD5 syndrome, CAMTA1 syndrome, early infantile epileptic encephalopathy type 2, childhood onset epileptic encephalopathy, 1p36 deletion syndrome, Rett syndrome, Kabuki syndrome 1, mental retardation autosomal dominant 23, Mowat-Wilson syndrome, cerebellar ataxia, fragile X syndrome, retinitis pigmentosa 13, Smith-Magenis syndrome, Rubinstein-Taybi syndrome, neurofibromatosis (e.g., type 1), Wiedmann-Steiner Syndrome, Sifrim-Hitz-Weiss Syndrome, Sotos Syndrome, MED13L Syndrome, SMC1A Syndrome, Nicolaides-Baraitser Syndrome, ARID1B-Related Disorder, White-Sutton Syndrome, KAT6B Disorder, Xia-Gibbs Syndrome, Menke-Hennekam Syndrome 2, IQSEC2-Related Disorder, TCF20-Related Disorder, Bainbridge-Ropers Syndrome, or KATA6 Syndrome.

In some embodiments, the target nuclear protein is CHD2 and the disease is childhood onset epileptic encephalopathy; the target nuclear protein is CHD2 and the disease is CHD2 encephalopathy; the target nuclear protein is RERE and the disease is 1p36 deletion syndrome; the target nuclear protein is CDKL5 and the disease is early infantile epileptic encephalopathy (e.g., type 2); the target nuclear protein is CDKL5 and the disease is CDKL5 deficiency disorder; the target nuclear protein is MECP2 and the disease is Rett syndrome; the target nuclear protein is KMT2D and the disease is Kabuki syndrome 1; the target nuclear protein is SETD5 and the disease is mental retardation autosomal dominant 23; the target nuclear protein is ZEB2 and the disease is Mowat-Wilson syndrome; the target nuclear protein is KMT2A, and the disease is Wiedmann-Steiner Syndrome; the target nuclear protein is CHD4, and the disease is Sifrim-Hitz-Weiss Syndrome; the target nuclear protein is NSD1, and the disease is Sotos Syndrome; the target nuclear protein is SMC1A, and the disease is SMC1A Syndrome; the target nuclear protein is SMARCA2, and the disease is Nicolaides-Baraitser Syndrome; the target nuclear protein is ARID1B, and the disease is ARID1B-Related Disorder; the target nuclear protein is POGZ, and the disease is White-Sutton Syndrome; the target nuclear protein is KAT6B, and the disease is KAT6B Disorder; the target nuclear protein is AHDC1, and the genetic disease is Xia-Gibbs Syndrome; the target nuclear protein is EP300, and the disease is Menke-Hennekam Syndrome 2; the target nuclear protein is IQSEC2, and the disease is IQSEC2-Related Disorder; the target nuclear protein is TCF20, and the disease is TCF20-Related Disorder; the target nuclear protein is ASXL3, and the disease is Bainbridge-Ropers Syndrome; the target nuclear protein is KAT6A, and the disease is KATA6 Syndrome; the target nuclear protein is MED13L, and the disease is MED13L Syndrome; the target nuclear protein is CAMTA1, and the disease is CAMTA1 Syndrome; the target nuclear protein is FMR1, and the disease is Fragile X syndrome; the target nuclear protein is PRPF8, and the disease is Retinitis pigmentosa 13; the target nuclear protein is RAI1, and the disease is Smith-Magenis Syndrome; the target nuclear protein is CREBBP, and the disease is Rubinstein-Taybi syndrome; or the target nuclear protein is NF1, and the disease is Neurofibromatosis (e.g., type 1).

In some embodiments, the disease is a haploinsufficiency disease. In some embodiments, the haploinsufficiency disease is selected from the group consisting of early infantile epileptic encephalopathy type 2, childhood onset epileptic encephalopathy, 1p36 deletion syndrome, Rett syndrome, mental retardation autosomal dominant 23, Mowat-Wilson syndrome, cerebellar ataxia, Smith-Magenis syndrome, or neurofibromatosis (e.g., type 1).

In some embodiments, the fusion protein is administered at a therapeutically effective dose. In some embodiments, the fusion protein is administered systematically or locally. In some embodiments, the fusion protein is administered intravenously, subcutaneously, or intramuscularly.

In one aspect, provided herein are fusion proteins described herein, polynucleotides described herein, DNA described herein, RNA described herein, vectors described herein, viral particles described herein, and pharmaceutical compositions described herein for use as a medicament.

In one aspect, provided herein are fusion proteins comprising: (a) an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and (b) a targeting domain comprising a targeting moiety that specifically binds a nuclear protein.

In some embodiments, the deubiquitinase is a cysteine protease or a metalloprotease.

In some embodiments, the cysteine protease is a USP. In some embodiments, the USP is selected from the group consisting of USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, and USP46.

In some embodiments, the cysteine protease is a UCH. In some embodiments, the UCH is selected from the group consisting of BAP1, UCHL1, UCHL3, and UCHL5.

In some embodiments, the cysteine protease is a MJD. In some embodiments, the MJD is selected from the group consisting of ATXN3 and ATXN3L.

In some embodiments, the cysteine protease is a OTU. In some embodiments, the OTU is selected from the group consisting of OTUB1 and OTUB2.

In some embodiments, the cysteine protease is a MINDY. In some embodiments, the MINDY is selected from the group consisting of MINDY1, MINDY2, MINDY3, and MINDY4.

In some embodiments, the cysteine protease is a ZUFSP. In some embodiments, the ZUFSP is ZUP1. In some embodiments, the deubiquitinase is a metalloprotease. In some embodiments, the metalloprotease is a Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain protease.

In some embodiments, the moiety that specifically binds a nuclear protein comprises an antibody, or functional fragment or functional variant thereof. In some embodiments, the antibody, or functional fragment or functional variant thereof, comprises a full-length antibody, a single chain variable fragment (scFv), a scFv2, a scFv-Fc, a Fab, a Fab′, a F(ab′)2, a F(v), or a VHH. In some embodiments, the antibody, or functional fragment or functional variant thereof, comprises a VHH.

In some embodiments, the nuclear protein is a transcription factor.

In some embodiments, the nuclear protein is selected from the group consisting of chromodomain-helicase-DNA-binding protein 2 (CHD2), arginine-glutamic acid dipeptide repeats protein (RERE), cyclin-dependent kinase-like 5 (CDKL5), methyl-CpG-binding protein 2 (MECP2), histone-lysine N-methyltransferase 2D (KMT2D), histone-lysine N-methyltransferase SETD5 (SETD5), zinc finger E-box-binding homeobox 2 (ZEB2), calmodulin-binding transcription activator 1 (CAMTA1), synaptic functional regulator FMR1 (FMR1), pre-mRNA-processing-splicing factor 8 (PRPF8), retinoic acid-induced protein 1 (RAI1), CREB-binding protein (CREBBP), neurofibromin (NF1), and histone-lysine N-methyltransferase 2A (KMT2A), chromodomain-helicase-DNA-binding protein 4 (CHD4), histone-lysine N-methyltransferase, H3 lysine-36 specific (NSD1), mediator of RNA polymerase II transcription subunit 13-like (MED13L), structural maintenance of chromosomes protein 1A (SMC1A), probable global transcription activator SNF2L2 (SMARCA2), AT-rich interactive domain-containing protein 1B (ARID1B), pogo transposable element with ZNF domain (POGZ), histone acetyltransferase KAT6B (KAT6B), AT-hook DNA-binding motif-containing protein 1 (AHDC1), histone acetyltransferase p300 (EP300), IQ motif and SEC7 domain-containing protein 2 (IQSEC2), transcription factor 20 (TCF20), putative polycomb group protein ASXL3(ASXL3), and histone acetyltransferase KAT6A (KAT6A).

In some embodiments, the nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 221-248.

In some embodiments, the effector domain is directly fused to the targeting domain. In some embodiments, the effector domain is indirectly fused to the targeting domain. In some embodiments, the effector domain is indirectly fused to the targeting domain via a peptide linker. In some embodiments, the effector domain is indirectly fused to the targeting domain via a peptide linker of sufficient length such that the effector domain and the targeting domain can simultaneous bind the respective target proteins.

In some embodiments, the effector domain is fused to the C terminus of the targeting domain. In some embodiments, the effector moiety is fused to the N terminus of the targeting domain.

In some embodiments, the fusion protein further comprises a nuclear localization signal (NLS). In some embodiments, the NLS is a at the N terminus of the fusion protein.

In one aspect, provided herein are nucleic acid molecules encoding the fusion protein described herein. In some embodiments, the nucleic acid molecule is a DNA molecule. In some embodiments, the nucleic acid molecule is an RNA molecule.

In one aspect, provided herein are vectors comprising a nucleic acid molecule described herein. In some embodiments, the vector is a plasmid or a viral vector.

In one aspect, provided herein are viral particles comprising a nucleic acid described herein.

In one aspect, described herein is an in vitro cell or population of cells comprising a fusion protein described herein, a nucleic acid molecule described herein, or a vector described herein.

In one aspect, provided herein are pharmaceutical compositions comprising a fusion protein described herein, a nucleic acid molecule described herein, a vector described herein, or a viral particle described herein, and an excipient.

In one aspect, provided herein are methods of making a fusion protein described herein, comprising (a) introducing into an in vitro cell or population of cells a nucleic acid described herein, a vector described herein, or a viral particle described herein; (b) culturing the cell or population of cells in a culture medium under conditions suitable for expression of the fusion protein, (c) isolating the fusion protein from the culture medium, and (d) optionally purifying the fusion protein.

In one aspect, provided herein are methods of treating a disease in a subject comprising administering a fusion protein described herein, a nucleic acid described herein, a vector described herein, or a viral particle described herein, or a pharmaceutical composition described herein, to a subject in need thereof.

In some embodiments, the subject is human.

In some embodiments, the disease is associated with decreased expression of a functional version of the mitochondrial protein relative to a non-diseased control.

In some embodiments, the disease is associated with decreased stability of a functional version of the mitochondrial protein relative to a non-diseased control.

In some embodiments, the disease is associated with increased ubiquitination and degradation of the mitochondrial protein relative to a non-diseased control.

In some embodiments, the disease is a genetic disease.

4. BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1D provides a schematic representation of exemplary fusion proteins described herein. FIG. 1A is a schematic of an engineered deubiquitinase comprising from N′ to C′ terminus a VHH that specifically binds a nuclear target protein and the catalytic domain of a deubiquitinase. In this specific embodiment, the C-terminus of the VHH is directly connected to the N-terminus of the catalytic domain of the deubiquitinase. FIG. 1B is a schematic of an engineered deubiquitinase comprising from N′ to C′ terminus the catalytic domain of a deubiquitinase that specifically binds a nuclear target protein and a VHH that specifically binds a nuclear target protein. In this specific embodiment, the C-terminus of the catalytic domain of the deubiquitinase is directly connected to the N-terminus of the VHH. FIG. 1C is a schematic of an engineered deubiquitinase comprising from N′ to C′ terminus a VHH that specifically binds a nuclear target protein and the catalytic domain of a deubiquitinase. In this specific embodiment, the C-terminus of the VHH is indirectly connected to the N-terminus of the catalytic domain of the deubiquitinase through a peptide linker. FIG. 1D is a schematic of an engineered deubiquitinase comprising from N′ to C′ terminus the catalytic domain of a deubiquitinase that specifically binds a nuclear target protein and a VHH that specifically binds a nuclear target protein. In this specific embodiment, the C-terminus of the catalytic domain of the deubiquitinase is indirectly connected to the N-terminus of the VHH through a peptide linker.

FIG. 2 is a schematic representation of the assay utilized in Example 3, to screen the effect of targeted deubiquitination of different nuclear proteins on target protein expression.

FIG. 3 is a bar graph depicting the fold change in SNRPG protein expression relative to control (deubiquitinase without the nanobody targeting the alfa-tag).

FIG. 4 is a bar graph depicting the fold change in LSM2 protein expression relative to control (deubiquitinase without the nanobody targeting the alfa-tag).

FIG. 5 is a bar graph depicting the fold change in NUPR2 protein expression relative to control (deubiquitinase without the nanobody targeting the alfa-tag).

5. DETAILED DESCRIPTION
5.1 Overview

Ubiquitination is the process by which ubiquitin ligases mediate the addition of ubiquitin, a 76 amino acid regulatory protein, to a substrate protein. Ubiquitination generally starts by the attachment of a single ubiquitin molecule to a lysine amino acid residue of the substrate protein. Mevissen T. et al. Mechanisms of Deubiquitinase Specificity and Regulation Annual Review of Biochemistry 86:1, 159-192 (2017), the entire contents of which is incorporated by reference herein. These monoubiquitination events are abundant and serve various functions. Ubiquitin itself contains seven lysine residues, all of which can be ubiquitinated resulting in polyubiquitinated proteins. Komander, D. et al. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-563 (2009), the entire contents of which is incorporated by reference herein. Mono and polyubiquitination can have multiple effects on the substrate protein, including marking the substrate protein for degradation via the proteasome, altering the protein's cellular location, altering the protein's activity, and/or promoting or preventing normal protein interactions. See e.g., Hershko A. et al. The ubiquitin system. Annu Rev Biochem. 67:425-79 (1998); Nandi D, et al. The ubiquitin-proteasome system. J Biosci. March; 31(1):137-55 (2006), the entire contents of each of which is incorporated by reference herein. The effects of ubiquitination can be reversed or prevented by removing the ubiquitin protein(s) from the substrate protein. The removal of ubiquitin from a substrate protein is mediated by deubiquitinase (DUB) proteins. Id.

Numerous genetic diseases are associated with or caused by a decrease in the level of expression of a functional nuclear protein or the stability of the nuclear protein. For example, haploinsufficiency genetic diseases are caused by the presence a single copy of a wild-type allele in heterozygous combination with a loss of function variant allele, wherein the level of functional protein expressed is insufficient to produce the standard phenotype. See e.g., Johnson, A. et al, Causes and effects of haploinsufficiency. Biol Rev, 94: 1774-1785 (2019), the entire contents of which is incorporated by reference herein. Haploinsufficiency can arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it produces little or no functional protein. Other genetic disorders result from the ubiquitination and subsequent degradation of variant but functional proteins, resulting in a decrease in expression of the functional protein.

The present disclosure provides, inter alia, novel fusion proteins that comprise the catalytic domain (or functional fragment thereof) of a deubiquitinase and a targeting moiety, such as a VHH, that specifically binds to a target nuclear protein. In some embodiments, decreased expression of a functional version of the target nuclear protein or decreased stability of a functional version of the target nuclear protein is associated with a disease phenotype. As such, the fusion proteins described herein are particularly useful in the treatment of genetic diseases characterized by a decrease in the level of expression of a functional target nuclear protein or the stability of the target nuclear protein. Upon expression of the fusion protein by host cells, the catalytic domain of the deubiquitinase will be specifically targeted to the target nuclear protein and deubiquitinated, resulting in increased expression of the target nuclear protein, e.g., to a level sufficient to alleviate the disease phenotype.

5.2 Definitions

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and/or “consisting essentially of” are also provided.

The term “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

The terms “about” or “comprising essentially of” refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “comprising essentially of” can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, “about” or “comprising essentially of” can mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of “about” or “comprising essentially of” should be assumed to be within an acceptable error range for that particular value or composition.

As used herein, the term “catalytic domain” in reference to a deubiquitinase refers to an amino acid sequence, or a variant thereof, of a deubiquitinase that is capable of mediating deubiquitination of a target protein. The catalytic domain may comprise a naturally occurring amino acid sequence of a deubiquitinase or it may comprise a variant amino acid sequence of a naturally occurring deubiquitinase. The catalytic domain may comprise the minimum amino acid sequence of a deubiquitinase to mediate deubiquitination of a target protein. The catalytic domain may comprise more than the minimum amino acid sequence of a deubiquitinase to mediate deubiquitination of a target protein.

The terms “polynucleotide” and “nucleic acid sequence” are used interchangeably herein and refer to a polymer of DNA or RNA. The polynucleotide sequence can be single-stranded or double-stranded; contain natural, non-natural, or altered nucleotides; and contain a natural, non-natural, or altered internucleotide linkage, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified polynucleotide sequence. Polynucleotide sequences include, but are not limited to, all polynucleotide sequences which are obtained by any means available in the art, including, without limitation, recombinant means, e.g., the cloning of polynucleotide sequences from a recombinant library or a cell genome, using ordinary cloning technology and polymerase chain reaction, and the like, and by synthetic means.

The terms “amino acid sequence” and “polypeptide” are used interchangeably herein and refer to a polymer of amino acids connected by one or more peptide bonds.

The term “functional variant” as used herein in reference to a protein or polypeptide refers to a protein that comprises at least one amino acid modification (e.g., a substitution, deletion, addition) compared to the amino acid sequence of a reference protein, that retains at least one particular function. In some embodiments, the reference protein is a wild type protein. For example, a functional variant of an IL-2 protein can refer to an IL-2 protein comprising an amino acid substitution as compared to a wild type IL-2 protein that retains the ability to bind the intermediate affinity IL-2 receptor but abrogates the ability of the protein to bind the high affinity IL-2 receptor. Not all functions of the reference wild type protein need be retained by the functional variant of the protein. In some instances, one or more functions are selectively reduced or eliminated.

The term “functional fragment” as used herein in reference to a protein or polypeptide refers to a fragment of a reference protein that retains at least one particular function. For example, a functional fragment of an anti-HER2 antibody can refer to a fragment of the anti-HER2 antibody that retains the ability to specifically bind the HER2 antigen. Not all functions of the reference protein need be retained by a functional fragment of the protein. In some instances, one or more functions are selectively reduced or eliminated.

As used herein, the term “modification,” with reference to a polynucleotide sequence, refers to a polynucleotide sequence that comprises at least one substitution, alteration, inversion, addition, or deletion of nucleotide compared to a reference polynucleotide sequence. Modifications can include non-naturally nucleotides. As used herein, the term “modification,” with reference to an amino acid sequence refers to an amino acid sequence that comprises at least one substitution, alteration, inversion, addition, or deletion of an amino acid residue compared to a reference amino acid sequence. Modifications can include the inclusion of non-naturally occurring amino acid residues.

As used herein, the term “derived from” with reference to an amino acid sequence refers to an amino acid sequence that has at least 80% sequence identity to a reference naturally occurring amino acid sequence. For example, a catalytic domain derived from a naturally occurring deubiquitinase means that the catalytic domain has an amino acid sequence with at least 80% sequence identity to the sequence of the deubiquitinase catalytic domain from which it is derived. The term “derived from” as used herein does not denote any specific process or method for obtaining the amino acid sequence. For example, the amino acid sequence can be chemically or recombinantly synthesized.

The term “fusion protein” and grammatical equivalents as used herein refers to a protein that comprises an amino acid sequence derived from at least two separate proteins. The amino acid sequence of the at least two separate proteins can be directly connected through a peptide bond; or can be operably connected through an amino acid linker. Therefore, the term fusion protein encompasses embodiments, wherein the amino acid sequence of e.g., Protein A is directly connected to the amino acid sequence of Protein B through a peptide bond (Protein A-Protein B), and embodiments, wherein the amino acid sequence of e.g., Protein A is operably connected to the amino acid sequence of Protein B through an amino acid linker (Protein A-linker-Protein B).

The term “fuse” and grammatical equivalents thereof as used herein refers to the operable connection of an amino acid sequence derived from one protein to the amino acid sequence derived from different protein. The term fuse encompasses both a direct connection of the two amino acid sequences through a peptide bond, and the indirect connection through an amino acid linker.

An “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds specifically to HER2 is substantially free of antibodies that bind specifically to antigens other than HER2). An isolated antibody that binds specifically to HER2 may, however, cross-react with other antigens, such as HER2 molecules from different species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. By comparison, an “isolated” nucleic acid refers to a nucleic acid composition of matter that is markedly different, i.e., has a distinctive chemical identity, nature and utility, from nucleic acids as they exist in nature. For example, an isolated DNA, unlike native DNA, is a freestanding portion of a native DNA and not an integral part of a larger structural complex, the chromosome, found in nature. Further, an isolated DNA, unlike native DNA, can be used as a PCR primer or a hybridization probe for, among other things, measuring gene expression and detecting biomarker genes or mutations for diagnosing disease or predicting the efficacy of a therapeutic. An isolated nucleic acid may also be purified so as to be substantially free of other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, using standard techniques well known in the art.

As used herein, the term “antibody” or “antibodies” are used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity (i.e. antigen binding fragments as defined herein). The term antibody thus includes, for example, include full-length antibodies, antigen-binding fragments of full-length antibodies, molecules comprising antibody CDRs, VH regions, and/or VL regions; and antibody-like scaffolds (e.g., fibronectins). Examples of antibodies include, without limitation, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (e.g., VHH, (VHH)₂), monovalent antibodies, single chain antibodies, single-chain Fvs (scFv; (scFv)₂), camelized antibodies, affybodies, Fab fragments (e.g., Fab, single chain Fab (scFab), F(ab′)₂fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), diabodies, tribodies, and antibody-like scaffolds (e.g., fibronectins), Fc fusions (e.g., Fab-Fc, scFv-Fc, VHH-Fc, (scFv)₂-Fc, (VHH)₂-Fc, and antigen-binding fragments of any of the above, and conjugates or fusion proteins comprising any of the above. In certain embodiments, antibodies described herein refer to polyclonal antibody populations. In certain embodiments, antibodies described herein refer to monoclonal antibody populations. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class (e.g., IgG₁, IgG₂, IgG₃, IgG₄, IgA₁or IgA₂), or any subclass (e.g., IgG_2aor IgG_2b) of immunoglobulin (Ig) molecule. In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgG₁or IgG₄) or subclass thereof. In a specific embodiment, the antibody is a humanized monoclonal antibody. In another specific embodiment, the antibody is a human monoclonal antibody.

The term “full-length antibody,” as used herein refers to an antibody having a structure substantially similar to a native antibody structure comprising two heavy chains and two light chains interconnected by disulfide bonds. In some embodiments, the two heavy chains comprise a substantially identical amino acid sequence; and the two light chains comprise a substantially identical amino acid sequence. Antibody chains may be substantially identical but not entirely identical if they differ due to post-translational modifications, such as C-terminal cleavage of lysine residues, alternative glycosylation patterns, etc.

The terms “antigen binding fragment” and “antigen binding domain” are used interchangeably herein and refer to one or more polypeptides, other than a full-length antibody, that is capable of specifically binding to antigen and comprises a portion of a full-length antibody (e.g., a VH, a VL). Exemplary antigen binding fragments include, but are not limited to, single domain antibodies (e.g., VHH, (VHH)₂), single chain antibodies, single-chain Fvs (scFv; (scFv)₂), camelized antibodies, affybodies, Fab fragments (e.g., Fab, single chain Fab (scFab), F(ab′)₂fragments, and disulfide-linked Fvs (sdFv). The antigen binding domain can be part of a larger protein, e.g., a full-length antibody.

The term “(scFv)₂” as used herein refers to an antibody that comprises a first and a second scFv operably connected (e.g., via a linker). The first and second scFv can specifically bind the same or different antigens. In some embodiments, the first and second scFv are operably connected by an amino via an amino acid linker.

The term “(VHH)₂” as used herein refers to an antibody that comprises a first and a second VHH operably connected (e.g., via a linker). The first and the second VHH can specifically bind the same or different antigens. In some embodiments, the first and second VHH are operably connected by an amino via an amino acid linker.

The term “Fab-Fc” as used herein refers to an antibody that comprises a Fab operably linked to an Fc domain or a subunit of an Fc domain. A full-length antibody described herein comprises two Fabs, one Fab operably connected to one Fc domain and the other Fab operably connected to a second Fc domain.

The term “scFv-Fc” as used herein refers to an antibody that comprises a scFv operably linked to an Fc domain or subunit of an Fc domain.

The term “VHH-Fc” as used herein refers to an antibody that comprises a VHH operably linked to an Fc domain or a subunit of an Fc domain.

The term “(scFv)₂-Fc” as used herein refers to a (scFv)₂operably linked to an Fc domain or a subunit of an Fc domain.

The term “(VHH)₂—Fc” as used herein refers to (VHH)₂operably linked to an Fc domain or a subunit of an Fc domain.

“Antibody-like scaffolds” are known in the art, for example, fibronectin and designed ankyrin repeat proteins (DARPins) have been used as alternative scaffolds for antigen-binding domains, see, e.g., Gebauer and Skerra, Engineered protein scaffolds as next-generation antibody therapeutics. Curr Opin Chem Biol 13:245-255 (2009) and Stumpp et al., Darpins: A new generation of protein therapeutics. Drug Discovery Today 13: 695-701 (2008). Exemplary antibody-like scaffold proteins include, but are not limited to, lipocalins (Anticalin), Protein A-derived molecules such as Z-domains of Protein A (Affibody), an A-domain (Avimer/Maxibody), a serum transferrin (trans-body); a designed ankyrin repeat protein (DARPin), VNAR fragments, a fibronectin (AdNectin), a C-type lectin domain (Tetranectin); a variable domain of a new antigen receptor beta-lactamase (VNAR fragments), a human gamma-crystallin or ubiquitin (Affilin molecules); a kunitz type domain of human protease inhibitors, microbodies such as the proteins from the knottin family, peptide aptamers and fibronectin (adnectin).

As used herein, the term “CDR” or “complementarity determining region” means the noncontiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), all of which are herein incorporated by reference in their entireties. Unless otherwise specified, the term “CDR” is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991).

As used herein, the term “framework (FR) amino acid residues” refers to those amino acids in the framework region of an antibody variable region. The term “framework region” or “FR region” as used herein, includes the amino acid residues that are part of the variable region, but are not part of the CDRs (e.g., using the Kabat definition of CDRs).

As used herein, the term “heavy chain” when used in reference to an antibody can refer to any distinct type, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG₁, IgG₂, IgG₃, and IgG₄.

As used herein, the term “light chain” when used in reference to an antibody can refer to any distinct type, e.g., kappa (κ) or lambda (λ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.

As used herein, the terms “variable region” refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In particular embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody.

The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody.

As used herein, the terms “constant region” and “constant domain” are interchangeable and are common in the art. The constant region is an antibody portion, e.g., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with an Fc receptor (e.g., Fc gamma receptor). The constant region of an immunoglobulin (Ig) molecule generally has a more conserved amino acid sequence relative to an immunoglobulin (Ig) variable domain.

The term “Fc region” as used herein refers to the C-terminal region of an immunoglobulin (Ig) heavy chain that comprises from N- to C-terminus at least a CH2 domain operably connected to a CH3 domain. In some embodiments, the Fc region comprises an immunoglobulin (Ig) hinge region operably connected to the N-terminus of the CH2 domain. Examples of proteins with engineered Fc regions can be found in Saunders 2019 (K. O. Saunders, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” 2019, Frontiers in Immunology, V. 10, Art. 1296, pp. 1-20, which is incorporated by reference herein).

As used herein, the term “EU numbering system” refers to the EU numbering convention for the constant regions of an antibody, as described in Edelman, G. M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al, Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991, each of which is herein incorporated by reference in its entirety.

As used herein, the term “Kabat numbering system” refers to the Kabat numbering convention for variable regions of an antibody, see e.g., Kabat et al, Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 5th edition, 1991. Unless otherwise noted, numbering of the variable regions of an antibody are denoted according to the Kabat numbering system.

As used herein, the terms “specifically binds,” refers to molecules that bind to an antigen (e.g., epitope or immune complex) as such binding is understood by one skilled in the art. For example, a molecule that specifically binds to an antigen can bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, BIAcore©, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specific embodiment, molecules that specifically bind to an antigen bind to the antigen with a K_Athat is at least 2 logs (e.g., factors of 10), 2.5 logs, 3 logs, 4 logs or greater than the K_Awhen the molecules bind non-specifically to another antigen. The skilled worker will appreciate that an antibody, as described herein, can specifically bind to more than one antigen (e.g., via different regions of the antibody molecule). The term specifically binds includes molecules that are cross reactive with the same antigen of a different species. For example, an antigen binding domain that specifically binds human CD20 may be cross reactive with CD20 of another species (e.g., cynomolgus monkey, or murine), and still be considered herein to specifically bind human CD20.

“Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antigen binding moiety and an antigen, or a receptor and its ligand). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD), which is the ratio of dissociation and association rate constants (koff and kon, respectively). Thus, equivalent affinities may comprise different rate constants, as long as the ratio of the rate constants remains the same. Affinity can be measured by well-established methods known in the art, including those described herein. A particular method for measuring affinity is Surface Plasmon Resonance (SPR).

The determination of “percent identity” between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul S F (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul S F (1993) PNAS 90: 5873-5877, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the BLASTN, BLASTP, BLASTX programs of Altschul S F et al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the BLASTP program parameters set, e.g., default settings; to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul S F et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of BLASTP and BLASTN) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, which is herein incorporated by reference in its entirety. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted. As described above, the percent identity is based on the amino acid matches between the smaller of two proteins. Therefore, for example, using NCBI Basic Local Alignment Tool—BLASTP program on the default settings (Search Parameters: word size 3, expect value 0.05, hitlist 100, Gapcosts 11,1; Matrix BLOSUM62, Filter string: F; Genetic Code: 1; Window Size: 40; Threshold: 11; Composition Based Stats: 2; Karlin-Altschul Statistics: Lambda: 0.31293; 0.267; K: 0.132922; 0.041; H: 0.401809; 0.14; and Relative Statistics: Effective search space: 288906); the percent identity between SEQ ID NO: 80 and SEQ ID NO: 423 is 100% identity.

As used herein, the term “operably connected” refers to a linkage of polynucleotide sequence elements or amino acid sequence elements in a functional relationship. For example, a polynucleotide sequence is operably connected when it is placed into a functional relationship with another polynucleotide sequence. In some embodiments, a transcription regulatory polynucleotide sequence e.g., a promoter, enhancer, or other expression control element is operably-linked to a polynucleotide sequence that encodes a protein if it affects the transcription of the polynucleotide sequence that encodes the protein.

The terms “subject” and “patient” are used interchangeably herein and include any human or nonhuman animal. The term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some embodiments, the subject is a human.

As used herein, the term “administering” refers to the physical introduction of a therapeutic agent (or a precursor of the therapeutic agent that is metabolized or altered within the body of the subject to produce the therapeutic agent in vivo) to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The term “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. A therapeutic agent may be administered via a non-parenteral route, or orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

A “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

The terms “disease,” “disorder,” and “syndrome” are used interchangeably herein.

As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disease and/or symptom(s) associated therewith or obtaining a desired pharmacologic and/or physiologic effect. It will be appreciated that, although not precluded, treating a disease does not require that the disease or symptoms associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and/or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a compositions as described herein.

5.3 Fusion Proteins

In certain aspects, provided herein are fusion proteins that comprise an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a moiety that specifically binds a target cytosolic protein.

5.3.1 Effector Domain

In some embodiments, the effector domain comprises a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof. In some embodiments, the deubiquitinase is human. In some embodiments, the catalytic domain is derived from a naturally occurring deubiquitinase (e.g., a naturally occurring human deubiquitinase).

In some embodiments, the amino acid sequence of the effector domain comprises the amino acid sequence of a full length deubiquitinase. In some embodiments, the amino acid sequence of the effector domain comprises the amino acid sequence of a catalytic domain of a deubiquitinase and an additional amino acid sequence at the N-terminal, C-terminal, or N-terminal and C-terminal end of the catalytic domain.

In some embodiments, the catalytic domain comprises a naturally occurring amino acid sequence of a deubiquitinase. In some embodiments, the catalytic domain comprises a variant of a naturally occurring deubiquitinase. In some embodiments, the amino acid sequence of the catalytic domain of the fusion protein is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of a naturally occurring deubiquitinase. In some embodiments, the amino acid sequence of the catalytic domain of the fusion protein comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 amino acid modifications compared to the amino acid sequence of the catalytic domain of a naturally occurring deubiquitinase.

In some embodiments, the catalytic domain comprises the minimum amino acid sequence of a naturally occurring deubiquitinase sufficient to mediate deubiquitination of a target protein. In some embodiments, the catalytic domain comprises more than the minimum amino acid sequence of a naturally occurring deubiquitinase sufficient to mediate deubiquitination of a target protein.

In some embodiments, the deubiquitinase is a cysteine protease or a metalloprotease. In some embodiments, the deubiquitinase is a cysteine protease. In some embodiments, the deubiquitinase is a metalloprotease. In some embodiments, the deubiquitinase is a ubiquitin-specific protease (USP), a ubiquitin C-terminal hydrolase (UCH), a Machado-Josephin domain protease (MJD), an ovarian tumor protease (OTU), a MINDY protease, or a ZUFSP protease.

Exemplary deubiquitinases include, but are not limited to, USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, USP46, BAP1, UCHL1, UCHL3, UCHL5, ATXN3, ATXN3L, OTUB1, OTUB2, MINDY1, MINDY2, MINDY3, MINDY4, and ZUP1. Exemplary deubiquitinases for use in the present disclosure are also disclosed in Komander, D. et al. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-563 (2009), the entire contents of which is incorporated by reference herein.

In some embodiments, the deubiquitinase is selected from the group consisting of USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, and USP46.

In some embodiments, the deubiquitinase is BAP1, UCHL1, UCHL3, or UCHL5. In some embodiments, the deubiquitinase is ATXN3 or ATXN3L. In some embodiments, the deubiquitinase is OTUB1 or OTUB2. In some embodiments, the deubiquitinase is MINDY1, MINDY2, MINDY3, or MINDY4. In some embodiments, the deubiquitinase is ZUP1. In some embodiments, the deubiquitinase is a Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain protease.

In some embodiments, the deubiquitinase is a deubiquitinase described in Table 1. In some embodiments, the amino acid sequence of the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a deubiquitinase in Table 1. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a catalytic domain of a deubiquitinase in Table 1. In some embodiments, the effector domain comprises a functional fragment of a deubiquitinase in Table 1. In some embodiments, the effector domain deubiquitinase comprises a functional variant of deubiquitinase in Table 1. In some embodiments, the catalytic domain comprises a functional fragment of a catalytic domain of a deubiquitinase in Table 1. In some embodiments, the catalytic domain comprises a functional variant of a catalytic domain of a deubiquitinase in Table 1.

In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 3. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 4. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 5. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 6. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 7. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 8. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 9. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 10. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 11. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 12. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 13. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 14. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 15. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 16. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 17. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 18. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 19. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 20. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 21. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 22. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 23. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 24. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 25. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 26. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 27. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 28. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 29. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 30. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 31. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 32. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 33. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 34. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 35. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 36. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 37. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 38. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 39. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 40. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 41. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 42. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 43. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 44. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 45. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 46. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 47. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 48. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 49. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 50. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 51. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 52. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 53. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 54. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 55. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 56. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 57. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 58. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 59. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 60. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 61. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 62. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 63. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 64. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 65. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 66. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 67. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 68. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 69. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 70. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 71. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 72. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 73. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 74. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 75. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 76. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 77. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 78. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 79. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 80. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 81. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 82. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 83. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 84. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 85. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 86. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 87. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 88. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 89. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 90. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 91. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 92. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 93. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 94. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 95. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 96. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 97. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 98. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 99. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 100. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 101. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 102. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 103. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 104. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 105. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 106. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 107. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 109. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 110. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 111. In some embodiments, the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 112.

In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 1. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 2. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 3. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 4. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 5. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 6. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 7. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 8. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 9. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 10. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 11. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 12. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 13. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 14. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 15. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 16. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 17. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 18. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 19. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 20. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 21. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 22. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 23. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 24. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 25. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 26. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 27. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 28. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 29. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 30. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 31. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 32. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 33. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 34. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 35. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 36. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 37. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 38. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 39. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 40. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 41. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 42. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 43. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 44. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 45. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 46. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 47. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 48. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 49. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 50. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 51. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 52. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 53. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 54. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 55. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 56. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 57. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 58. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 59. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 60. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 61. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 62. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 63. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 64. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 65. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 66. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 67. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 68. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 69. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 70. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 71. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 72. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 73. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 74. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 75. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 76. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 77. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 78. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 79. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 80. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 81. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 82. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 83. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 84. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 85. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 86. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 87. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 88. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 89. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 90. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 91. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 92. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 93. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 94. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 95. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 96. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 97. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 98. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 99. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 100. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 101. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 102. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 103. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 104. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 105. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 106. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 107. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 108. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 109. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 110. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 111. In some embodiments, the amino acid sequence of the effector domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the catalytic domain of SEQ ID NO: 112.

In some embodiments, the catalytic domain is derived from a deubiquitinase that comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 1-112. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 1-112.

In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 26. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 27. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 29. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 34. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 40. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 46. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 52. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 55. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 58. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 61. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 62. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 63. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 64. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 66. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 80. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 81. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 85. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 88. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 89. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 92. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 93. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 94. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 95. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 96. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 97. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 98. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 99. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 102. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 102. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 104. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 105. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 110. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the catalytic domain is derived from a deubiquitinase that consists of an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 112.

In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 114. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 116. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 121. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 124. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 133. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 137. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 140. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 143. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 144. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 145. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 146. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 147. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 148. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 149. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 150. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 151. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 152. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 153. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 154. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 155. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 156. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 157. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 158. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 159. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 160. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 161. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 162. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 163. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 164. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 165. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 166. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 167. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 168. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 169. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 170. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 171. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 172. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 173. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 174. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 175. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 176. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 177. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 178. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 179. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 180. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 181. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 182. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 183. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 184. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 185. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 186. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 187. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 188. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 189. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 190. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 191. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 192. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 193. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 194. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 195. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 196. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 197. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 198. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 199. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 200. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 201. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 202. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 203. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 204. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 205. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 206. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 207. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 208. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 209. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 210. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 211. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 212. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 213. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 214. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 215. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 216. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 218. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 219. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 220. In some embodiments, the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 423.

Table 1 below describes, the amino acid sequence of exemplary human deubiquitinases and exemplary catalytic domains of the exemplary human deubiquitinases. The catalytic domains are exemplary. A person of ordinary skill in the art could readily determine a sufficient amino acid sequence of a human deubiquitinase to mediate deubiquitination (e.g., a catalytic domain). Any of the human deubiquitinases (functional fragment or variants thereof) may be used to derive a catalytic domain for use in a fusion protein described herein.

TABLE 1

The amino acid sequence of exemplary human deubiquitinases and exemplary catalytic

domains of the same

SEQ

SEQ
Exemplary Catalytic Domains

Description
ID NO
Amino Acid Sequence
ID NO
(Amino Acid Sequence)

UBP27_HUMAN
1
MCKDYVYDKDIEQIAKEEQGEA
113
SSFTIGLRGLINLGNTCEMN

Ubiquitin

LKLQASTSTEVSHQQCSVPGLG

CIVQALTHTPILRDFFLSDR

carboxyl-

EKFPTWETTKPELELLGHNPRR

HRCEMPSPELCLVCEMSSLF

terminal

RRITSSFTIGLRGLINLGNTCF

RELYSGNPSPHVPYKLLHLV

hydrolase 27

MNCIVQALTHTPILRDFFLSDR

WIHARHLAGYRQQDAHEFLI

HRCEMPSPELCLVCEMSSLFRE

AALDVLHRHCKGDDVGKAAN

LYSGNPSPHVPYKLLHLVWIHA

NPNHCNCIIDQIFTGGLQSD

RHLAGYRQQDAHEFLIAALDVL

VTCQACHGVSTTIDPCWDIS

HRHCKGDDVGKAANNPNHCNCI

LDLPGSCTSFWPMSPGRESS

IDQIFTGGLQSDVTCQACHGVS

VNGESHIPGITTLTDCLRRF

TTIDPCWDISLDLPGSCTSFWP

TRPEHLGSSAKIKCGSCQSY

MSPGRESSVNGESHIPGITTLT

QESTKQLTMNKLPVVACFHF

DCLRRFTRPEHLGSSAKIKCGS

KRFEHSAKQRRKITTYISFP

CQSYQESTKQLTMNKLPVVACE

LELDMTPEMASSKESRMNGQ

HFKRFEHSAKQRRKITTYISFP

LQLPTNSGNNENKYSLFAVV

LELDMTPFMASSKESRMNGQLQ

NHQGTLESGHYTSFIRHHKD

LPTNSGNNENKYSLFAVVNHQG

QWFKCDDAVITKASIKDVLD

TLESGHYTSFIRHHKDQWEKCD

SEGYLLFYHKQVLEHESEKV

DAVITKASIKDVLDSEGYLLFY

KEMNTQAY

HKQVLEHESEKVKEMNTQAY

UBP48_HUMAN
2
MAPRLQLEKAAWRWAETVRPEE
114
NSFHNIDDPNCERRKKNSFV

Ubiquitin

VSQEHIETAYRIWLEPCIRGVC

GLTNLGATCYVNTFLQVWEL

carboxyl-

RRNCKGNPNCLVGIGEHIWLGE

NLELRQALYLCPSTCSDYML

terminal

IDENSFHNIDDPNCERRKKNSF

GDGIQEEKDYEPQTICEHLQ

hydrolase 48

VGLTNLGATCYVNTFLQVWELN

YLFALLQNSNRRYIDPSGFV

LELRQALYLCPSTCSDYMLGDG

KALGLDTGQQQDAQEFSKLE

IQEEKDYEPQTICEHLQYLFAL

MSLLEDTLSKQKNPDVRNIV

LQNSNRRYIDPSGFVKALGLDT

QQQFCGEYAYVTVCNQCGRE

GQQQDAQEFSKLFMSLLEDTLS

SKLLSKFYELELNIQGHKQL

KQKNPDVRNIVQQQFCGEYAYV

TDCISEFLKEEKLEGDNRYE

TVCNQCGRESKLLSKFYELELN

CENCQSKQNATRKIRLLSLP

IQGHKQLTDCISEFLKEEKLEG

CTLNLQLMRFVEDRQTGHKK

DNRYFCENCQSKQNATRKIRLL

KLNTYIGFSEILDMEPYVEH

SLPCTLNLQLMRFVEDRQTGHK

KGGSYVYELSAVLIHRGVSA

KKLNTYIGFSEILDMEPYVEHK

YSGHYIAHVKDPQSGEWYKF

GGSYVYELSAVLIHRGVSAYSG

NDEDIEKMEGKKLQLGIEED

HYIAHVKDPQSGEWYKENDEDI

LAEPSKSQTRKPKCGKGTHC

EKMEGKKLQLGIEEDLAEPSKS

SRNAYMLVYRLQT

QTRKPKCGKGTHCSRNAYMLVY

RLQTQEKPNTTVQVPAFLQELV

DRDNSKFEEWCIEMAEMRKQSV

DKGKAKHEEVKELYQRLPAGAE

PYEFVSLEWLQKWLDESTPTKP

IDNHACLCSHDKLHPDKISIMK

RISEYAADIFYSRYGGGPRLTV

KALCKECVVERCRILRLKNQLN

EDYKTVNNLLKAAVKGSDGFWV

GKSSLRSWRQLALEQLDEQDGD

AEQSNGKMNGSTLNKDESKEER

KEEEELNENEDILCPHGELCIS

ENERRLVSKEAWSKLQQYFPKA

PEFPSYKECCSQCKILEREGEE

NEALHKMIANEQKTSLPNLFQD

KNRPCLSNWPEDTDVLYIVSQF

FVEEWRKFVRKPTRCSPVSSVG

NSALLCPHGGLMFTFASMTKED

SKLIALIWPSEWQMIQKLFVVD

HVIKITRIEVGDVNPSETQYIS

EPKLCPECREGLLCQQQRDLRE

YTQATIYVHKVVDNKKVMKDSA

PELNVSSSETEEDKEEAKPDGE

KDPDFNQSNGGTKRQKISHQNY

IAYQKQVIRRSMRHRKVRGEKA

LLVSANQTLKELKIQIMHAFSV

APFDQNLSIDGKILSDDCATLG

TLGVIPESVILLKADEPIADYA

AMDDVMQVCMPEEGFKGTGLLG

H

UBP3_HUMAN
3
MECPHLSSSVCIAPDSAKEPNG
115
TAICATGLRNLGNTCEMNAI

Ubiquitin

SPSSWCCSVCRSNKSPWVCLTC

LQSLSNIEQFCCYFKELPAV

carboxyl-

SSVHCGRYVNGHAKKHYEDAQV

ELRNGKTAGRRTYHTRSQGD

terminal

PLTNHKKSEKQDKVQHTVCMDC

NNVSLVEEFRKTLCALWQGS

hydrolase 3

SSYSTYCYRCDDFVVNDTKLGL

QTAFSPESLFYVVWKIMPNF

VQKVREHLQNLENSAFTADRHK

RGYQQQDAHEFMRYLLDHLH

KRKLLENSTLNSKLLKVNGSTT

LELQGGENGVSRSAILQENS

AICATGLRNLGNTCEMNAILQS

TLSASNKCCINGASTVVTAI

LSNIEQFCCYFKELPAVELRNG

FGGILQNEVNCLICGTESRK

KTAGRRTYHTRSQGDNNVSLVE

FDPFLDLSLDIPSQFRSKRS

EFRKTLCALWQGSQTAFSPESL

KNQENGPVCSLRDCLRSFTD

FYVVWKIMPNERGYQQQDAHEF

LEELDETELYMCHKCKKKQK

MRYLLDHLHLELQGGENGVSRS

STKKFWIQKLPKVLCLHLKR

AILQENSTLSASNKCCINGAST

FHWTAYLRNKVDTYVEFPLR

VVTAIFGGILQNEVNCLICGTE

GLDMKCYLLEPENSGPESCL

SRKFDPFLDLSLDIPSQFERSKR

YDLAAVVVHHGSGVGSGHYT

SKNQENGPVCSLRDCLRSFTDL

AYATHEGRWFHENDSTVTLT

EELDETELYMCHKCKKKQKSTK

DEETVVKAKAYILFYVEHQ

KFWIQKLPKVLCLHLKRFHWTA

YLRNKVDTYVEFPLRGLDMKCY

LLEPENSGPESCLYDLAAVVVH

HGSGVGSGHYTAYATHEGRWFH

FNDSTVTLTDEETVVKAKAYIL

FYVEHQAKAGSDKL

U17LB_HUMAN
4
QLAPREKLPLSSRRPAAVGAGL
116
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

QNMGNTCYVNASLQCLTYTPPL

CLTYTPPLANYMLSREHSQT

carboxyl-

ANYMLSREHSQTCHRHKGCMLC

CHRHKGCMLCTMQAHITRAL

terminal

TMQAHITRALHNPGHVIQPSQA

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

LAAGFHRGKQEDAHEFLMFTVD

KQEDAHEFLMFTVDAMKKAC

like protein 11

AMKKACLPGHKQVDHHSKDTTL

LPGHKQVDHHSKDTTLIHQI

IHQIFGGYWRSQIKCLHCHGIS

FGGYWRSQIKCLHCHGISDT

DTFDPYLDIALDIQAAQSVQQA

FDPYLDIALDIQAAQSVQQA

LEQLVKPEELNGENAYHCGVCL

LEQLVKPEELNGENAYHCGV

QRAPASKTLTLHTSAKVLILVL

CLQRAPASKTLTLHTSAKVL

KRFSDVTGNKIAKNVQYPECLD

ILVLKRFSDVTGNKIAKNVQ

MQPYMSQTNTGPLVYVLYAVLV

YPECLDMQPYMSQTNTGPLV

HAGWSCHNGHYFSYVKAQEGQW

YVLYAVLVHAGWSCHNGHYF

YKMDDAEVTASSITSVLSQQAY

SYVKAQEGQWYKMDDAEVTA

VLFYIQKSEWERHSESVSRGRE

SSITSVLSQQAYVLFYIQKS

PRALGAEDTDRRATQGELKRDH

PCLQAPELDEHLVERATQESTL

DHWKFLQEQNKTKPEFNVRKVE

GTLPPDVLVIHQSKYKCGMKNH

HPEQQSSLLNLSSTTPTHQESM

NTGTLASLRGRARRSKGKNKHS

KRALLVCQ

UBP1_HUMAN
5
MPGVIPSESNGLSRGSPSKKNR
117
LPFVGLNNLGNTCYLNSILQ

Ubiquitin

LSLKFFQKKETKRALDFTDSQE

VLYFCPGFKSGVKHLENIIS

carboxyl-

NEEKASEYRASEIDQVVPAAQS

RKKEALKDEANQKDKGNCKE

terminal

SPINCEKRENLLPFVGLNNLGN

DSLASYELICSLQSLIISVE

hydrolase 1

TCYLNSILQVLYFCPGFKSGVK

QLQASFLLNPEKYTDELATQ

HLENIISRKKEALKDEANQKDK

PRRLLNTLRELNPMYEGYLQ

GNCKEDSLASYELICSLQSLII

HDAQEVLQCILGNIQETCQL

SVEQLQASFLLNPEKYTDELAT

LKKEEVKNVAELPTKVEEIP

QPRRLLNTLRELNPMYEGYLQH

HPKEEMNGINSIEMDSMRHS

DAQEVLQCILGNIQETCQLLKK

EDFKEKLPKGNGKRKSDTEF

EEVKNVAELPTKVEEIPHPKEE

GNMKKKVKLSKEHQSLEENQ

MNGINSIEMDSMRHSEDEKEKL

RQTRSKRKATSDTLESPPKI

PKGNGKRKSDTEFGNMKKKVKL

IPKYISENESPRPSQKKSRV

SKEHQSLEENQRQTRSKRKATS

KINWLKSATKQPSILSKFCS

DTLESPPKIIPKYISENESPRP

LGKITTNQGVKGQSKENECD

SQKKSRVKINWLKSATKQPSIL

PEEDLGKCESDNTTNGCGLE

SKFCSLGKITTNQGVKGQSKEN

SPGNTVTPVNVNEVKPINKG

ECDPEEDLGKCESDNTTNGCGL

EEQIGFELVEKLFQGQLVLR

ESPGNTVTPVNVNEVKPINKGE

TRCLECESLTERREDFQDIS

EQIGFELVEKLFQGQLVLRTRC

VPVQEDELSKVEESSEISPE

LECESLTERREDFQDISVPVQE

PKTEMKTLRWAISQFASVER

DELSKVEESSEISPEPKTEMKT

IVGEDKYFCENCHHYTEAER

LRWAISQFASVERIVGEDKYFC

SLLEDKMPEVITIHLKCFAA

ENCHHYTEAERSLLEDKMPEVI

SGLEFDCYGGGLSKINTPLL

TIHLKCFAASGLEFDCYGGGLS

TPLKLSLEEWSTKPTNDSYG

KINTPLLTPLKLSLEEWSTKPT

LFAVVMHSGITISSGHYTAS

NDSYGLFAVVMHSGITISSGHY

VKVTDLNSLELDKGNFVVDQ

TASVKVTDLNSLELDKGNFVVD

MCEIGKPEPLNEEEARGVVE

QMCEIGKPEPLNEEEARGVVEN

NYNDEEVSIRVGGNTQPSKV

YNDEEVSIRVGGNTQPSKVLNK

LNKKNVEAIGLLGGQKSKAD

KNVEAIGLLGGQKSKADYELYN

YELYNKASNPDKVASTAFAE

KASNPDKVASTAFAENRNSETS

NRNSETSDTTGTHESDRNKE

DTTGTHESDRNKESSDQTGINI

SSDQTGINISGFENKISYVV

SGFENKISYVVQSLKEYEGKWL

QSLKEYEGKWLLEDDSEVKV

LEDDSEVKVTEEKDELNSLSPS

TEEKDFLNSLSPSTSPTSTP

TSPTSTPYLLFYKKL

YLLFYKKI

UBP40_HUMAN
6
MFGDLFEEEYSTVSNNQYGKGK
118
FTNLSGIRNQGGTCYLNSLL

Ubiquitin

KLKTKALEPPAPREFTNLSGIR

QTLHFTPEFREALESLGPEE

carboxyl-

NQGGTCYLNSLLQTLHFTPEER

LGLFEDKDKPDAKVRIIPLQ

terminal

EALFSLGPEELGLFEDKDKPDA

LQRLFAQLLLLDQEAASTAD

hydrolase 40

KVRIIPLQLQRLFAQLLLLDQE

LTDSFGWTSNEEMRQHDVQE

AASTADLTDSFGWTSNEEMRQH

LNRILFSALETSLVGTSGHD

DVQELNRILFSALETSLVGTSG

LIYRLYHGTIVNQIVCKECK

HDLIYRLYHGTIVNQIVCKECK

NVSERQEDFLDLTVAVKNVS

NVSERQEDFLDLTVAVKNVSGL

GLEDALWNMYVEEEVEDCDN

EDALWNMYVEEEVEDCDNLYHC

LYHCGTCDRLVKAAKSAKLR

GTCDRLVKAAKSAKLRKLPPEL

KLPPELTVSLLRENEDFVKC

TVSLLRENEDEVKCERYKETSC

ERYKETSCYTFPLRINLKPF

YTFPLRINLKPFCEQSELDDLE

CEQSELDDLEYIYDLESVII

YIYDLFSVIIHKGGCYGGHYHV

HKGG

YIKDVDHLGNWQFQEEKSKPDV

CYGGHYHVYIKDVDHLGNWQ

NLKDLQSEEEIDHPLMILKAIL

FQEEKSKPDVNLKDLQSEEE

LEENNLIPVDQLGQKLLKKIGI

IDHPLMILKAILLEENNLIP

SWNKKYRKQHGPLRKFLQLHSQ

VDQLGQKLLKKIGISWNKKY

IFLLSSDESTVRLLKNSSLQAE

RKQHGPLRKFLQLHSQIFLL

SDFQRNDQQIFKMLPPESPGLN

SSDESTVRLLKNSSLQAESD

NSISCPHWEDINDSKVQPIREK

FQRNDQQIFKMLPPESPGLN

DIEQQFQGKESAYMLFYRKSQL

NSISCPHWEDINDSKVQPIR

QRPPEARANPRYGVPCHLLNEM

EKDIEQQFQGKESAYMLFYR

DAANIELQTKRAECDSANNTFE

KSQLQRPPEARANPRYGVPC

LHLHLGPQYHFFNGALHPVVSQ

HLLNEMDAANIELQTKRAEC

TESVWDLTEDKRKTLGDLRQSI

DSANNTFELHLHLGPQYHFF

FQLLEFWEGDMVLSVAKLVPAG

NGALHPVVSQTESVWDLTED

LHIYQSLGGDELTLCETEIADG

KRKTLGDLRQSIFQLLEFWE

EDIFVWNGVEVGGVHIQTGIDC

GDMVLSVAKLVPAGLHIYQS

EPLLLNVLHLDTSSDGEKCCQV

LGGDELTLCETEIADGEDIF

IESPHVFPANAEVGTVLTALAI

VWNGVEVGGVHIQTGIDCEP

PAGVIFINSAGCPGGEGWTAIP

LLLNVLHLDTSSDGEKCCQV

KEDMRKTFREQGLRNGSSILIQ

IESPHVEPANAEVGTVLTAL

DSHDDNSLLTKEEKWVTSMNEI

AIPAGVIFINSAGCPGGEGW

DWLHVKNLCQLESEEKQVKISA

TAIPKEDMRKTFREQGLRNG

TVNTMVEDIRIKAIKELKLMKE

SSILIQDSHDDNSLLTKEEK

LADNSCLRPIDRNGKLLCPVPD

WVTSMNEIDWLHVKNLCQLE

SYTLKEAELKMGSSLGLCLGKA

SEEKQVKISATVNTMVEDIR

PSSSQLFLFFAMGSDVQPGTEM

IKAIKELKLMKELADNSCLR

EIVVEETISVRDCLKLMLKKSG

PIDRNGKLLCPVPDSYTLKE

LQGDAWHLRKMDWCYEAGEPLC

AELKMGSSLGLCLGKAPSSS

EEDATLKELLICSGDTLLLIEG

QLFLFFAMGSDVQPGTEMEI

QLPPLGELKVPIWWYQLQGPSG

VVEETISVRDCLKLMLKKSG

HWESHQDQTNCTSSWGRVWRAT

LQGDAWHLRKMDWCYEAGEP

SSQGASGNEPAQVSLLYLGDIE

LCEEDATLKELLICSGDTLL

ISEDATLAELKSQAMTLPPFLE

LIEGQLPPLGFLKVPIWWYQ

FGVPSPAHLRAWTVERKRPGRL

LQGPSGHWESHQDQTNCTSS

LRTDRQPLREYKLGRRIEICLE

WGRVWRATSSQGASGNEPAQ

PLQKGENLGPQDVLLRTQVRIP

VSLLYLGDIEISEDATLAEL

GERTYAPALDLVWNAAQGGTAG

KSQAMTLPPFLEFGVPSPAH

SLRQRVADFYRLPVEKIEIAKY

LRAWTVERKRPGRLLRTDRQ

FPEKFEWLPISSWNQQITKRKK

PLREYKLGRRIEICLEPLQK

KKKQDYLQGAPYYLKDGDTIGV

GENLGPQDVLLRTQVRIPGE

KNLLIDDDDDESTIRDDTGKEK

RTYAPALDLVWNAAQGGTAG

QKQRALGRRKSQEALHEQSSYI

SLRQRVADFYRLPVEKIEIA

LSSAETPARPRAPETSLSIHVG

KYFPEKFEWLPISSWNQQIT

SFR

KRKKKKKQDYLQGAPYYLKD

GDTIGVKNLLIDDDDDESTI

RDDTGKEKQKQRALGRRKSQ

UBP7_HUMAN
7
MNHQQQQQQQKAGEQQLSEPED
119
TGYVGLKNQGATCYMNSLLQ

Ubiquitin

MEMEAGDTDDPPRITQNPVING

TLFFTNQLRKAVYMMPTEGD

carboxyl-

NVALSDGHNTAEEDMEDDTSWR

DSSKSVPLALQRVFYELQHS

terminal

SEATFQFTVERFSRLSESVLSP

DKPVGTKKLTKSFGWETLDS

hydrolase 7

PCFVRNLPWKIMVMPRFYPDRP

FMQHDVQELCRVLLDNVENK

HQKSVGFFLQCNAESDSTSWSC

MKGTCVEGTIPKLFRGKMVS

HAQAVLKIINYRDDEKSFSRRI

YIQCKEVDYRSDRREDYYDI

SHLFFHKENDWGESNEMAWSEV

QLSIKGKKNIFESFVDYVAV

TDPEKGFIDDDKVTFEVFVQAD

EQLDGDNKYDAGEHGLQEAE

APHGVAWDSKKHTGYVGLKNQG

KGVKFLTLPPVLHLQLMREM

ATCYMNSLLQTLFFTNQLRKAV

YDPQTDQNIKINDRFEFPEQ

YMMPTEGDDSSKSVPLALQRVE

LPLDEFLQKTDPKDPANYIL

YELQHSDKPVGTKKLTKSEGWE

HAVLVHSGDNHGGHYVVYLN

TLDSFMQHDVQELCRVLLDNVE

PKGDGKWCKFDDDVVSRCTK

NKMKGTCVEGTIPKLFRGKMVS

EEAIEHNYGGHDDDLSVRHC

YIQCKEVDYRSDRREDYYDIQL

TNAYMLVYIRE

SIKGKKNIFESFVDYVAVEQLD

GDNKYDAGEHGLQEAEKGVKFL

TLPPVLHLQLMREMYDPQTDQN

IKINDRFEFPEQLPLDEFLQKT

DPKDPANYILHAVLVHSGDNHG

GHYVVYLNPKGDGKWCKFDDDV

VSRCTKEEAIEHNYGGHDDDLS

VRHCTNAYMLVYIRESKLSEVL

QAVTDHDIPQQLVERLQEEKRI

EAQKRKERQEAHLYMQVQIVAE

DQFCGHQGNDMYDEEKVKYTVE

KVLKNSSLAEFVQSLSQTMGFP

QDQIRLWPMQARSNGTKRPAML

DNEADGNKTMIELSDNENPWTI

FLETVDPELAASGATLPKEDKD

HDVMLFLKMYDPKTRSLNYCGH

IYTPISCKIRDLLPVMCDRAGF

IQDTSLILYEEVKPNLTERIQD

YDVSLDKALDELMDGDIIVFQK

DDPENDNSELPTAKEYFRDLYH

RVDVIFCDKTIPNDPGFVVTLS

NRMNYFQVAKTVAQRLNTDPML

LQFFKSQGYRDGPGNPLRHNYE

GTLRDLLQFFKPRQPKKLYYQQ

LKMKITDFENRRSFKCIWLNSQ

FREEEITLYPDKHGCVRDLLEE

CKKAVELGEKASGKLRLLEIVS

YKIIGVHQEDELLECLSPATSR

TFRIEEIPLDQVDIDKENEMLV

TVAHFHKEVEGTEGIPFLLRIH

QGEHFREVMKRIQSLLDIQEKE

FEKFKFAIVMMGRHQYINEDEY

EVNLKDFEPQPGNMSHPRPWLG

LDHENKAPKRSRYTYLEKAIKI

HN

U17L5_HUMAN
8
MEDDSLYLRGEWQFNHESKLTS
120
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 5

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLAKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLAK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QPNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGA

EVTASSITSVLSQQAYVLFYIQ

EDTDRRATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGA

APEL

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKEL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSSTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

U17LL_HUMAN
9
MEEDSLYLGGEWQFNHESKLTS
121
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSNRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 21

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKMLTLLTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KMLTLLTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QPNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGA

EVTASSITSVLSQQAYVLFYIQ

EDTDRRATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGA

APEL

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKEL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSSTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

U17LA_HUMAN
10
MEDDSLYLGGEWQFNHFSKLTS
122
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYKPPLANYMLFREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KPPLSSRRPAAVGAGLQNMGNT

HIPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYKPPLANYMLF

KQEDAHEFLMFTVDAMRKAC

like protein 10

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDRHSKDTTLIHQI

TRALHIPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMRKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDRHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHNSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFPDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHNSAKVLILVLKRFPDV

YVLYAVLVHAGWSCHNGHYS

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QQNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYSSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGV

EVTASSITSVLSQQAYVLFYIQ

EDTDRRATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGV

APEL

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKEL

QEQNKTKPEFNVRRVEGTVPPD

VLVIHQSKYKCRMKNHHPEQQS

SLLNLSSTTPTDQESMNTGTLA

SLRGRTRRSKGKNKHSKRALLV

CQ

UBP41_HUMAN
11
MDGVLFRAHQCQYVHPCVHVYV
123
WGLVGLHNIGQTCCLNSLIQ

Putative

TVGLMDPLCERKEKASKQEREN

VFVMNVDFARILKRITVPRG

ubiquitin

PLAHLAAWGLVGLHNIGQTCCL

ADEQRRSVPFQMLLLLEKMQ

carboxyl-

NSLIQVFVMNVDFARILKRITV

DSRQKAVWPLELAYCLQKYN

terminal

PRGADEQRRSVPFQMLLLLEKM

VPLFVQHDAAQLYLKLWNLI

hydrolase 41

QDSRQKAVWPLELAYCLQKYNV

KDQIADVHLVERLQALYMIR

PLFVQHDAAQLYLKLWNLIKDQ

MKDSLICLDCAMESSRNSSM

IADVHLVERLQALYMIRMKDSL

LTLRLSFFDVDSKPLKTLED

ICLDCAMESSRNSSMLTLRLSF

ALHCFFQPRELSSKSKCFCE

FDVDSKPLKTLEDALHCFFQPR

NCGKKTRGKQVLKLTHLPQT

ELSSKSKCFCENCGKKTRGKQV

LTIHLMRESIRNSQTRKICH

LKLTHLPQTLTIHLMRESIRNS

SLYFPQSLDESQILPMKRES

QTRKICHSLYFPQSLDESQILP

CDAEEQSGGQYELFAVIAHV

MKRESCDAEEQSGGQYELFAVI

GMADSGHYCVYIRNAVDGKW

AHVGMADSGHYCVYIRNAVDGK

FCENDSNICLVSWEDIQCTY

WFCENDSNICLVSWEDIQCTYG

GNPNYHW

NPNYHW

UBP38_HUMAN
12
MDKILEGLVSSSHPLPLKRVIV
124
SETGKTGLINLGNTCYMNSV

Ubiquitin

RKVVESAEHWLDEAQCEAMEDL

IQALFMATDERRQVLSLNLN

carboxyl-

TTRLILEGQDPFQRQVGHQVLE

GCNSLMKKLQHLFAFLAHTQ

terminal

AYARYHRPEFESFENKTFVLGL

REAYAPRIFFEASRPPWFTP

hydrolase 38

LHQGYHSLDRKDVAILDYIHNG

RSQQDCSEYLRELLDRLHEE

LKLIMSCPSVLDLFSLLQVEVL

EKILKVQASHKPSEILECSE

RMVCERPEPQLCARLSDLLTDF

TSLQEVASKAAVLTETPRTS

VQCIPKGKLSITFCQQLVRTIG

DGEKTLIEKMFGGKLRTHIR

HFQCVSTQERELREYVSQVTKV

CLNCRSTSQKVEAFTDLSLA

SNLLQNIWKAEPATLLPSLQEV

FCPSSSLENMSVQDPASSPS

FASISSTDASFEPSVALASLVQ

IQDGGLMQASVPGPSEEPVV

HIPLQMITVLIRSLTTDPNVKD

YNPTTAAFICDSLVNEKTIG

ASMTQALCRMIDWLSWPLAQHV

SPPNEFYCSENTSVPNESNK

DTWVIALLKGLAAVQKFTILID

ILVNKDVPQKPGGETTPSVT

VTLLKIELVENRLWFPLVRPGA

DLLNYFLAPEILTGDNQYYC

LAVLSHMLLSFQHSPEAFHLIV

ENCASLQNAEKTMQITEEPE

PHVVNLVHSFKNDGLPSSTAFL

YLILTLLRFSYDQKYHVRRK

VQLTELIHCMMYHYSGFPDLYE

ILDNVSLPLVLELPVKRITS

PILEAIKDFPKPSEEKIKLILN

FSSLSESWSVDVDFTDLSEN

QSAWTSQSNSLASCLSRLSGKS

LAKKLKPSGTDEASCTKLVP

ETGKTGLINLGNTCYMNSVIQA

YLLSSVVVHSGISSESGHYY

LEMATDERRQVLSLNLNGCNSL

SYARNITSTDSSYQMYHQSE

MKKLQHLFAFLAHTQREAYAPR

ALALASSQSHLLGRDSPSAV

IFFEASRPPWFTPRSQQDCSEY

FEQDLENKEMSKEWFLENDS

LRFLLDRLHEEEKILKVQASHK

RVTFTSFQSVQKITSREPKD

PSEILECSETSLQEVASKAAVL

TAYVLLYKKQH

TETPRTSDGEKTLIEKMEGGKL

RTHIRCLNCRSTSQKVEAFTDL

SLAFCPSSSLENMSVQDPASSP

SIQDGGLMQASVPGPSEEPVVY

NPTTAAFICDSLVNEKTIGSPP

NEFYCSENTSVPNESNKILVNK

DVPQKPGGETTPSVTDLLNYEL

APEILTGDNQYYCENCASLQNA

EKTMQITEEPEYLILTLLRESY

DQKYHVRRKILDNVSLPLVLEL

PVKRITSFSSLSESWSVDVDET

DLSENLAKKLKPSGTDEASCTK

LVPYLLSSVVVHSGISSESGHY

YSYARNITSTDSSYQMYHQSEA

LALASSQSHLLGRDSPSAVFEQ

DLENKEMSKEWFLENDSRVTFT

SFQSVQKITSRFPKDTAYVLLY

KKQHSTNGLSGNNPTSGLWING

DPPLQKELMDAITKDNKLYLQE

QELNARARALQAASASCSERPN

GFDDNDPPGSCGPTGGGGGGGF

NTVGRLVF

UBP43_HUMAN
13
MDLGPGDAAGGGPLAPRPRRRR
125
RPPGAQGLKNHGNTCFMNAV

Ubiquitin

SLRRLESRELLALGSRSRPGDS

VQCLSNTDLLAEFLALGRYR

carboxyl-

PPRPQPGHCDGDGEGGFACAPG

AAPGRAEVTEQLAALVRALW

terminal

PVPAAPGSPGEERPPGPQPQLQ

TREYTPQLSAEFKNAVSKYG

hydrolase 43

LPAGDGARPPGAQGLKNHGNTC

SQFQGNSQHDALEFLLWLLD

FMNAVVQCLSNTDLLAEFLALG

RVHEDLEGSSRGPVSEKLPP

RYRAAPGRAEVTEQLAALVRAL

EATKTSENCLSPSAQLPLGQ

WTREYTPQLSAEFKNAVSKYGS

SFVQSHFQAQYRSSLTCPHC

QFQGNSQHDALEFLLWLLDRVH

LKQSNTFDPFLCVSLPIPLR

EDLEGSSRGPVSEKLPPEATKT

QTRFLSVTLVFPSKSQRELR

SENCLSPSAQLPLGQSFVQSHF

VGLAVPILSTVAALRKMVAE

QAQYRSSLTCPHCLKQSNTEDP

EGGVPADEVILVELYPSGFQ

FLCVSLPIPLRQTRFLSVTLVE

RSFFDEEDLNTIAEGDNVYA

PSKSQRFLRVGLAVPILSTVAA

FQVPPSPSQGTLSAHPLGLS

LRKMVAEEGGVPADEVILVELY

ASPRLAAREGQRFSLSLHSE

PSGFQRSFFDEEDLNTIAEGDN

SKVLILFCNLVGSGQQASRF

VYAFQVPPSPSQGTLSAHPLGL

GPPFLIREDRAVSWAQLQQS

SASPRLAAREGQRFSLSLHSES

ILSKVRHLMKSEAPVQNLGS

KVLILFCNLVGSGQQASRFGPP

LFSIRVVGLSVACSYLSPKD

FLIREDRAVSWAQLQQSILSKV

SRPLCHWAVDRVLHLRRPGG

RHLMKSEAPVQNLGSLESIRVV

PPHVKLAVEWDSSVKERLFG

GLSVACSYLSPKDSRPLCHWAV

SLQEERAQDADSVWQQQQAH

DRVLHLRRPGGPPHVKLAVEWD

QQHSCTLDECFQFYTKEEQL

SSVKERLFGSLQEERAQDADSV

AQDDAWKCPHCQVLQQGMVK

WQQQQAHQQHSCTLDECFQFYT

LSLWTLPDILIIHLKRFCQV

KEEQLAQDDAWKCPHCQVLQQG

GERRNKLSTLVKFPLSGLNM

MVKLSLWTLPDILIIHLKRFCQ

APHVAQRSTSPEAGLGPWPS

VGERRNKLSTLVKFPLSGLNMA

WKQPDCLPTSYPLDFLYDLY

PHVAQRSTSPEAGLGPWPSWKQ

AVCNHHGNLQGGHYTAYCRN

PDCLPTSYPLDFLYDLYAVCNH

SLDGQWYSYDDSTVEPLRED

HGNLQGGHYTAYCRNSLDGQWY

EVNTRGAYILFYQKRN

SYDDSTVEPLREDEVNTRGAYI

LFYQKRNSIPPWSASSSMRGST

SSSLSDHWLLRLGSHAGSTRGS

LLSWSSAPCPSLPQVPDSPIFT

NSLCNQEKGGLEPRRLVRGVKG

RSISMKAPTTSRAKQGPFKTMP

LRWSFGSKEKPPGASVELVEYL

ESRRRPRSTSQSIVSLLTGTAG

EDEKSASPRSNVALPANSEDGG

RAIERGPAGVPCPSAQPNHCLA

PGNSDGPNTARKLKENAGQDIK

LPRKFDLPLTVMPSVEHEKPAR

PEGQKAMNWKESFQMGSKSSPP

SPYMGFSGNSKDSRRGTSELDR

PLQGTLTLLRSVERKKENRRNE

RAEVSPQVPPVSLVSGGLSPAM

DGQAPGSPPALRIPEGLARGLG

SRLERDVWSAPSSLRLPRKASR

APRGSALGMSQRTVPGEQASYG

TFQRVKYHTLSLGRKKTLPESS

F

UBP2_HUMAN
14
MSQLSSTLKRYTESARYTDAHY
126
SAQGLAGLRNLGNTCEMNSI

Ubiquitin

AKSGYGAYTPSSYGANLAASLL

LQCLSNTRELRDYCLQRLYM

carboxyl-

EKEKLGFKPVPTSSFLTRPRTY

RDLHHGSNAHTALVEEFAKL

terminal

GPSSLLDYDRGRPLLRPDITGG

IQTIWTSSPNDVVSPSEFKT

hydrolase 2

GKRAESQTRGTERPLGSGLSGG

QIQRYAPRFVGYNQQDAQEF

SGFPYGVTNNCLSYLPINAYDQ

LRFLLDGLHNEVNRVTLRPK

GVTLTQKLDSQSDLARDESSLR

SNPENLDHLPDDEKGRQMWR

TSDSYRIDPRNLGRSPMLARTR

KYLEREDSRIGDLFVGQLKS

KELCTLQGLYQTASCPEYLVDY

SLTCTDCGYCSTVEDPEWDL

LENYGRKGSASQVPSQAPPSRV

SLPIAKRGYPEVTLMDCMRL

PEIISPTYRPIGRYTLWETGKG

FTKEDVLDGDEKPTCCRCRG

QAPGPSRSSSPGRDGMNSKSAQ

RKRCIKKFSIQRFPKILVLH

GLAGLRNLGNTCEMNSILQCLS

LKRFSESRIRTSKLTTFVNF

NTRELRDYCLQRLYMRDLHHGS

PLRDLDLREFASENTNHAVY

NAHTALVEEFAKLIQTIWTSSP

NLYAVSNHSGTTMGGHYTAY

NDVVSPSEFKTQIQRYAPRFVG

CRSPGTGEWHTENDSSVTPM

YNQQDAQEFLRFLLDGLHNEVN

SSSQVRTSDAYLLFYELAS

RVTLRPKSNPENLDHLPDDEKG

RQMWRKYLEREDSRIGDLFVGQ

LKSSLTCTDCGYCSTVEDPFWD

LSLPIAKRGYPEVTLMDCMRLF

TKEDVLDGDEKPTCCRCRGRKR

CIKKFSIQRFPKILVLHLKRES

ESRIRTSKLTTFVNFPLRDLDL

REFASENTNHAVYNLYAVSNHS

GTTMGGHYTAYCRSPGTGEWHT

FNDSSVTPMSSSQVRTSDAYLL

FYELASPPSRM

UBP45_HUMAN
15
MRVKDPTKALPEKAKRSKRPTV
127
LSVRGITNLGNTCFFNAVMQ

Ubiquitin

PHDEDSSDDIAVGLTCQHVSHA

NLAQTYTLTDLMNEIKESST

carboxyl-

ISVNHVKRAIAENLWSVCSECL

KLKIFPSSDSQLDPLVVELS

terminal

KERRFYDGQLVLTSDIWLCLKC

RPGPLTSALFLFLHSMKETE

hydrolase 45

GFQGCGKNSESQHSLKHFKSSR

KGPLSPKVLFNQLCQKAPRE

TEPHCIIINLSTWIIWCYECDE

KDFQQQDSQELLHYLLDAVR

KLSTHCNKKVLAQIVDFLQKHA

TEETKRIQASILKAFNNPTT

SKTQTSAFSRIMKLCEEKCETD

KTADDETRKKVKAYGKEGVK

EIQKGGKCRNLSVRGITNLGNT

MNFIDRIFIGELTSTVMCEE

CFFNAVMQNLAQTYTLTDLMNE

CANISTVKDPFIDISLPIIE

IKESSTKLKIFPSSDSQLDPLV

ERVSKPLLWGRMNKYRSLRE

VELSRPGPLTSALFLFLHSMKE

TDHDRYSGNVTIENIHQPRA

TEKGPLSPKVLENQLCQKAPRF

AKKHSSSKDKSQLIHDRKCI

KDFQQQDSQELLHYLLDAVRTE

RKLSSGETVTYQKNENLEMN

ETKRIQASILKAFNNPTTKTAD

GDSLMFASLMNSESRLNESP

DETRKKVKAYGKEGVKMNFIDR

TDDSEKEASHSESNVDADSE

IFIGELTSTVMCEECANISTVK

PSESESASKQTGLFRSSSGS

DPFIDISLPIIEERVSKPLLWG

GVQPDGPLYPLSAGKLLYTK

RMNKYRSLRETDHDRYSGNVTI

ETDSGDKEMAEAISELRLSS

ENIHQPRAAKKHSSSKDKSQLI

TVTGDQDEDRENQPLNISNN

HDRKCIRKLSSGETVTYQKNEN

LCFLEGKHLRSYSPQNAFQT

LEMNGDSLMFASLMNSESRLNE

LSQSYITTSKECSIQSCLYQ

SPTDDSEKEASHSESNVDADSE

FTSMELLMGNNKLLCENCTK

PSESESASKQTGLFRSSSGSGV

NKQKYQEETSFAEKKVEGVY

QPDGPLYPLSAGKLLYTKETDS

TNARKQLLISAVPAVLILHL

GDKEMAEAISELRLSSTVTGDQ

KRFHQAGLSLRKVNRHVDEP

DFDRENQPLNISNNLCFLEGKH

LMLDLAPFCSATCKNASVGD

LRSYSPQNAFQTLSQSYITTSK

KVLYGLYGIVEHSGSMREGH

ECSIQSCLYQFTSMELLMGNNK

YTAYVKVRTPSRKLSEHNTK

LLCENCTKNKQKYQEETSFAEK

KKNVPGLKAADNESAGQWVH

KVEGVYTNARKQLLISAVPAVL

VSDTYLQVVPESRALSAQAY

ILHLKRFHQAGLSLRKVNRHVD

LLFYERVL

FPLMLDLAPFCSATCKNASVGD

KVLYGLYGIVEHSGSMREGHYT

AYVKVRTPSRKLSEHNTKKKNV

PGLKAADNESAGQWVHVSDTYL

QVVPESRALSAQAYLLFYERVL

UBP32_HUMAN
16
MGAKESRIGELSYEEALRRVTD
128
TEKGATGLSNLGNTCEMNSS

Ubiquitin

VELKRLKDAFKRTCGLSYYMGQ

IQCVSNTQPLTQYFISGRHL

carboxyl-

HCFIREVLGDGVPPKVAEVIYC

YELNRTNPIGMKGHMAKCYG

terminal

SFGGTSKGLHENNLIVGLVLLT

DLVQELWSGTQKNVAPLKLR

hydrolase 32

RGKDEEKAKYIFSLESSESGNY

WTIAKYAPRENGFQQQDSQE

VIREEMERMLHVVDGKVPDTLR

LLAFLLDGLHEDLNRVHEKP

KCFSEGEKVNYEKERNWLELNK

YVELKDSDGRPDWEVAAEAW

DAFTFSRWLLSGGVYVTLTDDS

DNHLRRNRSIVVDLFHGQLR

DTPTFYQTLAGVTHLEESDIID

SQVKCKTCGHISVREDPENE

LEKRYWLLKAQSRTGREDLETF

LSLPLPMDSYMHLEITVIKL

GPLVSPPIRPSLSEGLENAFDE

DGTTPVRYGLRLNMDEKYTG

NRDNHIDFKEISCGLSACCRGP

LKKQLSDLCGLNSEQILLAE

LAERQKFCFKVEDVDRDGVLSR

VHGSNIKNFPQDNQKVRLSV

VELRDMVVALLEVWKDNRTDDI

SGFLCAFEIPVPVSPISASS

PELHMDLSDIVEGILNAHDTTK

PTQTDFSSSPSTNEMFTLTT

MGHLTLEDYQIWSVKNVLANEF

NGDLPRPIFIPNGMPNTVVP

LNLLFQVCHIVLGLRPATPEEE

CGTEKNFTNGMVNGHMPSLP

GQIIRGWLERESRYGLQAGHNW

DSPFTGYIIAVHRKMMRTEL

FIISMQWWQQWKEYVKYDANPV

YFLSSQKNRPSLFGMPLIVP

VIEPSSVLNGGKYSFGTAAHPM

CTVHTRKKDLYDAVWIQVSR

EQVEDRIGSSLSYVNTTEEKES

LASPLPPQEASNHAQDCDDS

DNISTASEASETAGSGELYSAT

MGYQYPFTLRVVQKDGNSCA

PGADVCFARQHNTSDNNNQCLL

WCPWYRFCRGCKIDCGEDRA

GANGNILLHLNPQKPGAIDNQP

FIGNAYIAVDWDPTALHLRY

LVTQEPVKATSLTLEGGRLKRT

QTSQERVVDEHESVEQSRRA

PQLIHGRDYEMVPEPVWRALYH

QAEPINLDSCLRAFTSEEEL

WYGANLALPRPVIKNSKTDIPE

GENEMYYCSKCKTHCLATKK

LELFPRYLLFLRQQPATRTQQS

LDLWRLPPILIIHLKRFQFV

NIWVNMGNVPSPNAPLKRVLAY

NGRWIKSQKIVKFPRESFDP

TGCFSRMQTIKEIHEYLSQRLR

SAFLVPRDPALCQHKPLTPQ

IKEEDMRLWLYNSENYLTLLDD

GDELSEPRILAREVKKVDAQ

EDHKLEYLKIQDEQHLVIEVRN

SSAGEEDVLLSKSPSSLSAN

KDMSWPEEMSFIANSSKIDRHK

IISSPKGSPSSSRKSGTSCP

VPTEKGATGLSNLGNTCEMNSS

SSKNSSPNSSPRTLGRSKGR

IQCVSNTQPLTQYFISGRHLYE

LRLPQIGSKNKLSSSKENLD

LNRTNPIGMKGHMAKCYGDLVQ

ASKENGAGQICELADALSRG

ELWSGTQKNVAPLKLRWTIAKY

HVLGGSQPELVTPQDHEVAL

APRENGFQQQDSQELLAFLLDG

ANGFLYEHEACGNGYSNGQL

LHEDLNRVHEKPYVELKDSDGR

GNHSEEDSTDDQREDTRIKP

PDWEVAAEAWDNHLRRNRSIVV

IYNLYAISCHSGILGGGHYV

DLFHGQLRSQVKCKTCGHISVR

TYAKNPNCKWYCYNDSSCKE

FDPFNFLSLPLPMDSYMHLEIT

LHPDEIDTDSAYILFYEQQG

VIKLDGTTPVRYGLRLNMDEKY

IDYAQFLPKTDGKKMADTSS

TGLKKQLSDLCGLNSEQILLAE

MDEDFESDYKKYCVLQ

VHGSNIKNFPQDNQKVRLSVSG

FLCAFEIPVPVSPISASSPTQT

DESSSPSTNEMFTLTTNGDLPR

PIFIPNGMPNTVVPCGTEKNFT

NGMVNGHMPSLPDSPFTGYIIA

VHRKMMRTELYFLSSQKNRPSL

FGMPLIVPCTVHTRKKDLYDAV

WIQVSRLASPLPPQEASNHAQD

CDDSMGYQYPFTLRVVQKDGNS

CAWCPWYRFCRGCKIDCGEDRA

FIGNAYIAVDWDPTALHLRYQT

SQERVVDEHESVEQSRRAQAEP

INLDSCLRAFTSEEELGENEMY

YCSKCKTHCLATKKLDLWRLPP

ILIIHLKRFQFVNGRWIKSQKI

VKFPRESEDPSAFLVPRDPALC

QHKPLTPQGDELSEPRILAREV

KKVDAQSSAGEEDVLLSKSPSS

LSANIISSPKGSPSSSRKSGTS

CPSSKNSSPNSSPRTLGRSKGR

LRLPQIGSKNKLSSSKENLDAS

KENGAGQICELADALSRGHVLG

GSQPELVTPQDHEVALANGFLY

EHEACGNGYSNGQLGNHSEEDS

TDDQREDTRIKPIYNLYAISCH

SGILGGGHYVTYAKNPNCKWYC

YNDSSCKELHPDEIDTDSAYIL

FYEQQGIDYAQFLPKTDGKKMA

DTSSMDEDFESDYKKYCVLQ

U17L6_HUMAN
17
MEDDSLYLRGEWQFNHFSKLTS
129
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 6

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGEH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QQNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EVTASSITSVLSQQAYVLFYIQ

KSEWERHSESVSRGREPRALGS

ED

UBP42_HUMAN
18
MTIVDKASESSDPSAYQNQPGS
130
RVGAGLQNLGNTCFANAALQ

Ubiquitin

SEAVSPGDMDAGSASWGAVSSL

CLTYTPPLANYMLSHEHSKT

carboxyl-

NDVSNHTLSLGPVPGAVVYSSS

CHAEGFCMMCTMQAHITQAL

terminal

SVPDKSKPSPQKDQALGDGIAP

SNPGDVIKPMEVINEMRRIA

hydrolase 42

PQKVLFPSEKICLKWQQTHRVG

RHFREGNQEDAHEFLQYTVD

AGLQNLGNTCFANAALQCLTYT

AMQKACLNGSNKLDRHTQAT

PPLANYMLSHEHSKTCHAEGFC

TLVCQIFGGYLRSRVKCLNC

MMCTMQAHITQALSNPGDVIKP

KGVSDTFDPYLDITLEIKAA

MFVINEMRRIARHFREGNQEDA

QSVNKALEQFVKPEQLDGEN

HEFLQYTVDAMQKACLNGSNKL

SYKCSKCKKMVPASKRFTIH

DRHTQATTLVCQIFGGYLRSRV

RSSNVLTLSLKRFANFTGGK

KCLNCKGVSDTFDPYLDITLEI

IAKDVKYPEYLDIRPYMSQP

KAAQSVNKALEQFVKPEQLDGE

NGEPIVYVLYAVLVHTGENC

NSYKCSKCKKMVPASKRFTIHR

HAGHYFCYIKASNGLWYQMN

SSNVLTLSLKRFANFTGGKIAK

DSIVSTSDIRSVLSQQAYVL

DVKYPEYLDIRPYMSQPNGEPI

FYIRSHDVKNGGE

VYVLYAVLVHTGENCHAGHYFC

YIKASNGLWYQMNDSIVSTSDI

RSVLSQQAYVLFYIRSHDVKNG

GELTHPTHSPGQSSPRPVISQR

VVTNKQAAPGFIGPQLPSHMIK

NPPHLNGTGPLKDTPSSSMSSP

NGNSSVNRASPVNASASVQNWS

VNRSSVIPEHPKKQKITISIHN

KLPVRQCQSQPNLHSNSLENPT

KPVPSSTITNSAVQSTSNASTM

SVSSKVTKPIPRSESCSQPVMN

GKSKLNSSVLVPYGAESSEDSD

EESKGLGKENGIGTIVSSHSPG

QDAEDEEATPHELQEPMTLNGA

NSADSDSDPKENGLAPDGASCQ

GQPALHSENPFAKANGLPGKLM

PAPLLSLPEDKILETERLSNKL

KGSTDEMSAPGAERGPPEDRDA

EPQPGSPAAESLEEPDAAAGLS

STKKAPPPRDPGTPATKEGAWE

AMAVAPEEPPPSAGEDIVGDTA

PPDLCDPGSLTGDASPLSQDAK

GMIAEGPRDSALAEAPEGLSPA

PPARSEEPCEQPLLVHPSGDHA

RDAQDPSQSLGAPEAAERPPAP

VLDMAPAGHPEGDAEPSPGERV

EDAAAPKAPGPSPAKEKIGSLR

KVDRGHYRSRRERSSSGEPARE

SRSKTEGHRHRRRRTCPRERDR

QDRHAPEHHPGHGDRLSPGERR

SLGRCSHHHSRHRSGVELDWVR

HHYTEGERGWGREKFYPDRPRW

DRCRYYHDRYALYAARDWKPFH

GGREHERAGLHERPHKDHNRGR

RGCEPARERERHRPSSPRAGAP

HALAPHPDRESHDRTALVAGDN

CNLSDRFHEHENGKSRKRRHDS

VENSDSHVEKKARRSEQKDPLE

EPKAKKHKKSKKKKKSKDKHRD

RDSRHQQDSDLSAACSDADLHR

HKKKKKKKKRHSRKSEDFVKDS

ELHLPRVTSLETVAQFRRAQGG

FPLSGGPPLEGVGPFREKTKHL

RMESRDDRCRLFEYGQGKRRYL

ELGR

U17L7_HUMAN
19
MEDDSLYLGGDWQFNHFSKLTS
131
AVGAGLQKIGNTFYVNVSLQ

Inactive

SRLDAAFAEIQRTSLSEKSPLS

CLTYTLPLSNYMLSREDSQT

ubiquitin

SETREDLCDDLAPVARQLAPRE

CHLHKCCMFCTMQAHITWAL

carboxyl-

KLPLSSRRPAAVGAGLQKIGNT

HSPGHVIQPSQVLAAGFHRG

terminal

FYVNVSLQCLTYTLPLSNYMLS

EQEDAHEFLMFTVDAMKKAC

hydrolase 17-

REDSQTCHLHKCCMFCTMQAHI

LPGHKQLDHHSKDTTLIHQI

like protein 7

TWALHSPGHVIQPSQVLAAGFH

FGAYWRSQIKYLHCHGVSDT

RGEQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQLDHHSKDTTLIHQIFG

LEQLVKPKELNGENAYHCGL

AYWRSQIKYLHCHGVSDTEDPY

CLQKAPASKTLTLPTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVTGNKLAKNVQ

PKELNGENAYHCGLCLQKAPAS

YPKCRDMQPYMSQQNTGPLV

KTLTLPTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKLAKNVQYPKCRDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QQNTGPLVYVLYAVLVHAGWSC

SGITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGA

EVTASGITSVLSQQAYVLFYIQ

EDTDRPATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGA

VPEL

EDTDRPATQGELKRDHPCLQVP

ELDEHLVERATQESTLDHWKFP

QEQNKTKPEFNVRKVEGTLPPN

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSTKPTDQESMNTGTLA

SLQGSTRRSKGNNKHSKRSLLV

CQ

U17LH_HUMAN
20
MEDDSLYLGGEWQFNHESKLTS
132
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 17

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QQNTGPLVYVLYAVLVHAGWSC

ASITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGA

EVTAASITSVLSQQAYVLFYIQ

EDTDRRATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGA

APEL

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKEL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSSTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

UBP13_HUMAN
21
MQRRGALFGMPGGSGGRKMAAG
133
YGPGYTGLKNLGNSCYLSSV

Ubiquitin

DIGELLVPHMPTIRVPRSGDRV

MQAIFSIPEFQRAYVGNLPR

carboxyl-

YKNECAFSYDSPNSEGGLYVCM

IFDYSPLDPTQDENTQMTKL

terminal

NTFLAFGREHVERHERKTGQSV

GHGLLSGQYSKPPVKSELIE

hydrolase 13

YMHLKRHVREKVRGASGGALPK

QVMKEEHKPQQNGISPRMEK

RRNSKIFLDLDTDDDLNSDDYE

AFVSKSHPEFSSNRQQDAQE

YEDEAKLVIFPDHYEIALPNIE

FELHLVNLVERNRIGSENPS

ELPALVTIACDAVLSSKSPYRK

DVFRELVEERIQCCQTRKVR

QDPDTWENELPVSKYANNLTQL

YTERVDYLMQLPVAMEAATN

DNGVRIPPSGWKCARCDLRENL

KDELIAYELTRREAEANRRP

WLNLTDGSVLCGKWFFDSSGGN

LPELVRAKIPESACLQAFSE

GHALEHYRDMGYPLAVKLGTIT

PENVDDFWSSALQAKSAGVK

PDGADVYSFQEEEPVLDPHLAK

TSRFASFPEYLVVQIKKFTF

HLAHFGIDMLHMHGTENGLQDN

GLDWVPKKFDVSIDMPDLLD

DIKLRVSEWEVIQESGTKLKPM

INHLRARGLQPGEEELPDIS

YGPGYTGLKNLGNSCYLSSVMQ

PPIVIPDDSKDRLMNQLIDP

AIFSIPEFQRAYVGNLPRIFDY

SDIDESSVMQLAEMGFPLEA

SPLDPTQDENTQMTKLGHGLLS

CRKAVYFTGNMGAEVAFNWI

GQYSKPPVKSELIEQVMKEEHK

IVHMEEPDFAEPLTMPGYGG

PQQNGISPRMFKAFVSKSHPEF

AASAGASVEGASGLDNQPPE

SSNRQQDAQEFFLHLVNLVERN

EIVAIITSMGFQRNQAIQAL

RIGSENPSDVFRELVEERIQCC

RATNNNLERALDWIFSHPEF

QTRKVRYTERVDYLMQLPVAME

EEDSDEVIEMENNANANIIS

AATNKDELIAYELTRREAEANR

EAKPEGPRVKDGSGTYELFA

RPLPELVRAKIPFSACLQAFSE

FISHMGTSTMSGHYICHIKK

PENVDDFWSSALQAKSAGVKTS

EGRWVIYNDHKVCASERPPK

RFASFPEYLVVQIKKFTFGLDW

DLGYMYFYRRIPS

VPKKFDVSIDMPDLLDINHLRA

RGLQPGEEELPDISPPIVIPDD

SKDRLMNQLIDPSDIDESSVMQ

LAEMGFPLEACRKAVYFTGNMG

AEVAFNWIIVHMEEPDFAEPLT

MPGYGGAASAGASVEGASGLDN

QPPEEIVAIITSMGFQRNQAIQ

ALRATNNNLERALDWIFSHPEF

EEDSDEVIEMENNANANIISEA

KPEGPRVKDGSGTYELFAFISH

MGTSTMSGHYICHIKKEGRWVI

YNDHKVCASERPPKDLGYMYFY

RRIPS

UBP11_HUMAN
22
MAVAPRLFGGLCFRERDQNPEV
134
KGQPGICGLTNLGNTCEMNS

Ubiquitin

AVEGRLPISHSCVGCRRERTAM

ALQCLSNVPQLTEYFLNNCY

carboxyl-

ATVAANPAAAAAAVAAAAAVTE

LEELNERNPLGMKGEIAEAY

terminal

DREPQHEELPGLDSQWRQIENG

ADLVKQAWSGHHRSIVPHVE

hydrolase 11

ESGRERPLRAGESWELVEKHWY

KNKVGHFASQFLGYQQHDSQ

KQWEAYVQGGDQDSSTFPGCIN

ELLSFLLDGLHEDLNRVKKK

NATLFQDEINWRLKEGLVEGED

EYVELCDAAGRPDQEVAQEA

YVLLPAAAWHYLVSWYGLEHGQ

WQNHKRRNDSVIVDTFHGLF

PPIERKVIELPNIQKVEVYPVE

KSTLVCPDCGNVSVTFDPFC

LLLVRHNDLGKSHTVQFSHTDS

YLSVPLPISHKRVLEVFFIP

IGLVLRTARERELVEPQEDTRL

MDPRRKPEQHRLVVPKKGKI

WAKNSEGSLDRLYDTHITVLDA

SDLCVALSKHTGISPERMMV

ALETGQLIIMETRKKDGTWPSA

ADVESHRFYKLYQLEEPLSS

QLHVMNNNMSEEDEDEKGQPGI

ILDRDDIFVYEVSGRIEAIE

CGLTNLGNTCEMNSALQCLSNV

GSREDIVVPVYLRERTPARD

PQLTEYFLNNCYLEELNERNPL

YNNSYYGLMLFGHPLLVSVP

GMKGEIAEAYADLVKQAWSGHH

RDRFTWEGLYNVLMYRLSRY

RSIVPHVFKNKVGHFASQFLGY

VTKPNSDDEDDGDEKEDDEE

QQHDSQELLSELLDGLHEDLNR

DKDDVPGPSTGGSLRDPEPE

VKKKEYVELCDAAGRPDQEVAQ

QAGPSSGVTNRCPFLLDNCL

EAWQNHKRRNDSVIVDTFHGLF

GTSQWPPRRRRKQLFTLQTV

KSTLVCPDCGNVSVTFDPFCYL

NSNGTSDRTTSPEEVHAQPY

SVPLPISHKRVLEVFFIPMDPR

IAIDWEPEMKKRYYDEVEAE

RKPEQHRLVVPKKGKISDLCVA

GYVKHDCVGYVMKKAPVRLQ

LSKHTGISPERMMVADVESHRF

ECIELFTTVETLEKENPWYC

YKLYQLEEPLSSILDRDDIFVY

PSCKQHQLATKKLDLWMLPE

EVSGRIEAIEGSREDIVVPVYL

ILIIHLKRFSYTKESREKLD

RERTPARDYNNSYYGLMLFGHP

TLVEFPIRDLDESEFVIQPQ

LLVSVPRDRFTWEGLYNVLMYR

NESNPELYKYDLIAVSNHYG

LSRYVTKPNSDDEDDGDEKEDD

GMRDGHYTTFACNKDSGQWH

EEDKDDVPGPSTGGSLRDPEPE

YFDDNSVSPVNENQIESKAA

QAGPSSGVTNRCPFLLDNCLGT

YVLFYQRQD

SQWPPRRRRKQLFTLQTVNSNG

TSDRTTSPEEVHAQPYIAIDWE

PEMKKRYYDEVEAEGYVKHDCV

GYVMKKAPVRLQECIELFTTVE

TLEKENPWYCPSCKQHQLATKK

LDLWMLPEILIIHLKRFSYTKE

SREKLDTLVEFPIRDLDESEFV

IQPQNESNPELYKYDLIAVSNH

YGGMRDGHYTTFACNKDSGQWH

YFDDNSVSPVNENQIESKAAYV

LFYQRQDVARRLLSPAGSSGAP

ASPACSSPPSSEFMDVN

U17L1_HUMAN
23
MGDDSLYLGGEWQFNHESKLTS
135
AVGAGLQNMGNTCYENASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTLPLANYMLSREHSQT

carboxyl-

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

hydrolase 17-

CYENASLQCLTYTLPLANYMLS

KQEDVHEFLMFTVDAMKKAC

like protein 1

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHCKDTTLIHQI

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDVHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHCKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTFDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRESDVAGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHDGHYF

AGNKLAKNVQYPECLDMQPYMS

SYVKAQEVQWYKMDDAEVTV

QQNTGPLVYVLYAVLVHAGWSC

CSIISVLSQQAYVLFYIQKS

HDGHYFSYVKAQEVQWYKMDDA

EVTVCSIISVLSQQAYVLFYIQ

KSEWERHSESVSRGREPRALGA

EDTDRRAKQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKEL

QEQNKTKPEFNVGKVEGTLPPN

ALVIHQSKYKCGMKNHHPEQQS

SLLNLSSTTRTDQESMNTGTLA

SLQGRTRRAKGKNKHSKRALLV

CQ

UBP14_HUMAN
24
MPLYSVTVKWGKEKFEGVELNT
136
ASAMELPCGLTNLGNTCYMN

Ubiquitin

DEPPMVFKAQLFALTGVQPARQ

ATVQCIRSVPELKDALKRYA

carboxyl-

KVMVKGGTLKDDDWGNIKIKNG

GALRASGEMASAQYITAALR

terminal

MTLLMMGSADALPEEPSAKTVE

DLFDSMDKTSSSIPPIILLQ

hydrolase 14

VEDMTEEQLASAMELPCGLTNL

FLHMAFPQFAEKGEQGQYLQ

GNTCYMNATVQCIRSVPELKDA

QDANECWIQMMRVLQQKLEA

LKRYAGALRASGEMASAQYITA

IEDDSVKETDSSSASAATPS

ALRDLFDSMDKTSSSIPPIILL

KKKSLIDQFFGVEFETTMKC

QFLHMAFPQFAEKGEQGQYLQQ

TESEEEEVTKGKENQLQLSC

DANECWIQMMRVLQQKLEAIED

FINQEVKYLFTGLKLRLQEE

DSVKETDSSSASAATPSKKKSL

ITKQSPTLQRNALYIKSSKI

IDQFFGVEFETTMKCTESEEEE

SRLPAYLTIQMVRFFYKEKE

VTKGKENQLQLSCFINQEVKYL

SVNAKVLKDVKFPLMLDMYE

FTGLKLRLQEEITKQSPTLQRN

LCTPELQEKMVSFRSKFKDL

ALYIKSSKISRLPAYLTIQMVR

EDKKVNQQPNTSDKKSSPQK

FFYKEKESVNAKVLKDVKFPLM

EVKYEPESFADDIGSNNCGY

LDMYELCTPELQEKMVSERSKE

YDLQAVLTHQGRSSSSGHYV

KDLEDKKVNQQPNTSDKKSSPQ

SWVKRKQDEWIKEDDDKVSI

KEVKYEPESFADDIGSNNCGYY

VTPEDILRLSGGGDWHIAYV

DLQAVLTHQGRSSSSGHYVSWV

LLYGPRR

KRKQDEWIKEDDDKVSIVTPED

ILRLSGGGDWHIAYVLLYGPRR

VEIMEEESEQ

Q13107|UBP4_
25
MAEGGGCRERPDAETQKSELGP
137
SHIQPGLCGLGNLGNTCEMN

HUMAN

LMRTTLQRGAQWYLIDSRWEKQ

SALQCLSNTAPLTDYELKDE

Ubiquitin

WKKYVGFDSWDMYNVGEHNLEP

YEAEINRDNPLGMKGEIAEA

carboxyl-

GPIDNSGLESDPESQTLKEHLI

YAELIKQMWSGRDAHVAPRM

terminal

DELDYVLVPTEAWNKLLNWYGC

FKTQVGRFAPQFSGYQQQDS

hydrolase 4

VEGQQPIVRKVVEHGLFVKHCK

QELLAFLLDGLHEDLNRVKK

VEVYLLELKLCENSDPTNVLSC

KPYLELKDANGRPDAVVAKE

HFSKADTIATIEKEMRKLENIP

AWENHRLRNDSVIVDTFHGL

AERETRLWNKYMSNTYEQLSKL

FKSTLVCPECAKVSVTFDPF

DNTVQDAGLYQGQVLVIEPQNE

CYLTLPLPLKKDRVMEVELV

DGTWPRQTLQSKSSTAPSRNFT

PADPHCRPTQYRVTVPLMGA

TSPKSSASPYSSVSASLIANGD

VSDLCEALSRLSGIAAENMV

STSTCGMHSSGVSRGGSGESAS

VADVYNHRFHKIFQMDEGLN

YNCQEPPSSHIQPGLCGLGNLG

HIMPRDDIFVYEVCSTSVDG

NTCFMNSALQCLSNTAPLTDYF

SECVTLPVYFRERKSRPSST

LKDEYEAEINRDNPLGMKGEIA

SSASALYGQPLLLSVPKHKL

EAYAELIKQMWSGRDAHVAPRM

TLESLYQAVCDRISRYVKQP

FKTQVGRFAPQFSGYQQQDSQE

LPDEFGSSPLEPGACNGSRN

LLAFLLDGLHEDLNRVKKKPYL

SCEGEDEEEMEHQEEGKEQL

ELKDANGRPDAVVAKEAWENHR

SETEGSGEDEPGNDPSETTQ

LRNDSVIVDTFHGLFKSTLVCP

KKIKGQPCPKRLFTFSLVNS

ECAKVSVTFDPFCYLTLPLPLK

YGTADINSLAADGKLLKLNS

KDRVMEVFLVPADPHCRPTQYR

RSTLAMDWDSETRRLYYDEQ

VTVPLMGAVSDLCEALSRLSGI

ESEAYEKHVSMLQPQKKKKT

AAENMVVADVYNHRFHKIFQMD

TVALRDCIELFTTMETLGEH

EGLNHIMPRDDIFVYEVCSTSV

DPWYCPNCKKHQQATKKEDL

DGSECVTLPVYFRERKSRPSST

WSLPKILVVHLKRFSYNRYW

SSASALYGQPLLLSVPKHKLTL

RDKLDTVVEFPIRGLNMSEF

ESLYQAVCDRISRYVKQPLPDE

VCNLSARPYVYDLIAVSNHY

FGSSPLEPGACNGSRNSCEGED

GAMGVGHYTAYAKNKLNGKW

EEEMEHQEEGKEQLSETEGSGE

YYFDDSNVSLASEDQIVTKA

DEPGNDPSETTQKKIKGQPCPK

AYVLFYQRRD

RLFTFSLVNSYGTADINSLAAD

GKLLKLNSRSTLAMDWDSETRR

LYYDEQESEAYEKHVSMLQPQK

KKKTTVALRDCIELFTTMETLG

EHDPWYCPNCKKHQQATKKEDL

WSLPKILVVHLKRFSYNRYWRD

KLDTVVEFPIRGLNMSEFVCNL

SARPYVYDLIAVSNHYGAMGVG

HYTAYAKNKLNGKWYYFDDSNV

SLASEDQIVTKAAYVLFYQRRD

DEFYKTPSLSSSGSSDGGTRPS

SSQQGFGDDEACSMDTN

UBP26_HUMAN
26
MAALFLRGFVQIGNCKTGISKS
138
KICHGLPNLGNTCYMNAVLQ

Ubiquitin

KEAFIEAVERKKKDRLVLYFKS

SLLSIPSFADDLLNQSFPWG

carboxyl-

GKYSTFRLSDNIQNVVLKSYRG

KIPLNALTMCLARLLFFKDT

terminal

NQNHLHLTLQNNNGLFIEGLSS

YNIEIKEMLLLNLKKAISAA

hydrolase 26

TDAEQLKIFLDRVHQNEVQPPV

AEIFHGNAQNDAHEFLAHCL

RPGKGGSVFSSTTQKEINKTSF

DQLKDNMEKLNTIWKPKSEF

HKVDEKSSSKSFEIAKGSGTGV

GEDNFPKQVFADDPDTSGES

LQRMPLLTSKLTLTCGELSENQ

CPVITNFELELLHSIACKAC

HKKRKRMLSSSSEMNEEFLKEN

GQVILKTELNNYLSINLPQR

NSVEYKKSKADCSRCVSYNREK

IKAHPSSIQSTEDLFFGAEE

QLKLKELEENKKLECESSCIMN

LEYKCAKCEHKTSVGVHSES

ATGNPYLDDIGLLQALTEKMVL

RLPRILIVHLKRYSLNEFCA

VFLLQQGYSDGYTKWDKLKLFF

LKKNDQEVIISKYLKVSSHC

ELFPEKICHGLPNLGNTCYMNA

NEGTRPPLPLSEDGEITDFQ

VLQSLLSIPSFADDLLNQSFPW

LLKVIRKMTSGNISVSWPAT

GKIPLNALTMCLARLLFFKDTY

KESKDILAPHIGSDKESEQK

NIEIKEMLLLNLKKAISAAAEI

KGQTVFKGASRRQQQKYLGK

FHGNAQNDAHEFLAHCLDQLKD

NSKPNELESVYSGDRAFIEK

NMEKLNTIWKPKSEFGEDNEPK

EPLAHLMTYLEDTSLCQFHK

QVFADDPDTSGFSCPVITNFEL

AGGKPASSPGTPLSKVDFQT

ELLHSIACKACGQVILKTELNN

VPENPKRKKYVKTSKFVAFD

YLSINLPQRIKAHPSSIQSTED

RIINPTKDLYEDKNIRIPER

LFFGAEELEYKCAKCEHKTSVG

FQKVSEQTQQCDGMRICEQA

VHSFSRLPRILIVHLKRYSLNE

PQQALPQSFPKPGTQGHTKN

FCALKKNDQEVIISKYLKVSSH

LLRPTKLNLQKSNRNSLLAL

CNEGTRPPLPLSEDGEITDFQL

GSNKNPRNKDILDKIKSKAK

LKVIRKMTSGNISVSWPATKES

ETKRNDDKGDHTYRLISVVS

KDILAPHIGSDKESEQKKGQTV

HLGKTLKSGHYICDAYDFEK

FKGASRRQQQKYLGKNSKPNEL

QIWFTYDDMRVLGIQEAQMQ

ESVYSGDRAFIEKEPLAHLMTY

EDRRCTGYIFFYMHN

LEDTSLCQFHKAGGKPASSPGT

PLSKVDFQTVPENPKRKKYVKT

SKFVAFDRIINPTKDLYEDKNI

RIPERFQKVSEQTQQCDGMRIC

EQAPQQALPQSFPKPGTQGHTK

NLLRPTKLNLQKSNRNSLLALG

SNKNPRNKDILDKIKSKAKETK

RNDDKGDHTYRLISVVSHLGKT

LKSGHYICDAYDFEKQIWFTYD

DMRVLGIQEAQMQEDRRCTGYI

FFYMHNEIFEEMLKREENAQLN

SKEVEETLQKE

UBP19_HUMAN
27
MSGGASATGPRRGPPGLEDTTS
139
LPGFTGLVNLGNTCEMNSVI

Ubiquitin

KKKQKDRANQESKDGDPRKETG

QSLSNTRELRDFFHDRSFEA

carboxyl-

SRYVAQAGLEPLASGDPSASAS

EINYNNPLGTGGRLAIGFAV

terminal

HAAGITGSRHRTRLFFPSSSGS

LLRALWKGTHHAFQPSKLKA

hydrolase 19

ASTPQEEQTKEGACEDPHDLLA

IVASKASQFTGYAQHDAQEF

TPTPELLLDWRQSAEEVIVKLR

MAFLLDGLHEDLNRIQNKPY

VGVGPLQLEDVDAAFTDTDCVV

TETVDSDGRPDEVVAEEAWQ

RFAGGQQWGGVFYAEIKSSCAK

RHKMRNDSFIVDLFQGQYKS

VQTRKGSLLHLTLPKKVPMLTW

KLVCPVCAKVSITFDPFLYL

PSLLVEADEQLCIPPLNSQTCL

PVPLPQKQKVLPVFYFAREP

LGSEENLAPLAGEKAVPPGNDP

HSKPIKFLVSVSKENSTASE

VSPAMVRSRNPGKDDCAKEEMA

VLDSLSQSVHVKPENLRLAE

VAADAATLVDEPESMVNLAFVK

VIKNRFHRVELPSHSLDTVS

NDSYEKGPDSVVVHVYVKEICR

PSDTLLCFELLSSELAKERV

DTSRVLFREQDETLIFQTRDGN

VVLEVQQRPQVPSVPISKCA

FLRLHPGCGPHTTFRWQVKLRN

ACQRKQQSEDEKLKRCTRCY

LIEPEQCTFCFTASRIDICLRK

RVGYCNQLCQKTHWPDHKGL

RQSQRWGGLEAPAARVGGAKVA

CRPENIGYPFLVSVPASRLT

VPTGPTPLDSTPPGGAPHPLTG

YARLAQLLEGYARYSVSVFQ

QEEARAVEKDKSKARSEDTGLD

PPFQPGRMALESQSPGCTTL

SVATRTPMEHVTPKPETHLASP

LSTGSLEAGDSERDPIQPPE

KPTCMVPPMPHSPVSGDSVEEE

LQLVTPMAEGDTGLPRVWAA

EEEEKKVCLPGFTGLVNLGNTC

PDRGPVPSTSGISSEMLASG

FMNSVIQSLSNTRELRDFFHDR

PIEVGSLPAGERVSRPEAAV

SFEAEINYNNPLGTGGRLAIGE

PGYQHPSEAMNAHTPQFFIY

AVLLRALWKGTHHAFQPSKLKA

KIDSSNREQRLEDKGDTPLE

IVASKASQFTGYAQHDAQEFMA

LGDDCSLA

FLLDGLHEDLNRIQNKPYTETV

LVWRNNERLQEFVLVASKEL

DSDGRPDEVVAEEAWQRHKMRN

ECAEDPGSAGEAARAGHFTL

DSFIVDLFQGQYKSKLVCPVCA

DQCLNLFTRPEVLAPEEAWY

KVSITFDPFLYLPVPLPQKQKV

CPQCKQHREASKQLLLWRLP

LPVFYFAREPHSKPIKFLVSVS

NVLIVQLKRFSFRSFIWRDK

KENSTASEVLDSLSQSVHVKPE

INDLVEFPVRNLDLSKFCIG

NLRLAEVIKNRFHRVELPSHSL

QKEEQLPSYDLYAVINHYGG

DTVSPSDTLLCFELLSSELAKE

MIGGHYTACARLPNDRSSQR

RVVVLEVQQRPQVPSVPISKCA

SDVGWRLEDDSTVTTVDESQ

ACQRKQQSEDEKLKRCTRCYRV

VVTRYAYVLFYRRRN

GYCNQLCQKTHWPDHKGLCRPE

NIGYPFLVSVPASRLTYARLAQ

LLEGYARYSVSVFQPPFQPGRM

ALESQSPGCTTLLSTGSLEAGD

SERDPIQPPELQLVTPMAEGDT

GLPRVWAAPDRGPVPSTSGISS

EMLASGPIEVGSLPAGERVSRP

EAAVPGYQHPSEAMNAHTPQFF

IYKIDSSNREQRLEDKGDTPLE

LGDDCSLALVWRNNERLQEFVL

VASKELECAEDPGSAGEAARAG

HFTLDQCLNLFTRPEVLAPEEA

WYCPQCKQHREASKQLLLWRLP

NVLIVQLKRFSFRSFIWRDKIN

DLVEFPVRNLDLSKFCIGQKEE

QLPSYDLYAVINHYGGMIGGHY

TACARLPNDRSSQRSDVGWRLF

DDSTVTTVDESQVVTRYAYVLE

YRRRNSPVERPPRAGHSEHHPD

LGPAAEAAASQASRIWQELEAE

EEPVPEGSGPLGPWGPQDWVGP

LPRGPTTPDEGCLRYFVLGTVA

ALVALVLNVFYPLVSQSRWR

UBP10_HUMAN
28
MALHSPQYIFGDESPDEFNQFF
140
SLQPRGLINKGNWCYINATL

Ubiquitin

VTPRSSVELPPYSGTVLCGTQA

QALVACPPMYHLMKFIPLYS

carboxyl-

VDKLPDGQEYQRIEFGVDEVIE

KVQRPCTSTPMIDSFVRLMN

terminal

PSDTLPRTPSYSISSTLNPQAP

EFTNMPVPPKPRQALGDKIV

hydrolase 10

EFILGCTASKITPDGITKEASY

RDIRPGAAFEPTYIYRLLTV

GSIDCQYPGSALALDGSSNVEA

NKSSLSEKGRQEDAEEYLGF

EVLENDGVSGGLGQRERKKKKK

ILNGLHEEMLNLKKLLSPSN

RPPGYYSYLKDGGDDSISTEAL

EKLTISNGPKNHSVNEEEQE

VNGHANSAVPNSVSAEDAEFMG

EQGEGSEDEWEQVGPRNKTS

DMPPSVTPRTCNSPQNSTDSVS

VTRQADFVQTPITGIFGGHI

DIVPDSPFPGALGSDTRTAGQP

RSVVYQQSSKESATLQPFFT

EGGPGADFGQSCFPAEAGRDTL

LQLDIQSDKIRTVQDALESL

SRTAGAQPCVGTDTTENLGVAN

VARESVQGYTTKTKQEVEIS

GQILESSGEGTATN

RRVTLEKLPPVLVLHLKRFV

GVELHTTESIDLDPTKPESASP

YEKTGGCQKLIKNIEYPVDL

PADGTGSASGTLPVSQPKSWAS

EISKELLSPGVKNKNEKCHR

LFHDSKPSSSSPVAYVETKYSP

TYRLFAVVYHHGNSATGGHY

PAISPLVSEKQVEVKEGLVPVS

TTDVFQIGLNGWLRIDDQTV

EDPVAIKIAELLENVTLIHKPV

KVINQYQVVKPTAERTAYLL

SLQPRGLINKGNWCYINATLQA

YYRRVD

LVACPPMYHLMKFIPLYSKVQR

PCTSTPMIDSFVRLMNEFTNMP

VPPKPRQALGDKIVRDIRPGAA

FEPTYIYRLLTVNKSSLSEKGR

QEDAEEYLGFILNGLHEEMLNL

KKLLSPSNEKLTISNGPKNHSV

NEEEQEEQGEGSEDEWEQVGPR

NKTSVTRQADFVQT

PITGIFGGHIRSVVYQQSSKES

ATLQPFFTLQLDIQSDKIRTVQ

DALESLVARESVQGYTTKTKQE

VEISRRVTLEKLPPVLVLHLKR

FVYEKTGGCQKLIKNIEYPVDL

EISKELLSPGVKNKNFKCHRTY

RLFAVVYHHGNSATGGHYTTDV

FQIGLNGWLRIDDQTVKVINQY

QVVKPTAERTAYLLYYRRVDLL

UBP49_HUMAN
29
MDRCKHVGRLRLAQDHSILNPQ
141
MDRCKHVGRLRLAQDHSILN

Ubiquitin

KWCCLECATTESVWACLKCSHV

PQKWCCLECATTESVWACLK

carboxyl-

ACGRYIEDHALKHFEETGHPLA

CSHVACGRYIEDHALKHFEE

terminal

MEVRDLYVFCYLCKDYVLNDNP

TGHPLAMEVRDLYVFCYLCK

hydrolase 49

EGDLKLLRSSLLAVRGQKQDTP

DYVLNDNPEGDLKLLRSSLL

VRRGRTLRSMASGEDVVLPQRA

AVRGQKQDTPVRRGRTLRSM

PQGQPQMLTALWYRRQRLLART

ASGEDVVLPQRAPQGQPQML

LRLWFEKSSRGQAKLEQRRQEE

TALWYRRQRLLARTLRLWFE

ALERKKEEARRRRREVKRRLLE

KSSRGQAKLEQRRQEEALER

ELASTPPRKSARLLLHTPRDAG

KKEEARRRRREVKRRLLEEL

PAASRPAALPTSRRVPAATLKL

ASTPPRKSARLLLHTPRDAG

RRQPAMAPGVTGLRNLGNTCYM

PAASRPAALPTSRRVPAATL

NSILQVLSHLQKFRECELNLDP

KLRRQPAMAPGVTGLRNLGN

SKTEHLFPKATNGK

TCYMNSILQVLSHLQKFREC

TQLSGKPTNSSATELSLRNDRA

FLNLDPSKTEHLFPKATNGK

EACEREGFCWNGRASISRSLEL

TQLSGKPTNSSATELSLRND

IQNKEPSSKHISLCRELHTLER

RAEACEREGFCWNGRASISR

VMWSGKWALVSPFAMLHSVWSL

SLELIQNKEPSSKHISLCRE

IPAFRGYDQQDAQEFLCELLHK

LHTLFRVMWSGKWALVSPFA

VQQELESEGTTRRILIPFSQRK

MLHSVWSLIPAFRGYDQQDA

LTKQVLKVVNTIFHGQLLSQVT

QEFLCELLHKVQQELESEGT

CISCNYKSNTIEPFWDLSLEEP

TRRILIPFSQRKLTKQVLKV

ERYHCIEKGFVPLNQTECLLTE

VNTIFHGQLLSQVTCISCNY

MLAKFTETEALEGRIYACDQCN

KSNTIEPFWDLSLEFPERYH

SKRRKSNPKPLVLSEARKQLMI

CIEKGFVPLNQTECLLTEML

YRLPQVLRLHLKRFRWSGRNHR

AKFTETEALEGRIYACDQCN

EKIGVHVVEDQVLTMEPYCCRD

SKRRKSNPKPLVLSEARKQL

MLSSLDKETFAYDL

MIYRLPQVLRLHLKRFRWSG

SAVVMHHGKGFGSGHYTAYCYN

RNHREKIGVHVVEDQVLTME

TEGGFWVHCNDSKLNVCSVEEV

PYCCRDMLSSLDKETFAYDL

CKTQAYILFYTQRTVQGNARIS

SAVVMHHGKGFGSGHYTAYC

ETHLQAQVQSSNNDEGRPQTES

YNTEGGFWVHCNDSKLNVCS

VEEVCKTQAYILFYTQRT

U17L8_HUMAN
30
MEDDSLYLGGEWQFNHFSKLTS
142
AVGAGLQNMGNTCYLNASLQ

Inactive

PRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

ubiquitin

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

carboxyl-

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

terminal

CYLNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

hydrolase 17-

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

like protein 8

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYPCGL

GCWRSQIKCLHCHGISDTEDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFCDVTGNKLAKNVQ

PEELNGENAYPCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRFCDV

YVLYAVLVHAGWSCHNGYYF

TGNKLAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQQNTGPLVYVLYAV

CSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGYYFSYVKAQEG

QWYKMDDAEVTACSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRPATQGELKR

DHPCLQVPELDEHLVERATEES

TLDHWKFPQEQNKMKPEFNVRK

VEGTLPPNVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSMNSTDQE

SMNTGTLASLQGRTRRSKGKNK

HSKRSLLVCQ

6VN6_1
31
GSKKHTGYVGLKNQGATCYMNS
143
TGYVGLKNQGATCYMNSLLQ

LLQTLFFTNQLRKAVYMMPTEG

TLFFTNQLRKAVYMMPTEGD

DDSSKSVPLALQRVFYELQHSD

DSSKSVPLALQRVFYELQHS

KPVGTKKLTKSFGWETLDSEMQ

DKPVGTKKLTKSFGWETLDS

HDVQELCRVLLDNVENKMKGTC

FMQHDVQELCRVLLDNVENK

VEGTIPKLFRGKMVSYIQCKEV

MKGTCVEGTIPKLFRGKMVS

DYRSDRREDYYDIQLSIKGKKN

YIQCKEVDYRSDRREDYYDI

IFESFVDYVAVEQLDGDNKYDA

QLSIKGKKNIFESFVDYVAV

GEHGLQEAEKGVKFLTLPPVLH

EQLDGDNKYDAGEHGLQEAE

LQLMRFMYDPQTDQNIKINDRE

KGVKFLTLPPVLHLQLMREM

EFPEQLPLDEFLQKTDPKDPAN

YDPQTDQNIKINDRFEFPEQ

YILHAVLVHSGDNHGGHYVVYL

LPLDEFLQKTDPKDPANYIL

NPKGDGKWCKFDDDVVSRCTKE

HAVLVHSGDNHGGHYVVYLN

EAIEHNYGGHDDDLSVRHCTNA

PKGDGKWCKFDDDVVSRCTK

YMLVYIRESKLSEVLQAVTDHD

EEAIEHNYGGHDDDLSVRHC

IPQQLVERLQEEKRIEAQKR

TNAYMLVYIRE

6DGF_1
32
AQGLAGLRNLGNTCEMNSILQC
144
AQGLAGLRNLGNTCEMNSIL

LSNTRELRDYCLQRLYMRDLHH

QCLSNTRELRDYCLQRLYMR

GSNAHTALVEEFAKLIQTIWTS

DLHHGSNAHTALVEEFAKLI

SPNDVVSPSEFKTQIQRYAPRE

QTIWTSSPNDVVSPSEFKTQ

VGYNQQDAQEFLRELLDGLHNE

IQRYAPRFVGYNQQDAQEFL

VNRVTLRPKSNPENLDHLPDDE

RFLLDGLHNEVNRVTLRPKS

KGRQMWRKYLEREDSRIGDLFV

NPENLDHLPDDEKGRQMWRK

GQLKSSLTCTDCGYCSTVEDPF

YLEREDSRIGDLFVGQLKSS

WDLSLPIAKRGYPEVTLMDCMR

LTCTDCGYCSTVEDPEWDLS

LFTKEDVLDGDEKPTCCRCRGR

LPIAKRGYPEVTLMDCMRLF

KRCIKKFSIQRFPKILVLHLKR

TKEDVLDGDEKPTCCRCRGR

FSESRIRTSKLTTFVNFPLRDL

KRCIKKFSIQRFPKILVLHL

DLREFASENTNHAVYNLYAVSN

KRFSESRIRTSKLTTFVNFP

HSGTTMGGHYTAYCRSPGTGEW

LRDLDLREFASENTNHAVYN

HTFNDSSVTPMSSSQVRTSDAY

LYAVSNHSGTTMGGHYTAYC

LLFYELASPPSRM

RSPGTGEWHTENDSSVTPMS

SSQVRTSDAYLLFYELAS

2VHF_1
33
GLEIMIGKKKGIQGHYNSCYLD
145
MIGKKKGIQGHYNSCYLDST

STLFCLFAFSSVLDTVLLRPKE

LFCLFAFSSVLDTVLLRPKE

KNDVEYYSETQELLRTEIVNPL

KNDVEYYSETQELLRTEIVN

RIYGYVCATKIMKLRKILEKVE

PLRIYGYVCATKIMKLRKIL

AASGFTSEEKDPEEFLNILFHH

EKVEAASGFTSEEKDPEEFL

ILRVEPLLKIRSAGQKVQDCYF

NILFHHILRVEPLLKIRSAG

YQIFMEKNEKVGVPTIQQLLEW

QKVQDCYFYQIFMEKNEKVG

SFINSNLKFAEAPSCLIIQMPR

VPTIQQLLEWSFINSNLKFA

FGKDFKLFKKIFPSLELNITDL

EAPSCLIIQMPRFGKDFKLE

LEDTPRQCRICGGLAMYECREC

KKIFPSLELNITDLLEDTPR

YDDPDISAGKIKQFCKTCNTQV

QCRICGGLAMYECRECYDDP

HLHPKRLNHKYNPVSLPKDLPD

DISAGKIKQFCKTCNTQVHL

WDWRHGCIPCQNMELFAVLCIE

HPKRLNHKYNPVSLPKDLPD

TSHYVAFVKYGKDDSAWLFFDS

WDWRHGCIPCQNMELFAVLC

MADRDGGQNGENIPQVTPCPEV

IETSHYVAFVKYGKDDSAWL

GEYLKMSLEDLHSLDSRRIQGC

FFDSMADRDGGQNGFNIPQV

ARRLLCDAYMCMYQSPTMSLYK

TPCPEVGEYLKMSLEDLHSL

DSRRIQGCARRLLCDAYMCM

YQS

U17LI_HUMAN
34
MEDDSLYLGGEWQFNHESKLTS
146
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 18

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQTNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQTNTGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTASSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRAKQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSTTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

UBP22_HUMAN
35
MVSRPEPEGEAMDAELAVAPPG
147
LGNTCFMNCIVQALTHTPLL

Ubiquitin

CSHLGSFKVDNWKQNLRAIYQC

RDFFLSDRHRCEMQSPSSCL

carboxyl-

FVWSGTAEARKRKAKSCICHVC

VCEMSSLFQEFYSGHRSPHI

terminal

GVHLNRLHSCLYCVFFGCFTKK

PYKLLHLVWTHARHLAGYEQ

hydrolase 22

HIHEHAKAKRHNLAIDLMYGGI

QDAHEFLIAALDVLHRHCKG

YCFLCQDYIYDKDMEIIAKEEQ

DDNGKKANNPNHCNCIIDQI

RKAWKMQGVGEKESTWEPTKRE

FTGGLQSDVTCQVCHGVSTT

LELLKHNPKRRKITSNCTIGLR

IDPFWDISLDLPGSSTPFWP

GLINLGNTCEMNCIVQALTHTP

LSPGSEGNVVNGESHVSGTT

LLRDFFLSDRHRCEMQSPSSCL

TLTDCLRRFTRPEHLGSSAK

VCEMSSLFQEFYSGHRSPHIPY

IKCSGCHSYQESTKQLTMKK

KLLHLVWTHARHLAGYEQQDAH

LPIVACFHLKRFEHSAKLRR

EFLIAALDVLHRHCKGDDNGKK

KITTYVSFPLELDMTPFMAS

ANNPNHCNCIIDQIFTGGLQSD

SKESRMNGQYQQPTDSLNND

VTCQVCHGVSTTIDPFWDISLD

NKYSLFAVVNHQGTLESGHY

LPGSSTPFWPLSPGSEGNVVNG

TSFIRQHKDQWFKCDDAIIT

ESHVSGTTTLTDCLRRETRPEH

KASIKDVLDSEGYLLFYHKQ

LGSSAKIKCSGCHSYQESTKQL

F

TMKKLPIVACFHLKRFEHSAKL

RRKITTYVSFPLELDMTPEMAS

SKESRMNGQYQQPTDSLNNDNK

YSLFAVVNHQGTLESGHYTSFI

RQHKDQWFKCDDAIITKASIKD

VLDSEGYLLFYHKQFLEYE

UBP18_HUMAN
36
MSKAFGLLRQICQSILAESSQS
148
KGLVPGLVNLGNTCEMNSLL

Ubl

PADLEEKKEEDSNMKREQPRER

QGLSACPAFIRWLEEFTSQY

carboxyl-

PRAWDYPHGLVGLHNIGQTCCL

SRDQKEPPSHQYLSLTLLHL

terminal

NSLIQVFVMNVDFTRILKRITV

LKALSCQEVTDDEVLDASCL

hydrolase 18

PRGADEQRRSVPFQMLLLLEKM

LDVLRMYRWQISSFEEQDAH

QDSRQKAVRPLELAYCLQKCNV

ELFHVITSSLEDERDRQPRV

PLFVQHDAAQLYLKLWNLIKDQ

THLFDVHSLEQQSEITPKQI

ITDVHLVERLQALYTIRVKDSL

TCRTRGSPHPTSNHWKSQHP

ICVDCAMESSRNSSMLTLPLSL

FHGRLTSNMVCKHCEHQSPV

FDVDSKPLKTLEDALHCFFQPR

RFDTFDSLSLSIPAATWGHP

ELSSKSKCFCENCGKKTRGKQV

LTLDHCLHHFISSESVRDVV

LKLTHLPQTLTIHLMRESIRNS

CDNCTKIEAKGTLNGEKVEH

QTRKICHSLYFPQSLDESQILP

QRTTFVKQLKLGKLPQCLCI

MKRESCDAEEQSGG

HLQRLSWSSHGTPLKRHEHV

QYELFAVIAHVGMADSGHYCVY

QFNEFLMMDIYKYHLLGHKP

IRNAVDGKWFCENDSNICLVSW

SQHNPKLNKNPGPTLELQDG

EDIQCTYGNPNYHWQETAYLLV

PGAPTPVLNQPGAPKTQIFM

YMKMEC

NGACSPSLLPTLSAPMPFPL

PVVPDYSSSTYLERLMAVVV

HHGDMHSGHFVTYRRSPPSA

RNPLSTSNQWLWVSDDTVRK

ASLQEVLSSSAYLLFYERVL

UBP28_HUMAN
37
MTAELQQDDAAGAADGHGSSCQ
149
GWPVGLKNVGNTCWFSAVIQ

Ubiquitin

MLLNQLREITGIQDPSFLHEAL

SLFQLPEFRRLVLSYSLPQN

carboxyl-

KASNGDITQAVSLLTDERVKEP

VLENCRSHTEKRNIMFMQEL

terminal

SQDTVATEPSEVEGSAANKEVL

QYLFALMMGSNRKFVDPSAA

hydrolase 28

AKVIDLTHDNKDDLQAAIALSL

LDLLKGAFRSSEEQQQDVSE

LESPKIQADGRDLNRMHEATSA

FTHKLLDWLEDAFQLAVNVN

ETKRSKRKRCEVWGENPNPNDW

SPRNKSENPMVQLFYGTELT

RRVDGWPVGLKNVGNTCWFSAV

EGVREGKPFCNNETFGQYPL

IQSLFQLPEFRRLVLSYSLPQN

QVNGYRNLDECLEGAMVEGD

VLENCRSHTEKRNIMFMQELQY

VELLPSDHSVKYGQERWFTK

LFALMMGSNRKFVDPSAALDLL

LPPVLTFELSRFEFNQSLGQ

KGAFRSSEEQQQDVSEFTHKLL

PEKIHNKLEFPQIIYMDRYM

DWLEDAFQLAVNVNSPRNKSEN

YRSKELIRNKRECIRKLKEE

PMVQLFYGTELTEG

IKILQQKLERYVKYGSGPAR

VREGKPFCNNETFGQYPLQVNG

FPLPDMLKYVIEFASTKPAS

YRNLDECLEGAMVEGDVELLPS

ESCPPESDTHMTLPLSSVHC

DHSVKYGQERWFTKLPPVLTFE

SVSDQTSKESTSTESSSQDV

LSRFEFNQSLGQPEKIHNKLEF

ESTESSPEDSLPKSKPLTSS

PQIIYMDRYMYRSKELIRNKRE

RSSMEMPSQPAPRTVTDEEI

CIRKLKEEIKILQQKLERYVKY

NFVKTCLQRWRSEIEQDIQD

GSGPARFPLPDMLKYVIEFAST

LKTCIASTTQTIEQMYCDPL

KPASESCPPESDTHMTLPLSSV

LRQVPYRLHAVLVHEGQANA

HCSVSDQTSKESTSTESSSQDV

GHYWAYIYNQPRQSWLKYND

ESTESSPEDSLPKSKPLTSSRS

ISVTESSWEEVERDSYGGLR

SMEMPSQPAPRTVTDEEINFVK

NVSAYCLMYINDKLPY

TCLQRWRSEIEQDIQDLKTCIA

STTQTIEQMYCDPLLRQVPYRL

HAVLVHEGQANAGHYWAYIYNQ

PRQSWLKYNDISVTESSWEEVE

RDSYGGLRNVSAYCLMYINDKL

PYFNAEAAPTESDQMSEVEALS

VELKHYIQEDNWRFEQEVEEWE

EEQSCKIPQMESSINSSSQDYS

TSQEPSVASSHGVRCLSSEHAV

IVKEQTAQAIANTARAYEKSGV

EAALSEVMLSPAMQGVILAIAK

ARQTFDRDGSEAGLIKAFHEEY

SRLYQLAKETPTSHSDPRLQHV

LVYFFQNEAPKRVVERTLLEQF

ADKNLSYDERSISIMKVAQAKL

KEIGPDDMNMEEYKKWHEDYSL

FRKVSVYLLTGLELYQKGKYQE

ALSYLVYAYQSNAALLMKGPRR

GVKESVIALYRRKCLLELNAKA

ASLFETNDDHSVTEGINVMNEL

IIPCIHLIINNDISKDDLDAIE

VMRNHWCSYLGQDIAENLQLCL

GEFLPRLLDPSAEIIVLKEPPT

IRPNSPYDLCSRFAAVMESIQG

VSTVTVK

U17L2_HUMAN
38
MEDDSLYLGGEWQFNHESKLTS
150
AVGAGLQNMGNTCYENASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

SEARVDLCDDLAPVARQLAPRK

CQRPKCCMLCTMQAHITWAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

hydrolase 17

CYENASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVTGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHDGHYF

TGNKLAKNVQYPEC

SYVKAQEGQWYKMDDAKVTA

LDMQPYMSQQNTGPLVYVLYAV

CSITSVLSQQAYVLFYIQKS

LVHAGWSCHDGHYFSYVKAQEG

QWYKMDDAKVTACSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDERLVERATQES

TLDHWKFPQEQNKTKPEFNVRK

VEGTLPPNVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSTTRTDQE

SVNTGTLASLQGRTRRSKGKNK

HSKRALLVCQ

UBP31_HUMAN
39
MSKVTAPGSGPPAAASGKEKRS
151
PVPGVAGLRNHGNTCFMNAT

Ubiquitin

FSKRLERSGRAGGGGAGGPGAS

LQCLSNTELFAEYLALGQYR

carboxyl-

GPAAPSSPSSPSSARSVGSEMS

AGRPEPSPDPEQPAGRGAQG

terminal

RVLKTLSTLSHLSSEGAAPDRG

QGEVTEQLAHLVRALWTLEY

hydrolase 31

GLRSCFPPGPAAAPTPPPCPPP

TPQHSRDFKTIVSKNALQYR

PASPAPPACAAEPVPGVAGLRN

GNSQHDAQEFLLWLLDRVHE

HGNTCFMNATLQCLSNTELFAE

DLNHSVKQSGQPPLKPPSET

YLALGQYRAGRPEPSPDPEQPA

DMMPEGPSFPVCSTFVQELF

GRGAQGQGEVTEQLAHLVRALW

QAQYRSSLTCPHCQKQSNTF

TLEYTPQHSRDEKTIVSKNALQ

DPFLCISLPIPLPHTRPLYV

YRGNSQHDAQEFLLWLLDRVHE

TVVYQGKCSHCMRIGVAVPL

DLNHSVKQSGQPPLKPPSETDM

SGTVARLREAVSMETKIPTD

MPEGPSFPVCSTFVQELFQAQY

QIVLTEMYYDGFHRSFCDTD

RSSLTCPHCQKQSN

DLETVHESDCIFAFETPEIF

TFDPFLCISLPIPLPHTRPLYV

RPEGILSQRGIHLNNNLNHL

TVVYQGKCSHCMRIGVAVPLSG

KFGLDYHRLSSPTQTAAKQG

TVARLREAVSMETKIPTDQIVL

KMDSPTSRAGSDKIVLLVCN

TEMYYDGFHRSFCDTDDLETVH

RACTGQQGKRFGLPFVLHLE

ESDCIFAFETPEIFRPEGILSQ

KTIAWDLLQKEILEKMKYFL

RGIHLNNNLNHLKFGLDYHRLS

RPTVCIQVCPFSLRVVSVVG

SPTQTAAKQGKMDSPTSRAGSD

ITYLLPQEEQPLCHPIVE

KIVLLVCNRACTGQQGKRFGLP

RALKSCGPGGTAHVKLVVEW

FVLHLEKTIAWDLLQKEILEKM

DKETRDELFVNTEDEYIPDA

KYFLRPTVCIQVCPFSLRVVSV

ESVRLQRERHHQPQTCTLSQ

VGITYLLPQEEQPLCHPIVERA

CFQLYTKEERLAPDDAWRCP

LKSCGPGGTAHVKLVVEWDKET

HCKQLQQGSITLSLWTLPDV

RDELFVNTEDEYIPDAESVRLQ

LIIHLKRFRQEGDRRMKLQN

RERHHQPQTCTLSQ

MVKFPLTGLDMTPHVVKRSQ

CFQLYTKEERLAPDDAWRCPHC

SSWSLPSHWSPWRRPYGLGR

KQLQQGSITLSLWTLPDVLIIH

DPEDYIYDLYAVCNHHGTMQ

LKRFRQEGDRRMKLQNMVKFPL

GGHYTAYCKNSVDGLWYCFD

TGLDMTPHVVKRSQSSWSLPSH

DSDVQQLSEDEVCTQTAYIL

WSPWRRPYGLGRDPEDYIYDLY

FYQRRT

AVCNHHGTMQGGHYTAYCKNSV

DGLWYCFDDSDVQQLSEDEVCT

QTAYILFYQRRTAIPSWSANSS

VAGSTSSSLCEHWVSRLPGSKP

ASVTSAASSRRTSLASLSESVE

MTGERSEDDGGFSTRPFVRSVQ

RQSLSSRSSVTSPLAVNENCMR

PSWSLSAKLQMRSNSPSRESGD

SPIHSSASTLEKIG

EAADDKVSISCFGSLRNLSSSY

QEPSDSHSRREHKAVGRAPLAV

MEGVFKDESDTRRLNSSVVDTQ

SKHSAQGDRLPPLSGPFDNNNQ

IAYVDQSDSVDSSPVKEVKAPS

HPGSLAKKPESTTKRSPSSKGT

SEPEKSLRKGRPALASQESSLS

STSPSSPLPVKVSLKPSRSRSK

ADSSSRGSGRHSSPAPAQPKKE

SSPKSQDSVSSPSPQKQKSASA

LTYTASSTSAKKASGPATRSPF

PPGKSRTSDHSLSREGSRQSLG

SDRASATSTSKPNSPRVSQARA

GEGRGAGKHVRSSS

MASLRSPSTSIKSGLKRDSKSE

DKGLSFFKSALRQKETRRSTDL

GKTALLSKKAGGSSVKSVCKNT

GDDEAERGHQPPASQQPNANTT

GKEQLVTKDPASAKHSLLSARK

SKSSQLDSGVPSSPGGRQSAEK

SSKKLSSSMQTSARPSQKPQ

U17LJ_HUMAN
40
MEEDSLYLGGEWQFNHESKLTS
152
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 19

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQTNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQTNTGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

EWERHSESVSRGREPRALGA

QWYKMDDAEVTASSITSVLSQQ

EDTDRRATQGELKRDHPCLQ

AYVLFYIQKSEWERHSESVSRG

APEL

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLKLSSTTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

U17LF_HUMAN
41
MEDDSLYLGGEWQFNHESKLTS
153
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 15

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIDKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMKLYMSQTNSGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIDKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMKLYMSQTNSGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTASSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSTTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQWSQWKYRPTRRG

AHTHAHTQTHT

UBP47_HUMAN
42
MVPGEENQLVPKEDVEWRCRQN
154
ETGYVGLVNQAMTCYLNSLL

Ubiquitin

IFDEMKKKFLQIENAAEEPRVL

QTLEMTPEFRNALYKWEFEE

carboxyl-

CIIQDTTNSKTVNERITLNLPA

SEEDPVTSIPYQLQRLFVLL

terminal

STPVRKLFEDVANKVGYINGTF

QTSKKRAIETTDVTRSFGWD

hydrolase 47

DLVWGNGINTADMAPLDHTSDK

SSEAWQQHDVQELCRVMEDA

SLLDANFEPGKKNFLHLTDKDG

LEQKWKQTEQADLINELYQG

EQPQILLEDSSAGEDSVHDREI

KLKDYVRCLECGYEGWRIDT

GPLPREGSGGSTSDYVSQSYSY

YLDIPLVIRPYGSSQAFASV

SSILNKSETGYVGLVNQAMTCY

EEALHAFIQPEILDGPNQYF

LNSLLQTLEMTPEFRNALYKWE

CERCKKKCDARKGLRFLHFP

FEESEEDPVTSIPYQLQRLEVL

YLLTLQLKRFDEDYTTMHRI

LQTSKKRAIETTDVTRSFGWDS

KLNDRMTFPEELDMSTFIDV

SEAWQQHDVQELCRVMEDALEQ

EDEKSPQTESCTDSGAENEG

KWKQTEQADLINEL

SCHSDQMSNDESNDDGVDEG

YQGKLKDYVRCLECGYEGWRID

ICLETNSGTEKISKSGLEKN

TYLDIPLVIRPYGSSQAFASVE

SLIYELFSVMVHSGSAAGGH

EALHAFIQPEILDGPNQYFCER

YYACIKSFSDEQWYSENDQH

CKKKCDARKGLRFLHFPYLLTL

VSRITQEDIKKTHGGSSGSR

QLKRFDEDYTTMHRIKLNDRMT

GYYSSAFASSTNAYMLIYRL

FPEELDMSTFIDVEDEKSPQTE

KD

SCTDSGAENEGSCHSDQMSNDE

SNDDGVDEGICLETNSGTEKIS

KSGLEKNSLIYELFSVMVHSGS

AAGGHYYACIKSFSDEQWYSEN

DQHVSRITQEDIKKTHGGSSGS

RGYYSSAFASSTNAYMLIYRLK

DPARNAKFLEVDEYPEHIKNLV

QKERELEEQEKRQR

EIERNTCKIKLFCLHPTKQVMM

ENKLEVHKDKTLKEAVEMAYKM

MDLEEVIPLDCCRLVKYDEFHD

YLERSYEGEEDTPMGLLLGGVK

STYMEDLLLETRKPDQVFQSYK

PGEVMVKVHVVDLKAESVAAPI

TVRAYLNQTVTEFKQLISKAIH

LPAETMRIVLERCYNDLRLLSV

SSKTLKAEGFFRSNKVFVESSE

TLDYQMAFADSHLWKLLDRHAN

TIRLFVLLPEQSPVSYSKRTAY

QKAGGDSGNVDDDCERVKGPVG

SLKSVEAILEESTEKLKSLSLQ

QQQDGDNGDSSKST

ETSDFENIESPLNERDSSASVD

NRELEQHIQTSDPENFQSEERS

DSDVNNDRSTSSVDSDILSSSH

SSDTLCNADNAQIPLANGLDSH

SITSSRRTKANEGKKETWDTAE

EDSGTDSEYDESGKSRGEMQYM

YFKAEPYAADEGSGEGHKWLMV

HVDKRITLAAFKQHLEPFVGVL

SSHFKVERVYASNQEFESVRLN

ETLSSESDDNKITIRLGRALKK

GEYRVKVYQLLVNEQEPCKELL

DAVFAKGMTVRQSKEELIPQLR

EQCGLELSIDRERLRKKTWKNP

GTVFLDYHIYEEDI

NISSNWEVELEVLDGVEKMKSM

SQLAVLSRRWKPSEMKLDPEQE

VVLESSSVDELREKLSEISGIP

LDDIEFAKGRGTFPCDISVLDI

HQDLDWNPKVSTLNVWPLYICD

DGAVIFYRDKTEELMELTDEQR

NELMKKESSRLQKTGHRVTYSP

RKEKALKIYLDGAPNKDLTQD

UBP51_HUM
43
MAQVRETSLPSGSGVRWISGGG
155
YTVGLRGLINLGNTCEMNCI

AN Ubiquitin

GGASPEEAVEKAGKMEEAAAGA

VQALTHIPLLKDFFLSDKHK

carboxyl-

TKASSRREAEEMKLEPLQEREP

CIMTSPSLCLVCEMSSLFHA

terminal

APEENLTWSSSGGDEKVLPSIP

MYSGSRTPHIPYKLLHLIWI

hydrolase 51

LRCHSSSSPVCPRRKPRPRPQP

HAEHLAGYRQQDAHEFLIAI

RARSRSQPGLSAPPPPPARPPP

LDVLHRHSKDDSGGQEANNP

PPPPPPPPAPRPRAWRGSRRRS

NCCNCIIDQIFTGGLQSDVT

RPGSRPQTRRSCSGDLDGSGDP

CQACHSVSTTIDPCWDISLD

GGLGDWLLEVEFGQGPTGCSHV

LPGSCATFDSQNPERADSTV

ESFKVGKNWQKNLRLIYQRFVW

SRDDHIPGIPSLTDCLQWFT

SGTPETRKRKAKSCICHVCSTH

RPEHLGSSAKIKCNSCQSYQ

MNRLHSCLSCVFFGCFTEKHIH

ESTKQLTMKKLPIVACFHLK

KHAETKQHHLAVDLYHGVIYCF

RFEHVGKQRRKINTFISFPL

MCKDYVYDKDIEQI

ELDMTPFLASTKESRMKEGQ

AKETKEKILRLLTSTSTDVSHQ

PPTDCVPNENKYSLFAVINH

QFMTSGFEDKQSTCETKEQEPK

HGTLESGHYTSFIRQQKDQW

LVKPKKKRRKKSVYTVGLRGLI

FSCDDAIITKATIEDLLYSE

NLGNTCFMNCIVQALTHIPLLK

GYLLFYHKQG

DFFLSDKHKCIMTSPSLCLVCE

MSSLFHAMYSGSRTPHIPYKLL

HLIWIHAEHLAGYRQQDAHEFL

IAILDVLHRHSKDDSGGQEANN

PNCCNCIIDQIFTGGLQSDVTC

QACHSVSTTIDPCWDISLDLPG

SCATFDSQNPERADSTVSRDDH

IPGIPSLTDCLQWFTRPEHLGS

SAKIKCNSCQSYQESTKQLTMK

KLPIVACFHLKRFE

HVGKQRRKINTFISFPLELDMT

PFLASTKESRMKEGQPPTDCVP

NENKYSLFAVINHHGTLESGHY

TSFIRQQKDQWFSCDDAIITKA

TIEDLLYSEGYLLFYHKQGLEK

D

UBP36_HUMAN
44
MPIVDKLKEALKPGRKDSADDG
156
RVGAGLHNLGNTCFLNATIQ

Ubiquitin

ELGKLLASSAKKVLLQKIEFEP

CLTYTPPLANYLLSKEHARS

carboxyl-

ASKSFSYQLEALKSKYVLLNPK

CHQGSFCMLCVMQNHIVQAF

terminal

TEGASRHKSGDDPPARRQGSEH

ANSGNAIKPVSFIRDLKKIA

hydrolase 36

TYESCGDGVPAPQKVLFPTERL

RHFREGNQEDAHEFLRYTID

SLRWERVERVGAGLHNLGNTCF

AMQKACLNGCAKLDRQTQAT

LNATIQCLTYTPPLANYLLSKE

TLVHQIFGGYLRSRVKCSVC

HARSCHQGSFCMLCVMQNHIVQ

KSVSDTYDPYLDVALEIRQA

AFANSGNAIKPVSFIRDLKKIA

ANIVRALELFVKADVLSGEN

RHFREGNQEDAHEFLRYTIDAM

AYMCAKCKKKVPASKRFTIH

QKACLNGCAKLDRQTQATTLVH

RTSNVLTLSLKRFANFSGGK

QIFGGYLRSRVKCSVCKSVSDT

ITKDVGYPEFLNIRPYMSQN

YDPYLDVALEIRQAANIVRALE

NG

LFVKADVLSGENAY

DPVMYGLYAVLVHSGYSCHA

MCAKCKKKVPASKRFTIHRTSN

GHYYCYVKASNGQWYQMNDS

VLTLSLKRFANFSGGKITKDVG

LVHSSNVKVVLNQQAYVLFY

YPEFLNIRPYMSQNNGDPVMYG

LRIP

LYAVLVHSGYSCHAGHYYCYVK

ASNGQWYQMNDSLVHSSNVKVV

LNQQAYVLFYLRIPGSKKSPEG

LISRTGSSSLPGRPSVIPDHSK

KNIGNGIISSPLTGKRQDSGTM

KKPHTTEEIGVPISRNGSTLGL

KSQNGCIPPKLPSGSPSPKLSQ

TPTHMPTILDDPGKKVKKPAPP

QHFSPRTAQGLPGTSNSNSSRS

GSQRQGSWDSRDVVLSTSPKLL

ATATANGHGLKGND

ESAGLDRRGSSSSSPEHSASSD

STKAPQTPRSGAAHLCDSQETN

CSTAGHSKTPPSGADSKTVKLK

SPVLSNTTTEPASTMSPPPAKK

LALSAKKASTLWRATGNDLRPP

PPSPSSDLTHPMKTSHPVVAST

WPVHRARAVSPAPQSSSRLQPP

FSPHPTLLSSTPKPPGTSEPRS

CSSISTALPQVNEDLVSLPHQL

PEASEPPQSPSEKRKKTEVGEP

QRLGSETRLPQHIREATAAPHG

KRKRKKKKRPEDTAASALQEGQ

TQRQPGSPMYRREGQAQLPAVR

RQEDGTQPQVNGQQ

VGCVTDGHHASSRKRRRKGAEG

LGEEGGLHQDPLRHSCSPMGDG

DPEAMEESPRKKKKKKRKQETQ

RAVEEDGHLKCPRSAKPQDAVV

PESSSCAPSANGWCPGDRMGLS

QAPPVSWNGERESDVVQELLKY

SSDKAYGRKVLTWDGKMSAVSQ

DAIEDSRQARTETVVDDWDEEF

DRGKEKKIKKFKREKRRNFNAF

QKLQTRRNEWSVTHPAKAASLS

YRR

UBP44_HUMAN
45
MLAMDTCKHVGQLQLAQDHSSL
157
TPGVTGLRNLGNTCYMNSVL

Ubiquitin

NPQKWHCVDCNTTESIWACLSC

QVLSHLLIFRQCFLKLDLNQ

carboxyl-

SHVACGRYIEEHALKHFQESSH

WLAMTASEKTRSCKHPPVTD

terminal

PVALEVNEMYVFCYLCDDYVLN

TVVYQMNECQEKDTGFVCSR

hydrolase 44

DNTTGDLKLLRRTLSAIKSQNY

QSSLSSGLSGGASKGRKMEL

HCTTRSGRFLRSMGTGDDSYFL

IQPKEPTSQYISLCHELHTL

HDGAQSLLQSEDQLYTALWHRR

FQVMWSGKWALVSPFAMLHS

RILMGKIFRTWFEQSPIGRKKQ

VWRLIPAFRGYAQQDAQEFL

EEPFQEKIVVKREVKKRRQELE

CELLDKIQRELETTGTSLPA

YQVKAELESMPPRKSLRLQGLA

LIPTSQRKLIKQVLNVVNNI

QSTIIEIVSVQVPAQTPASPAK

FHGQLLSQVTCLACDNKSNT

DKVLSTSENEISQKVSDSSVKR

IEPFWDLSLEFPERYQCSGK

RPIVTPGVTGLRNLGNTCYMNS

DIASQPCLVTEMLAKFTETE

VLQVLSHLLIFRQC

ALEGKIYVCDQCNSKRRRES

FLKLDLNQWLAMTASEKTRSCK

SKPVVLTEAQKQLMICHLPQ

HPPVTDTVVYQMNECQEKDTGF

VLRLHLKRFRWSGRNNREKI

VCSRQSSLSSGLSGGASKGRKM

GVHVGFEEILNMEPYCCRET

ELIQPKEPTSQYISLCHELHTL

LKSLRPECFIYDLSAVVMHH

FQVMWSGKWALVSPFAMLHSVW

GKGFGSGHYTAYCYNSEGGE

RLIPAFRGYAQQDAQEFLCELL

WVHCNDSKLSMCTMDEVCKA

DKIQRELETTGTSLPALIPTSQ

QAYILFYTQRV

RKLIKQVLNVVNNIFHGQLLSQ

VTCLACDNKSNTIEPFWDLSLE

FPERYQCSGKDIASQPCLVTEM

LAKFTETEALEGKIYVCDQCNS

KRRRFSSKPVVLTEAQKQLMIC

HLPQVLRLHLKRFRWSGRNNRE

KIGVHVGFEEILNM

EPYCCRETLKSLRPECFIYDLS

AVVMHHGKGFGSGHYTAYCYNS

EGGFWVHCNDSKLSMCTMDEVC

KAQAYILFYTQRVTENGHSKLL

PPELLLGSQHPNEDADTSSNEI

LS

UBP8_HUMAN
46
MPAVASVPKELYLSSSLKDLNK
158
PALTGLRNLGNTCYMNSILQ

Ubiquitin

KTEVKPEKISTKSYVHSALKIF

CLCNAPHLADYENRNCYQDD

carboxyl-

KTAEECRLDRDEERAYVLYMKY

INRSNLLGHKGEVAEEFGII

terminal

VTVYNLIKKRPDFKQQQDYFHS

MKALWTGQYRYISPKDFKIT

hydrolase 8

ILGPGNIKKAVEEAERLSESLK

IGKINDQFAGYSQQDSQELL

LRYEEAEVRKKLEEKDRQEEAQ

LFLMDGLHEDLNKADNRKRY

RLQQKRQETGREDGGTLAKGSL

KEENNDHLDDFKAAEHAWQK

ENVLDSKDKTQKSNGEKNEKCE

HKQLNESIIVALFQGQFKST

TKEKGAITAKELYTMMTDKNIS

VQCLTCHKKSRTFEAFMYLS

LIIMDARRMQDYQDSCILHSLS

LPLASTSKCTLQDCLRLESK

VPEEAISPGVTASWIEAHLPDD

EEKLTDNNRFYCSHCRARRD

SKDTWKKRGNVEYVVLLDWESS

SLKKIEIWKLPPVLLVHLKR

AKDLQIGTTLRSLKDALFKWES

FSYDGRWKQKLQTSVDEPLE

KTVLRNEPLVLEGG

NLDLSQYVIGPKNNLKKYNL

YENWLLCYPQYTTNAKVTPPPR

FSVSNHYGGLDGGHYTAYCK

RQNEEVSISLDFTYPSLEESIP

NAARQRWFKEDDHEVSDISV

SKPAAQTPPASIEVDENIELIS

SSVKSSAAYILFYTSLG

GQNERMGPLNISTPVEPVAASK

SDVSPIIQPVPSIKNVPQIDRT

KKPAVKLPEEHRIKSESTNHEQ

QSPQSGKVIPDRSTKPVVESPT

LMLTDEEKARIHAETALLMEKN

KQEKELRERQQEEQKEKLRKEE

QEQKAKKKQEAEENEITEKQQK

AKEEMEKKESEQAKKEDKETSA

KRGKEITGVKRQSKSEHETSDA

KKSVEDRGKRCPTPEIQKKSTG

DVPHTSVTGDSGSG

KPFKIKGQPESGILRTGTFRED

TDDTERNKAQREPLTRARSEEM

GRIVPGLPSGWAKFLDPITGTF

RYYHSPTNTVHMYPPEMAPSSA

PPSTPPTHKAKPQIPAERDREP

SKLKRSYSSPDITQAIQEEEKR

KPTVTPTVNRENKPTCYPKAEI

SRLSASQIRNLNPVFGGSGPAL

TGLRNLGNTCYMNSILQCLCNA

PHLADYFNRNCYQDDINRSNLL

GHKGEVAEEFGIIMKALWTGQY

RYISPKDFKITIGKINDQFAGY

SQQDSQELLLFLMDGLHEDLNK

ADNRKRYKEENNDH

LDDFKAAEHAWQKHKQLNESII

VALFQGQFKSTVQCLTCHKKSR

TFEAFMYLSLPLASTSKCTLQD

CLRLFSKEEKLTDNNRFYCSHC

RARRDSLKKIEIWKLPPVLLVH

LKRFSYDGRWKQKLQTSVDFPL

ENLDLSQYVIGPKNNLKKYNLF

SVSNHYGGLDGGHYTAYCKNAA

RQRWFKEDDHEVSDISVSSVKS

SAAYILFYTSLGPRVTDVAT

UBP37_HUMAN
47
MSPLKIHGPIRIRSMQTGITKW
159
QQLQGFSNLGNTCYMNAILQ

Ubiquitin

KEGSFEIVEKENKVSLVVHYNT

SLFSLQSFANDLLKQGIPWK

carboxyl-

GGIPRIFQLSHNIKNVVLRPSG

KIPLNALIRRFAHLLVKKDI

terminal

AKQSRLMLTLQDNSFLSIDKVP

CNSETKKDLLKKVKNAISAT

hydrolase 37

SKDAEEMRLELDAVHQNRLPAA

AERESGYMQNDAHEFLSQCL

MKPSQGSGSFGAILGSRTSQKE

DQLKEDMEKLNKTWKTEPVS

TSRQLSYSDNQASAKRGSLETK

GEENSPDISATRAYTCPVIT

DDIPFRKVLGNPGRGSIKTVAG

NLEFEVQHSIICKACGEIIP

SGIARTIPSLTSTSTPLRSGLL

KREQFNDLSIDLPRRKKPLP

ENRTEKRKRMISTGSELNEDYP

PRSIQDSLDLFFRAEELEYS

KENDSSSNNKAMTDPSRKYLTS

CEKCGGKCALVRHKENRLPR

SREKQLSLKQSEENRTSGLLPL

VLILHLKRYSENVALSLNNK

QSSSFYGSRAGSKEHSSGGTNL

IGQQVIIPRYLTLSSHCTEN

DRTNVSSQTPSAKR

TKP

SLGFLPQPVPLSVKKLRCNQDY

PFTLGWSAHMAISRPLKASQ

TGWNKPRVPLSSHQQQQLQGES

MVNSCITSPSTPSKKFTEKS

NLGNTCYMNAILQSLFSLQSFA

KSSLALCLDSDSEDELKRSV

NDLLKQGIPWKKIPLNALIRRF

ALSQRLCEMLGNEQQQEDLE

AHLLVKKDICNSETKKDLLKKV

KDSKLCPIEPDKSELENSGF

KNAISATAERFSGYMQNDAHEF

DRMSEEELLAAVLEISKRDA

LSQCLDQLKEDMEKLNKTWKTE

SPSLSHEDDDKPTSSPDTGF

PVSGEENSPDISATRAYTCPVI

AEDDIQEMPENPDTMETEKP

TNLEFEVQHSIICKACGEIIPK

KTITELDPASFTEITKDCDE

REQENDLSIDLPRRKKPLPPRS

NKENKTPEGSQGEVDWLQQY

IQDSLDLFFRAEELEYSCEKCG

DMEREREEQELQQALAQSLQ

GKCALVRHKENRLPRVLILHLK

EQEAWEQKEDDDLKRATELS

RYSENVALSLNNKIGQQVIIPR

LQEFNNSFVDALGSDEDSGN

YLTLSSHCTENTKP

EDVEDMEYTEAEAEELKRNA

PFTLGWSAHMAISRPLKASQMV

ETGNLPHSYRLISVVSHIGS

NSCITSPSTPSKKFTFKSKSSL

TSSSGHYISDVYDIKKQAWF

ALCLDSDSEDELKRSVALSQRL

TYNDLEVSKIQEAAVQSDRD

CEMLGNEQQQEDLEKDSKLCPI

RSGYIFFYMHK

EPDKSELENSGEDRMSEEELLA

AVLEISKRDASPSLSHEDDDKP

TSSPDTGFAEDDIQEMPENPDT

METEKPKTITELDPASFTEITK

DCDENKENKTPEGSQGEVDWLQ

QYDMEREREEQELQQALAQSLQ

EQEAWEQKEDDDLKRATELSLQ

EFNNSFVDALGSDEDSGNEDVE

DMEYTEAEAEELKRNAETGNLP

HSYRLISVVSHIGS

TSSSGHYISDVYDIKKQAWFTY

NDLEVSKIQEAAVQSDRDRSGY

IFFYMHKEIFDELLETEKNSQS

LSTEVGKTTRQAL

U17LD_HUMAN
48
MEEDSLYLGGEWQFNHESKLTS
160
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRLDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLVPEARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 13

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHPSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHPSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQQNTGPLVYVLYAV

ASITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTAASITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDRWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSSTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

U17L3_HUMAN
49
MGDDSLYLGGEWQFNHESKLTS
161
AVGAGLQNMGNTCYENASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTLPLANYMLSREHSQT

carboxyl-

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALASGFHRG

hydrolase 17-

CYENASLQCLTYTLPLANYMLS

KQEDVHEFLMFTVDAMKKAC

like protein 3

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TWALHSPGHVIQPSQALASGEH

FGGCWRSQIKCLHCHGISDT

RGKQEDVHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTEDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVAGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHDGHYF

AGNKLAKNVQYPEC

SYVKAQEGQWYKMDDAEVTV

LDMQPYMSQQNTGPLVYVLYAV

CSITSVLSQQAYVLFYIQKS

LVHAGWSCHDGHYFSYVKAQEG

QWYKMDDAEVTVCSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRAKQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVGK

VEGTLPPNALVIHQSKYKCGMK

NHHPEQQSSLLNLSSTTRTDQE

SMNTGTLASLQGRTRRAKGKNK

HSKRALLVCQ

UBP54_HUMAN
50
MSWKRNYFSGGRGSVQGMFAPR
162
APSKGLSNEPGQNSCFLNSA

Inactive

SSTSIAPSKGLSNEPGQNSCEL

LQVLWHLDIFRRSFRQLTTH

ubiquitin

NSALQVLWHLDIFRRSFRQLTT

KCMGDSCIFCALKGIFNQFQ

carboxyl-

HKCMGDSCIFCALKGIFNQFQC

CSSEKVLPSDTLRSALAKTE

terminal

SSEKVLPSDTLRSALAKTFQDE

QDEQRFQLGIMDDAAECFEN

hydrolase 54

QRFQLGIMDDAAECFENLLMRI

LLMRIHFHIADETKEDICTA

HFHIADETKEDICTAQHCISHQ

QHCISHQKFAMTLFEQCVCT

KFAMTLFEQCVCTSCGATSDPL

SCGATSDPLPFIQ

PFIQMVHYISTTSLCNQAICML

MVHYISTTSLCNQAICMLER

ERREKPSPSMFGELLQNASTMG

REKPSPSMFGELLQNASTMG

DLRNCPSNCGERIRIRRVLMNA

DLRNCPSNCGERIRIRRVLM

PQIITIGLVWDSDHSDLAEDVI

NAPQIITIGLVWDSDHSDLA

HSLGTCLKLGDLFFRVTDDRAK

EDVIHSLGTCLKLGDLFFRV

QSELYLVGMICYYG

TDDRAKQSELYLVGMICYYG

KHYSTFFFQTKIRKWMYEDDAH

KHYSTFFFQTKIRKWMYFDD

VKEIGPKWKDVVTKCIKGHYQP

AHVKEIGPKWKDVVTKCIKG

LLLLYADPQGTPVSTQDLPPQA

HYQPLLLLYADPQGTPVSTQ

EFQSYSRTCYDSEDSGREPSIS

DLPPQAEFQSYSRTCYDSED

SDTRTDSSTESYPYKHSHHESV

SGREPSISSDTRTDSSTESY

VSHFSSDSQGTVIYNVENDSMS

PYKHSHHESVVSHESSDSQG

QSSRDTGHLTDSECNQKHTSKK

TVIYNVEND

GSLIERKRSSGRVRRKGDEPQA

SGYHSEGETLKEKQAPRNASKP

SSSTNRLRDFKETVSNMIHNRP

SLASQTNVGSHCRGRGGDQPDK

KPPRTLPLHSRDWEIESTSSES

KSSSSSKYRPTWRPKRESLNID

SIFSKDKRKHCGYT

QLSPFSEDSAKEFIPDEPSKPP

SYDIKFGGPSPQYKRWGPARPG

SHLLEQHPRLIQRMESGYESSE

RNSSSPVSLDAALPESSNVYRD

PSAKRSAGLVPSWRHIPKSHSS

SILEVDSTASMGGWTKSQPFSG

EEISSKSELDELQEEVARRAQE

QELRRKREKELEAAKGENPHPS

RFMDLDELQNQGRSDGFERSLQ

EAESVFEESLHLEQKGDCAAAL

ALCNEAISKLRLALHGASCSTH

SRALVDKKLQISIRKARSLQDR

MQQQQSPQQPSQPSACLPTQAG

TLSQPTSEQPIPLQ

VLLSQEAQLESGMDTEFGASSE

FHSPASCHESHSSLSPESSAPQ

HSSPSRSALKLLTSVEVDNIEP

SAFHRQGLPKAPGWTEKNSHHS

WEPLDAPEGKLQGSRCDNSSCS

KLPPQEGRGIAQEQLFQEKKDP

ANPSPVMPGIATSERGDEHSLG

CSPSNSSAQPSLPLYRTCHPIM

PVASSFVLHCPDPVQKTNQCLQ

GQSLKTSLTLKVDRGSEETYRP

EFPSTKGLVRSLAEQFQRMQGV

SMRDSTGFKDRSLSGSLRKNSS

PSDSKPPFSQGQEKGHWPWAKQ

QSSLEGGDRPLSWE

ESTEHSSLALNSGLPNGETSSG

GQPRLAEPDIYQEKLSQVRDVR

SKDLGSSTDLGTSLPLDSWVNI

TRFCDSQLKHGAPRPGMKSSPH

DSHTCVTYPERNHILLHPHWNQ

DTEQETSELESLYQASLQASQA

GCSGWGQQDTAWHPLSQTGSAD

GMGRRLHSAHDPGLSKTSTAEM

EHGLHEARTVRTSQATPCRGLS

RECGEDEQYSAENLRRISRSLS

GTVVSEREEAPVSSHSFDSSNV

RKPLETGHRCSSSSSLPVIHDP

SVELLGPQLYLPQPQFLSPDVL

MPTMAGEPNRLPGT

SRSVQQFLAMCDRGETSQGAKY

TGRTLNYQSLPHRSRTDNSWAP

WSETNQHIGTRFLTTPGCNPQL

TYTATLPERSKGLQVPHTQSWS

DLFHSPSHPPIVHPVYPPSSSL

HVPLRSAWNSDPVPGSRTPGPR

RVDMPPDDDWRQSSYASHSGHR

RTVGEGFLFVLSDAPRREQIRA

RVLQHSQW

SNUT2_HUMAN
51
MSGRSKRESRGSTRGKRESESR
163
LPGIVGLNNIKANDYANAVL

U4/U6.U5

GSSGRVKRERDREREPEAASSR

QALSNVPPLRNYFLEEDNYK

tri-snRNP-

GSPVRVKREFEPASAREAPASV

NIKRPPGDIMELLVQREGEL

associated

VPFVRVKREREVDEDSEPEREV

MRKLWNPRNFKAHVSPHEML

protein 2

RAKNGRVDSEDRRSRHCPYLDT

QAVVLCSKKTFQITKQGDGV

INRSVLDEDFEKLCSISLSHIN

DFLSWFLNALHSALGGTKKK

AYACLVCGKYFQGRGLKSHAYI

KKTIVTDVFQGSMRIFTKKL

HSVQFSHHVELNLHTLKFYCLP

PHPDLPAEEKEQLLHNDEYQ

DNYEIIDSSLEDITYVLKPTFT

ETMVESTFMYLTLDLPTAPL

KQQIANLDKQAKLSRAYDGTTY

YKDEKEQLIIPQVPLENILA

LPGIVGLNNIKANDYANAVLQA

KFNGITEKEYKTYKENFLKR

LSNVPPLRNYFLEEDNYKNIKR

FQLTKLPPYLIFCIKRFTKN

PPGDIMFLLVQRFGELMRKLWN

NFFVEKNPTIVNFPITNVDL

PRNFKAHVSPHEML

REYLSEEVQAVHKNTTYDLI

QAVVLCSKKTFQITKQGDGVDE

ANIVHDGKPSEGSYRIHVLH

LSWFLNALHSALGGTKKKKKTI

HGTGKWYELQDLQVTDILPQ

VTDVFQGSMRIFTKKLPHPDLP

MITLSEAYIQIWKRRD

AEEKEQLLHNDEYQETMVESTE

MYLTLDLPTAPLYKDEKEQLII

PQVPLENILAKENGITEKEYKT

YKENFLKRFQLTKLPPYLIFCI

KRFTKNNFFVEKNPTIVNFPIT

NVDLREYLSEEVQAVHKNTTYD

LIANIVHDGKPSEGSYRIHVLH

HGTGKWYELQDLQVTDILPQMI

TLSEAYIQIWKRRDNDETNQQG

A

UBP35_HUMAN
52
MDKILEAVVTSSYPVSVKQGLV
164
SDTGKIGLINLGNTCYVNSI

Ubiquitin

RRVLEAARQPLEREQCLALLAL

LQALFMASDERHCVLRLTEN

carboxyl-

GARLYVGGAEELPRRVGCQLLH

NSQPLMTKLQWLFGFLEHSQ

terminal

VAGRHHPDVFAEFFSARRVLRL

RPAISPENELSASWTPWESP

hydrolase 35

LQGGAGPPGPRALACVQLGLQL

GTQQDCSEYLKYLLDRLHEE

LPEGPAADEVFALLRREVLRTV

EKTGTRICQKLKQSSSPSPP

CERPGPAACAQVARLLARHPRC

EEPPAPSSTSVEKMFGGKIV

VPDGPHRLLFCQQLVRCLGRER

TRICCLCCLNVSSREEAFTD

CPAEGEEGAVEFLEQAQQVSGL

LSLAFPPPERCRRRRLGSVM

LAQLWRAQPAAILPCLKELFAV

RPTEDITARELPPPTSAQGP

ISCAEEEPPSSALASVVQHLPL

GRVGPRRQRKHCITEDTPPT

ELMDGVVRNLSNDDSVTDSQML

SLYIEGLDSKEAGGQSSQEE

TAISRMIDWVSWPLGKNIDKWI

RIEREEEGKEERTEKEEVGE

IALLKGLAAVKKES

EEESTRGEGEREKEEEVEEE

ILIEVSLTKIEKVESKLLYPIV

EEKVE

RGAALSVLKYMLLTFQHSHEAF

KETEKEAEQEKEEDSLGAGT

HLLLPHIPPMVASLVKEDSNSG

HPDAAIPSGERTCGSEGSRS

TSCLEQLAELVHCMVFRFPGEP

VLDLVNYFLSPEKLTAENRY

DLYEPVMEAIKDLHVPNEDRIK

YCESCASLQDAEKVVELSQG

QLLGQDAWTSQKSELAGFYPRL

PCYLILTLLRESFDLRTMRR

MAKSDTGKIGLINLGNTCYVNS

RKILDDVSIPLLLRLPLAGG

ILQALFMASDERHCVLRLTENN

RGQAYDLCSVVVHSGVSSES

SQPLMTKLQWLFGFLEHSQRPA

GHYYCYAREGAARPAASLGT

ISPENFLSASWTPWFSPGTQQD

ADRPEPENQWYLENDTRVSF

CSEYLKYLLDRLHEEEKTGTRI

SSFESVSNVTSFFPKDTAYV

CQKLKQSSSPSPPEEPPAPSST

LFYRQRP

SVEKMEGGKIVTRICCLCCLNV

SSREEAFTDLSLAF

PPPERCRRRRLGSVMRPTEDIT

ARELPPPTSAQGPGRVGPRRQR

KHCITEDTPPTSLYIEGLDSKE

AGGQSSQEERIEREEEGKEERT

EKEEVGEEEESTRGEGEREKEE

EVEEEEEKVEKETEKEAEQEKE

EDSLGAGTHPDAAIPSGERTCG

SEGSRSVLDLVNYFLSPEKLTA

ENRYYCESCASLQDAEKVVELS

QGPCYLILTLLRFSEDLRTMRR

RKILDDVSIPLLLRLPLAGGRG

QAYDLCSVVVHSGVSSESGHYY

CYAREGAARPAASLGTADRPEP

ENQWYLENDTRVSE

SSFESVSNVTSFFPKDTAYVLE

YRQRPREGPEAELGSSRVRTEP

TLHKDLMEAISKDNILYLQEQE

KEARSRAAYISALPTSPHWGRG

FDEDKDEDEGSPGGCNPAGGNG

GDFHRLVE

UBP15_HUMAN
53
MAEGGAADLDTQRSDIATLLKT
165
EQPGLCGLSNLGNTCFMNSA

Ubiquitin

SLRKGDTWYLVDSRWFKQWKKY

IQCLSNTPPLTEYFLNDKYQ

carboxyl-

VGFDSWDKYQMGDQNVYPGPID

EELNFDNPLGMRGEIAKSYA

terminal

NSGLLKDGDAQSLKEHLIDELD

ELIKQMWSGKFSYVTPRAFK

hydrolase 15

YILLPTEGWNKLVSWYTLMEGQ

TQVGRFAPQFSGYQQQDCQE

EPIARKVVEQGMFVKHCKVEVY

LLAFLLDGLHEDLNRIRKKP

LTELKLCENGNMNNVVTRRESK

YIQLKDADGRPDKVVAEEAW

ADTIDTIEKEIRKIFSIPDEKE

ENHLKRNDSIIVDIFHGLFK

TRLWNKYMSNTFEPLNKPDSTI

STLVCPECAKISVTEDPFCY

QDAGLYQGQVLVIEQKNEDGTW

LTLPLPMKKERTLEVYLVRM

PRGPSTPKSPGASNESTLPKIS

DPLTKPMQYKVVVPKIGNIL

PSSLSNNYNNMNNRNVKNSNYC

DLCTALSALSGIPADKMIVT

LPSYTAYKNYDYSEPGRNNEQP

DIYNHRFHRIFAMDENLSSI

GLCGLSNLGNTCEM

MERDDIYVFEININRTEDTE

NSAIQCLSNTPPLTEYFLNDKY

HVIIPVCLREKFRHSSYTHH

QEELNFDNPLGMRGEIAKSYAE

TGSSLFGQPFLMAVPRNNTE

LIKQMWSGKFSYVTPRAFKTQV

DKLYNLLLLRMCRYVKISTE

GRFAPQFSGYQQQDCQELLAFL

TEETEGSLHCCKDQNINGNG

LDGLHEDLNRIRKKPYIQLKDA

PNGIHEEGSPSEMETDEPDD

DGRPDKVVAEEAWENHLKRNDS

ESSQDQELPSENENSQSEDS

IIVDIFHGLFKSTLVCPECAKI

VGGDNDSENGLCTEDTCKGQ

SVTFDPFCYLTLPLPMKKERTL

LTGHKKRLFTFQFNNLGNTD

EVYLVRMDPLTKPMQYKVVVPK

INYIKDDTRHIREDDRQLRL

IGNILDLCTALSALSGIPADKM

DERSFLALDWDPDLKKRYED

IVTDIYNHRFHRIFAMDENLSS

ENAAEDFEKHESVEYKPPKK

IMERDDIYVFEININRTEDTEH

PFVKLKDCIELFTTKEKLGA

VIIPVCLREKFRHSSYTHHTGS

EDPWYCPNCKEHQQATKKLD

SLFGQPFLMAVPRN

LWSLPPVLVVHLKRESYSRY

NTEDKLYNLLLLRMCRYVKIST

MRDKLDTLVDFPINDLDMSE

ETEETEGSLHCCKDQNINGNGP

FLINPNAGPCRYNLIAVSNH

NGIHEEGSPSEMETDEPDDESS

YGGMGGGHYTAFAKNKDDGK

QDQELPSENENSQSEDSVGGDN

WYYFDDSSVSTASEDQIVSK

DSENGLCTEDTCKGQLTGHKKR

AAYVLFYQRQD

LFTFQENNLGNTDINYIKDDTR

HIREDDRQLRLDERSFLALDWD

PDLKKRYFDENAAEDFEKHESV

EYKPPKKPFVKLKDCIELFTTK

EKLGAEDPWYCPNCKEHQQATK

KLDLWSLPPVLVVHLKRESYSR

YMRDKLDTLVDFPINDLDMSEF

LINPNAGPCRYNLIAVSNHYGG

MGGGHYTAFAKNKD

DGKWYYFDDSSVSTASEDQIVS

KAAYVLFYQRQDTESGTGFFPL

DRETKGASAATGIPLESDEDSN

DNDNDIENENCMHTN

UBP29_HUMAN
54
MISLKVCGFIQIWSQKTGMTKL
166
QLQQGFPNLGNTCYMNAVLQ

Ubiquitin

KEALIETVQRQKEIKLVVTEKS

SLFAIPSFADDLLTQGVPWE

carboxyl-

GKFIRIFQLSNNIRSVVLRHCK

YIPFEALIMTLTQLLALKDE

terminal

KRQSHLRLTLKNNVELFIDKLS

CSTKIKRELLGNVKKVISAV

hydrolase 29

YRDAKQLNMELDIIHQNKSQQP

AEIFSGNMQNDAHEFLGQCL

MKSDDDWSVFESRNMLKEIDKT

DQLKEDMEKLNATLNTGKEC

SFYSICNKPSYQKMPLFMSKSP

GDENSSPQMHVGSAATKVEV

THVKKGILENQGGKGQNTLSSD

CPVVANFEFELQLSLICKAC

VQTNEDILKEDNPVPNKKYKTD

GHAVLKVEPNNYLSINLHQE

SLKYIQSNRKNPSSLEDLEKDR

TKPLPLSIQNSLDLFFKEEE

DLKLGPSENTNCNGNPNLDETV

LEYNCQMCKQKSCVARHTES

LATQTLNAKNGLTSPLEPEHSQ

RLSRVLIIHLKRYSENNAWL

GDPRCNKAQVPLDSHSQQLQQG

LVKNNEQVYIPKSLSLSSYC

FPNLGNTCYMNAVL

NESTKPPLPLSSSAPVGKCE

QSLFAIPSFADDLLTQGVPWEY

VLEVSQEMISEINSPLTPSM

IPFEALIMTLTQLLALKDFCST

KLTSESSDSLVLPVEPDKNA

KIKRELLGNVKKVISAVAEIFS

DLQRFQRDCGDASQEQHQRD

GNMQNDAHEFLGQCLDQLKEDM

LENGSALESELVHERDRAIG

EKLNATLNTGKECGDENSSPQM

EKELPVADSLMDQGDISLPV

HVGSAATKVFVCPVVANFEFEL

MYEDGGKLISSPDTRLVEVH

QLSLICKACGHAVLKVEPNNYL

LQEVPQHPELQKYEKTNTFV

SINLHQETKPLPLSIQNSLDLE

EFNFDSVTESTNGFYDCKEN

FKEEELEYNCQMCKQKSCVARH

RIPEGSQGMAEQLQQCIEES

TFSRLSRVLIIHLKRYSENNAW

IIDEFLQQAPPPGVRKLDAQ

LLVKNNEQVYIPKSLSLSSYCN

EHTEETLNQSTELRLQKADL

ESTKPPLPLSSSAPVGKCEVLE

NHLGALGSDNPGNKNILDAE

VSQEMISEINSPLTPSMKLTSE

NTRGEAKELTRNVKMGDPLQ

SSDSLVLPVEPDKN

AYRLISVVSHIGSSPNSGHY

ADLQRFQRDCGDASQEQHQRDL

ISDVYDFQKQAWFTYNDLCV

ENGSALESELVHERDRAIGEKE

SEISETKMQEARLHSGYIFF

LPVADSLMDQGDISLPVMYEDG

YMHN

GKLISSPDTRLVEVHLQEVPQH

PELQKYEKTNTFVEFNEDSVTE

STNGFYDCKENRIPEGSQGMAE

QLQQCIEESIIDEFLQQAPPPG

VRKLDAQEHTEETLNQSTELRL

QKADLNHLGALGSDNPGNKNIL

DAENTRGEAKELTRNVKMGDPL

QAYRLISVVSHIGSSPNSGHYI

SDVYDFQKQAWFTYNDLCVSEI

SETKMQEARLHSGYIFFYMHNG

IFEELLRKAENSRLPSTQAGVI

PQGEYEGDSLYRPA

UBP6_HUMAN
55
MDMVENADSLQAQERKDILMKY
167
KGATGLSNLGNTCEMNSSIQ

Ubiquitin

DKGHRAGLPEDKGPEPVGINSS

CVSNTQPLTQYFISGRHLYE

carboxyl-

IDRFGILHETELPPVTAREAKK

LNRTNPIGMKGHMAKCYGDL

terminal

IRREMTRTSKWMEMLGEWETYK

VQELWSGTQKSVAPLKLRRT

hydrolase 6

HSSKLIDRVYKGIPMNIRGPVW

IAKYAPKFDGFQQQDSQELL

SVLLNIQEIKLKNPGRYQIMKE

AFLLDGLHEDLNRVHEKPYV

RGKRSSEHIHHIDLDVRTTLRN

ELKDSDGRPDWE

HVFFRDRYGAKQRELFYILLAY

VAAEAWDNHLRRNRSIIVDL

SEYNPEVGYCRDLSHITALFLL

FHGQLRSQVKCKTCGHISVR

YLPEEDAFWALVQLLASERHSL

FDPNFLSLPLPMDSYMDLEI

PGFHSPNGGTVQGLQDQQEHVV

TVIKLDGTTPVRYGLRLNMD

PKSQPKTMWHQDKEGLCGQCAS

EKYTGLKKQLRDLCGLNSEQ

LGCLLRNLIDGISLGLTLRLWD

ILLAEVHDSNIKNFPQDNQK

VYLVEGEQVLMPIT

VQLSVSGELCAFEIPVPSSP

SIALKVQQKRLMKTSRCGLWAR

ISASSPTQIDESSSPSTNGM

LRNQFFDTWAMNDDTVLKHLRA

FTLTTNGDLPKPIFIPNGMP

STKKLTRKQGDLPPPAKREQGS

NTVVPCGTEKNFTNGMVNGH

LAPRPVPASRGGKTLCKGYRQA

MPSLPDSPFTGYIIAVHRKM

PPGPPAQFQRPICSASPPWASR

MRTELYFLSPQENRPSLFGM

FSTPCPGGAVREDTYPVGTQGV

PLIVPCTVHTRKKDLYDAVW

PSLALAQGGPQGSWRFLEWKSM

IQVSWLARPLPPQEASIHAQ

PRLPTDLDIGGPWFPHYDFEWS

DRDNCMGYQYPFTLRVVQKD

CWVRAISQEDQLATCWQAEHCG

GNSCAWCPQYRFCRGCKIDC

EVHNKDMSWPEEMSFTANSSKI

GEDRAFIGNAYIAVDWHPTA

DRQKVPTEKGATGLSNLGNTCF

LHLRYQTSQERVVDKHESVE

MNSSIQCVSNTQPLTQYFISGR

QSRRAQAEPINLDSCLRAFT

HLYELNRTNPIGMKGHMAKCYG

SEEELGESEMYYCSKCKTHC

DLVQELWSGTQKSV

LATKKLDLWRLPPFLIIHLK

APLKLRRTIAKYAPKEDGFQQQ

RFQFVNDQWIKSQKIVRFLR

DSQELLAFLLDGLHEDLNRVHE

ESFDPSAFLVPRDPALCQHK

KPYVELKDSDGRPDWEVAAEAW

PLTPQGDELSKPRILAREVK

DNHLRRNRSIIVDLFHGQLRSQ

KVDAQSSAGKEDMLLSKSPS

VKCKTCGHISVREDPENELSLP

SLSANISSSPKGSPSSSRKS

LPMDSYMDLEITVIKLDGTTPV

GTSCPSSKNSSPNSSPRTLG

RYGLRLNMDEKYTGLKKQLRDL

RSKGRLRLPQIGSKNKPSSS

CGLNSEQILLAEVHDSNIKNFP

KKNLDASKENGAGQICELAD

QDNQKVQLSVSGFLCAFEIPVP

ALSRGHMRGGSQPELVTPQD

SSPISASSPTQIDFSSSPSTNG

HEVALANGFLYEHEACGNGC

MFTLTTNGDLPKPIFIPNGMPN

GDGYSNGQLGNHSEEDSTDD

TVVPCGTEKNFTNGMVNGHMPS

QREDTHIKPIYNLYAISCHS

LPDSPFTGYIIAVHRKMMRTEL

GILSGGHYITYAKNPNCKWY

YFLSPQENRPSLFG

CYNDSSCEELHPDEIDTDSA

MPLIVPCTVHTRKKDLYDAVWI

YILFYEQQG

QVSWLARPLPPQEASIHAQDRD

NCMGYQYPFTLRVVQKDGNSCA

WCPQYRFCRGCKIDCGEDRAFI

GNAYIAVDWHPTALHLRYQTSQ

ERVVDKHESVEQSRRAQAEPIN

LDSCLRAFTSEEELGESEMYYC

SKCKTHCLATKKLDLWRLPPEL

IIHLKRFQFVNDQWIKSQKIVR

FLRESFDPSAFLVPRDPALCQH

KPLTPQGDELSKPRILAREVKK

VDAQSSAGKEDMLLSKSPSSLS

ANISSSPKGSPSSSRKSGTSCP

SSKNSSPNSSPRTL

GRSKGRLRLPQIGSKNKPSSSK

KNLDASKENGAGQICELADALS

RGHMRGGSQPELVTPQDHEVAL

ANGFLYEHEACGNGCGDGYSNG

QLGNHSEEDSTDDQREDTHIKP

IYNLYAISCHSGILSGGHYITY

AKNPNCKWYCYNDSSCEELHPD

EIDTDSAYILFYEQQGIDYAQF

LPKIDGKKMADTSSTDEDSESD

YEKYSMLQ

UBP53_HUMAN
56
MAWVKFLRKPGGNLGKVYQPGS
168
APTKGLLNEPGQNSCFLNSA

Inactive

MLSLAPTKGLLNEPGQNSCFLN

VQVLWQLDIFRRSLRVLTGH

ubiquitin

SAVQVLWQLDIFRRSLRVLTGH

VCQGDACIFCALKTIFAQFQ

carboxyl-

VCQGDACIFCALKTIFAQFQHS

HSREKALPSDNIRHALAESF

terminal

REKALPSDNIRHALAESFKDEQ

KDEQRFQLGLMDDAAECFEN

hydrolase 53

RFQLGLMDDAAECFENMLERIH

MLERIHFHIVPSRDADMCTS

FHIVPSRDADMCTSKSCITHQK

KSCITHQKFAMTLYEQCVCR

FAMTLYEQCVCRSCGASSDPLP

SCGASSDPLPFTEFVRYIST

FTEFVRYISTTALCNEVERMLE

TALCNEVERMLERHERFKPE

RHERFKPEMFAELLQAANTTDD

MFAELLQAANTTDDYRKCPS

YRKCPSNCGQKIKIRRVLMNCP

NCGQKIKIRRVLMNCPEIVT

EIVTIGLVWDSEHSDLTEAVVR

IGLVWDSEHSDLTEAVVRNL

NLATHLYLPGLFYRVTDENAKN

ATHLYLPGLFYRVTDENAKN

SELNLVGMICYTSQ

SELNLVGMICYTSQHYCAFA

HYCAFAFHTKSSKWVFEDDANV

FHTKSSKWVFEDDANVKEIG

KEIGTRWKDVVSKCIRCHFQPL

TRWKDVVSKCIRCHFQPLLL

LLFYANPDGTAVSTEDALRQVI

FYANPDGTAVSTEDALRQVI

SWSHYKSVAENMGCEKPVIHKS

SWSHYKSVAENMGCEKPVIH

DNLKENGFGDQAKQRENQKEPT

KSDNLKENGFGDQAKQRENQ

DNISSSNRSHSHTGVGKGPAKL

KFPTDNISSSNRSHSHTGVG

SHIDQREKIKDISRECALKAIE

KGPAKLSHIDQREKIKDISR

QKNLLSSQRKDLEKGQRKDLGR

ECALKAIEQKNLLSSQRKDL

HRDLVDEDLSHFQSGSPPAPNG

EKGQRK

FKQHGNPHLYHSQGKGSYKHDR

VVPQSRASAQIISSSKSQILAP

GEKITGKVKSDNGTGYDTDSSQ

DSRDRGNSCDSSSKSRNRGWKP

MRETLNVDSIFSES

EKRQHSPRHKPNISNKPKSSKD

PSFSNWPKENPKQKGLMTIYED

EMKQEIGSRSSLESNGKGAEKN

KGLVEGKVHGDNWQMQRTESGY

ESSDHISNGSTNLDSPVIDGNG

TVMDISGVKETVCESDQITTSN

LNKERGDCTSLQSQHHLEGERK

ELRNLEAGYKSHEFHPESHLQI

KNHLIKRSHVHEDNGKLEPSSS

LQIPKDHNAREHIHQSDEQKLE

KPNECKESEWLNIENSERTGLP

FHVDNSASGKRVNSNEPSSLWS

SHLRTVGLKPETAPLIQQQNIM

DQCYFENSLSTECI

IRSASRSDGCQMPKLFCQNLPP

PLPPKKYAITSVPQSEKSESTP

DVKLTEVFKATSHLPKHSLSTA

SEPSLEVSTHMNDERHKETFQV

RECFGNTPNCPSSSSTNDEQAN

SGAIDAFCQPELDSISTCPNET

VSLTTYFSVDSCMTDTYRLKYH

QRPKLSFPESSGFCNNSLS

U17LO_HUMAN
57
MEDDSLYLRGEWQFNHESKLTS
169
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 24

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KTLTLHTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQPNTGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTASSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSSTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

U17LM_HUMAN

MEDDSLYLGGEWQFNHESKLTS

AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 22

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTEDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQQNTGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTASSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLKLSSTTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

UBP5_HUMAN
58
MAELSEEALLSVLPTIRVPKAG
170
FGPGYTGIRNLGNSCYLNSV

Ubiquitin

DRVHKDECAFSEDTPESEGGLY

VQVLESIPDFQRKYVDKLEK

carboxyl-

ICMNTFLGFGKQYVERHENKTG

IFQNAPTDPTQDESTQVAKL

terminal

QRVYLHLRRTRRPKEEDPATGT

GHGLLSGEYSKPVPESGDGE

hydrolase 5

GDPPRKKPTRLAIGVEGGEDLS

RVPEQKEVQDGIAPRMEKAL

EEKFELDEDVKIVILPDYLEIA

IGKGHPEFSTNRQQDAQEFF

RDGLGGLPDIVRDRVTSAVEAL

LHLINMVERNCRSSENPNEV

LSADSASRKQEVQAWDGEVRQV

FRFLVEEKIKCLATEKVKYT

SKHAFSLKQLDNPARIPPCGWK

QRVDYIMQLPVPMDAALNKE

CSKCDMRENLWLNLTDGSILCG

ELLEYEEKKRQAEEEKMALP

RRYFDGSGGNNHAVEHYRETGY

ELVRAQVPESSCLEAYGAPE

PLAVKLGTITPDGADVYSYDED

QVDDFWSTALQAKSVAVKTT

DMVLDPSLAEHLSHFGIDMLKM

RFASFPDYLVIQIKKFTFGL

QKTDKTMTELEIDM

DWVPKKLDVSIEMPEELDIS

NQRIGEWELIQESGVPLKPLFG

QLRGTGLQPGEEELPDIAPP

PGYTGIRNLGNSCYLNSVVQVL

LVTPDEPKGSLGFYGNEDED

FSIPDFQRKYVDKLEKIFQNAP

SFCSPHFSSPTSPMLDESVI

TDPTQDESTQVAKLGHGLLSGE

IQLVEMGFPMDACRKAVYYT

YSKPVPESGDGERVPEQKEVQD

GNSGAEAAMNWVMSHMDDPD

GIAPRMFKALIGKGHPEFSTNR

FANPLILPGSSGPGSTSAAA

QQDAQEFFLHLINMVERNCRSS

DPPPEDCVTTIVSMGFSRDQ

ENPNEVERELVEEKIKCLATEK

ALKALRATNNSLERAVDWIE

VKYTQRVDYIMQLPVPMDAALN

SHIDDLDAEAAMDISEGRSA

KEELLEYEEKKRQAEEEKMALP

ADSISESVPVGPKVRDGPGK

ELVRAQVPFSSCLEAYGAPEQV

YQLFAFISHMGTSTMCGHYV

DDFWSTALQAKSVAVKTTRFAS

CHIKKEGRWVIYNDQKVCAS

FPDYLVIQIKKFTFGLDWVPKK

EKPPKDLGYIYFYQRVA

LDVSIEMPEELDIS

QLRGTGLQPGEEELPDIAPPLV

TPDEPKGSLGFYGNEDEDSFCS

PHESSPTSPMLDESVIIQLVEM

GFPMDACRKAVYYTGNSGAEAA

MNWVMSHMDDPDFANPLILPGS

SGPGSTSAAADPPPEDCVTTIV

SMGFSRDQALKALRATNNSLER

AVDWIFSHIDDLDAEAAMDISE

GRSAADSISESVPVGPKVRDGP

GKYQLFAFISHMGTSTMCGHYV

CHIKKEGRWVIYNDQKVCASEK

PPKDLGYIYFYQRVAS

UBP25_HUMAN
59
MTVEQNVLQQSAAQKHQQTELN

KAPVGLKNVGNTCWFSAVIQ

Ubiquitin

QLREITGINDTQILQQALKDSN

SLENLLEFRRLVLNYKPPSN

carboxyl-

GNLELAVAFLTAKNAKTPQQEE

AQDLPRNQKEHRNLPEMREL

terminal

TTYYQTALPGNDRYISVGSQAD

RYLFALLVGTKRKYVDPSRA

hydrolase 25

TNVIDLTGDDKDDLQRAIALSL

VEILKDAFKSNDSQQQDVSE

AESNRAFRETGITDEEQAISRV

FTHKLLDWLEDAFQMKAEEE

LEASIAENKACLKRTPTEVWRD

TDEEKPKNPMVELFYGRFLA

SRNPYDRKRQDKAPVGLKNVGN

VGVLEGKKFENTEMFGQYPL

TCWFSAVIQSLENLLEFRRLVL

QVNGFKDLHECLEAAMIEGE

NYKPPSNAQDLPRNQKEHRNLP

IESLHSENSGKSGQEHWFTE

FMRELRYLFALLVGTKRKYVDP

LPPVLTFELSRFEFNQALGR

SRAVEILKDAFKSNDSQQQDVS

PEKIHNKLEFPQVLYLDRYM

EFTHKLLDWLEDAFQMKAEEET

HRNREITRIKREEIKRLKDY

DEEKPKNPMVELFY

LTVLQQRLERYLSYGSGPKR

GRFLAVGVLEGKKFENTEMEGQ

FPLVDVLQYALEFASSKPVC

YPLQVNGFKDLHECLEAAMIEG

TSPVDDIDASSPPSGSIPSQ

EIESLHSENSGKSGQEHWFTEL

TLPSTTEQQGALSSELPSTS

PPVLTFELSRFEFNQALGRPEK

PSSVAAISSRSVIHKPFTQS

IHNKLEFPQVLYLDRYMHRNRE

RIPPDLPMHPAPRHITEEEL

ITRIKREEIKRLKDYLTVLQQR

SVLESCLHRWRTEIENDTRD

LERYLSYGSGPKRFPLVDVLQY

LQESISRIHRTIELMYSDKS

ALEFASSKPVCTSPVDDIDASS

MIQVPYRLHAVLVHEGQANA

PPSGSIPSQTLPSTTEQQGALS

GHYWAYIFDHRESRWMKYND

SELPSTSPSSVAAISSRSVIHK

IAVTKSSWEELVRDSFGGYR

PFTQSRIPPDLPMHPAPRHITE

NAS

EELSVLESCLHRWRTEIENDTR

DLQESISRIHRTIELMYSDKSM

IQVPYRLHAVLVHE

GQANAGHYWAYIFDHRESRWMK

YNDIAVTKSSWEELVRDSFGGY

RNASAYCLMYINDKAQFLIQEE

FNKETGQPLVGIETLPPDLRDF

VEEDNQRFEKELEEWDAQLAQK

ALQEKLLASQKLRESETSVTTA

QAAGDPEYLEQPSRSDFSKHLK

EETIQIITKASHEHEDKSPETV

LQSAIKLEYARLVKLAQEDTPP

ETDYRLHHVVVYFIQNQAPKKI

IEKTLLEQFGDRNLSFDERCHN

IMKVAQAKLEMIKPEEVNLEEY

EEWHQDYRKERETTMYLIIGLE

NFQRESYIDSLLEL

ICAYQNNKELLSKGLYRGHDEE

LISHYRRECLLKLNEQAAELFE

SGEDREVNNGLIIMNEFIVPEL

PLLLVDEMEEKDILAVEDMRNR

WCSYLGQEMEPHLQEKLTDELP

KLLDCSMEIKSFHEPPKLPSYS

THELCERFARIMLSLSRTPADG

R

UBP33_HUMAN
60
MTGSNSHITILTLKVLPHFESL
171
ARGLTGLKNIGNTCYMNAAL

Ubiquitin

GKQEKIPNKMSAFRNHCPHLDS

QALSNCPPLTQFELDCGGLA

carboxyl-

VGEITKEDLIQKSLGTCQDCKV

RTDKKPAICKSYLKLMTELW

terminal

QGPNLWACLENRCSYVGCGESQ

HKSRPGSVVPTTLFQGIKTV

hydrolase 33

VDHSTIHSQETKHYLTVNLTTL

NPTFRGYSQQDAQEFLRCLM

RVWCYACSKEVELDRKLGTQPS

DLLHEELKEQVMEVEEDPQT

LPHVRQPHQIQENSVQDFKIPS

ITTEETMEEDKSQSDVDFQS

NTTLKTPLVAVEDDLDIEADEE

CESCSNSDRAENENGSRCFS

DELRARGLTGLKNIGNTCYMNA

EDNNETTMLIQDDENNSEMS

ALQALSNCPPLTQFELDCGGLA

KDWQKEKMCNKINKVNSEGE

RTDKKPAICKSYLKLMTELWHK

FDKDRDSISETVDLNNQETV

SRPGSVVPTTLFQGIKTVNPTF

KVQIHSRASEYITDVHSNDL

RGYSQQDAQEFLRCLMDLLHEE

STPQILPSNEGVNPRLSASP

LKEQVMEVEEDPQT

PKSGNLWPGLAPPHKKAQSA

ITTEETMEEDKSQSDVDFQSCE

SPKRKKQHKKYRSVISDIED

SCSNSDRAENENGSRCFSEDNN

GTIISSVQCLTCDRVSVTLE

ETTMLIQDDENNSEMSKDWQKE

TFQDLSLPIPGKEDLAKLHS

KMCNKINKVNSEGEFDKDRDSI

SSHPTSIVKAGSCGEAYAPQ

SETVDLNNQETVKVQIHSRASE

GWIAFFMEYVKRFVVSCVPS

YITDVHSNDLSTPQILPSNEGV

WFWGPVVTLQDCLAAFFARD

NPRLSASPPKSGNLWPGLAPPH

ELKGDNMYSCEKCKKLRNGV

KKAQSASPKRKKQHKKYRSVIS

KFCKVQNFPEILCIHLKRER

DIFDGTIISSVQCLTCDRVSVT

HELMESTKISTHVSFPLEGL

LETFQDLSLPIPGKEDLAKLHS

DLQPFLAKDSPAQIVTYDLL

SSHPTSIVKAGSCGEAYAPQGW

SVICHHGTASSGHYIAYCRN

IAFFMEYVKRFVVSCVPSWFWG

NLNNLWYEFDDQSVTEVSES

PVVTLQDCLAAFFARDELKGDN

TVQNAEAYVLFYRKSS

MYSCEKCKKLRNGV

KFCKVQNFPEILCIHLKRFRHE

LMFSTKISTHVSFPLEGLDLQP

FLAKDSPAQIVTYDLLSVICHH

GTASSGHYIAYCRNNLNNLWYE

FDDQSVTEVSESTVQNAEAYVL

FYRKSSEEAQKERRRISNLLNI

MEPSLLQFYISRQWLNKFKTFA

EPGPISNNDFLCIHGGVPPRKA

GYIEDLVLMLPQNIWDNLYSRY

GGGPAVNHLYICHTCQIEAEKI

EKRRKTELEIFIRLNRAFQKED

SPATFYCISMQWFREWESFVKG

KDGDPPGPIDNTKIAVTKCGNV

MLRQGADSGQISEETWNFLQSI

YGGGPEVILRPPVVHVDPDILQ

AEEKIEVETRSL

UBP21_HUMAN
61
MPQASEHRLGRTREPPVNIQPR
172
LGSGHVGLRNLGNTCFLNAV

Ubiquitin

VGSKLPFAPRARSKERRNPASG

LQCLSSTRPLRDFCLRRDER

carboxyl-

PNPMLRPLPPRPGLPDERLKKL

QEVPGGGRAQELTEAFADVI

terminal

ELGRGRTSGPRPRGPLRADHGV

GALWHPDSCEAVNPTRFRAV

hydrolase 21

PLPGSPPPTVALPLPSRTNLAR

FQKYVPSFSGYSQQDAQEFL

SKSVSSGDLRPMGIALGGHRGT

KLLMERLHLEINRRGRRAPP

GELGAALSRLALRPEPPTLRRS

ILANGPVPSPPRRGGALLEE

TSLRRLGGFPGPPTLFSIRTEP

PELSDDDRANLMWK

PASHGSFHMISARSSEPFYSDD

RYLEREDSKIVDLFVGQLKS

KMAHHTLLLGSGHVGLRNLGNT

CLKCQACGYRSTTFEVECDL

CFLNAVLQCLSSTRPLRDFCLR

SLPIPKKGFAGGKVSLRDCF

RDFRQEVPGGGRAQELTEAFAD

NLFTKEEELESENAPVCDRC

VIGALWHPDSCEAVNPTRERAV

RQKTRSTKKLTVQRFPRILV

FQKYVPSFSGYSQQ

LHLNRFSASRGSIKKSSVGV

DAQEFLKLLMERLHLEINRRGR

DFPLQRLSLGDFASDKAGSP

RAPPILANGPVPSPPRRGGALL

VYQLYALCNHSGSVHYGHYT

EEPELSDDDRANLMWKRYLERE

ALCRCQTGWHVYNDSRVSPV

DSKIVDLFVGQLKSCLKCQACG

SENQVASSEGYVLFYQLMQ

YRSTTFEVFCDLSLPIPKKGFA

GGKVSLRDCENLFTKEEELESE

NAPVCDRCRQKTRSTKKLTVQR

FPRILVLHLNRESASRGSIKKS

SVGVDFPLQRLSLGDFASDKAG

SPVYQLYALCNHSGSVHYGHYT

ALCRCQTGWHVYNDSRVSPVSE

NQVASSEGYVLFYQLMQEPPRC

L

U17L4_HUMAN
62
MGDDSLYLGGEWQFNHESKLTS
173
AVGAGLQNMGNTCYENASLQ

Inactive

SRPDAAFAEIQRTSLPEKSPLS

CLTYTLPLANYMLSREHSQT

ubiquitin

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

carboxyl-

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

terminal

CYENASLQCLTYTLPLANYMLS

KQEDVHEFLMFTVDAMKKAC

hydrolase 17-

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

like protein 4

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDVHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTEDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVAGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRESDV

YVLYAVLVHAGWSCHDGYYF

AGNKLAKNVQYPEC

SYVKAQEGQWYKMDDAEVTV

LDMQPYMSQQNTGPLVYVLYAV

CSITSVLSQQAYVLFYIQKS

LVHAGWSCHDGYYFSYVKAQEG

QWYKMDDAEVTVCSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRPATQGELKR

DHPCLQVPELDEHLVERATEES

TLDHWKFPQEQNKMKPEFNVRK

VEGTLPPNVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSMNSTDQE

SMNTGTLASLQGRTRRSKGKNK

HSKRSLLVCQ

U17LK_HUMAN
63
MEDDSLYLGGEWQFNHESKLTS
174
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 20

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QPNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EVTASSITSVLSQQAYVLFYIQ

KSEWERHSESVSRGREPRALGA

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKEL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSTTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

UBP12_HUMAN
64
MEILMTVSKFASICTMGANASA
175
EHYFGLVNFGNTCYCNSVLQ

Ubiquitin

LEKEIGPEQFPVNEHYFGLVNE

ALYFCRPFREKVLAYKSQPR

carboxyl-

GNTCYCNSVLQALYFCRPFREK

KKESLLTCLADLFHSIATQK

terminal

VLAYKSQPRKKESLLTCLADLF

KKVGVIPPKKFITRLRKENE

hydrolase 12

HSIATQKKKVGVIPPKKFITRL

LFDNYMQQDAHEFLNYLLNT

RKENELFDNYMQQDAHEFLNYL

IADILQEERKQEKQNGRLPN

LNTIADILQEERKQEKQNGRLP

GNIDNENNNSTPDPTWVHEI

NGNIDNENNNSTPDPTWVHEIF

FQGTLTNETRCLTCETISSK

QGTLTNETRCLTCETISSKDED

DEDFLDLSVDVEQNTSITHC

FLDLSVDVEQNTSITHCLRGES

LRGFSNTETLCSEYKYYCEE

NTETLCSEYKYYCEECRSKQEA

CRSKQEAHKRMKVKKLPMIL

HKRMKVKKLPMILALHLKRFKY

ALHLKRFKYMDQLHRYTKLS

MDQLHRYTKLSYRVVFPLELRL

YRVVFPLELRLENTSGDATN

FNTSGDATNPDRMY

PDRMYDLVAVVVHCGSGPNR

DLVAVVVHCGSGPNRGHYIAIV

GHYIAIVKSHDFWLLEDDDI

KSHDEWLLEDDDIVEKIDAQAI

VEKIDAQAIEEFYGLTSDIS

EEFYGLTSDISKNSESGYILFY

KNSESGYILFYQSR

QSRD

UL17C_HUMAN
65
MEEDSLYLGGEWQFNHESKLTS
176
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSNRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase 17-

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

like protein 12

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKMLTLLTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KMLTLLTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQPNTGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTASSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLKLSSTTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

UBP20_HUMAN
66
MGDSRDLCPHLDSIGEVTKEDL
177
PRGLTGMKNLGNSCYMNAAL

Ubiquitin

LLKSKGTCQSCGVTGPNLWACL

QALSNCPPLTQFFLECGGLV

carboxyl-

QVACPYVGCGESFADHSTIHAQ

RTDKKPALCKSYQKLVSEVW

terminal

AKKHNLTVNLTTFRLWCYACEK

HKKRPSYVVPTSLSHGIKLV

hydrolase

EVFLEQRLAAPLLGSSSKESEQ

NPMFRGYAQQDTQEFLRCLM

DSPPPSHPLKAVPIAVADEGES

DQLHEELKEPVVATVALTEA

ESEDDDLKPRGLTGMKNLGNSC

RDSDSSDTDEKREGDRSPSE

YMNAALQALSNCPPLTQFFLEC

DEFLSCDSSSDRGEGDGQGR

GGLVRTDKKPALCKSYQKLVSE

GGGSSQAETELLIPDEAGRA

VWHKKRPSYVVPTSLSHGIKLV

ISEKERMKDRKFSWGQQRTN

NPMFRGYAQQDTQEFLRCLMDQ

SEQVDEDADVDTAMAALDDQ

LHEELKEPVVATVALTEARDSD

PAEAQPPSPRSSSPCRTPEP

SSDTDEKREGDRSPSEDEFLSC

DNDAHLRSSSRPCSPVHHHE

DSSSDRGEGDGQGR

GHAKLSSSPPRASPVRMAPS

GGGSSQAETELLIPDEAGRAIS

YVLKKAQVLSAGSRRRKEQR

EKERMKDRKFSWGQQRTNSEQV

YRSVISDIFDGSILSLVQCL

DEDADVDTAMAALDDQPAEAQP

TCDRVSTTVETFQDLSLPIP

PSPRSSSPCRTPEPDNDAHLRS

GKEDLAKLHSAIYQNVPAKP

SSRPCSPVHHHEGHAKLSSSPP

GACGDSYAAQGWLAFIVEYI

RASPVRMAPSYVLKKAQVLSAG

RRFVVSCTPSWFWGPVVTLE

SRRRKEQRYRSVISDIFDGSIL

DCLAAFFAADELKGDNMYSC

SLVQCLTCDRVSTTVETFQDLS

ERCKKLRNGVKYCKVLRLPE

LPIPGKEDLAKLHSAIYQNVPA

ILCIHLKRFRHEVMYSFKIN

KPGACGDSYAAQGWLAFIVEYI

SHVSFPLEGLDLRPFLAKEC

RRFVVSCTPSWFWGPVVTLEDC

TSQITTYDLLSVICHHGTAG

LAAFFAADELKGDNMYSCERCK

SGHYIAYCQNVINGQWYEFD

KLRNGVKYCKVLRLPEILCIHL

DQYVTEVHETVVQNAEGYVL

KRFRHEVMYSEKIN

FYRKSS

SHVSFPLEGLDLRPFLAKECTS

QITTYDLLSVICHHGTAGSGHY

IAYCQNVINGQWYEFDDQYVTE

VHETVVQNAEGYVLFYRKSSEE

AMRERQQVVSLAAMREPSLLRF

YVSREWLNKENTFAEPGPITNQ

TFLCSHGGIPPHKYHYIDDLVV

ILPQNVWEHLYNRFGGGPAVNH

LYVCSICQVEIEALAKRRRIEI

DTFIKLNKAFQAEESPGVIYCI

SMQWFREWEAFVKGKDNEPPGP

IDNSRIAQVKGSGHVQLKQGAD

YGQISEETWTYLNSLYGGGPEI

AIRQSVAQPLGPENLHGEQKIE

AETRAV

UBP46_HUMAN
67
MTVRNIASICNMGTNASALEKD
178
EHYFGLVNFGNTCYCNSVLQ

Ubiquitin

IGPEQFPINEHYFGLVNEGNTC

ALYFCRPFRENVLAYKAQQK

carboxyl-

YCNSVLQALYFCRPFRENVLAY

KKENLLTCLADLEHSIATQK

terminal

KAQQKKKENLLTCLADLFHSIA

KKVGVIPPKKFISRLRKEND

hydrolase 46

TQKKKVGVIPPKKFISRLRKEN

LFDNYMQQDAHEFLNYLLNT

DLEDNYMQQDAHEFLNYLLNTI

IADILQEEKKQEKQNGKLKN

ADILQEEKKQEKQNGKLKNGNM

GNMNEPAENNKPELTWVHEI

NEPAENNKPELTWVHEIFQGTL

FQGTLTNETRCLNCETVSSK

TNETRCLNCETVSSKDEDELDL

DEDFLDLSVDVEQNTSITHC

SVDVEQNTSITHCLRDESNTET

LRDESNTETLCSEQKYYCET

LCSEQKYYCETCCSKQEAQKRM

CCSKQEAQKRMRVKKLPMIL

RVKKLPMILALHLKRFKYMEQL

ALHLKRFKYMEQLHRYTKLS

HRYTKLSYRVVFPLELRLENTS

YRVVFPLELRLENTSSDAVN

SDAVNLDRMYDLVA

LDRMYDLVAVVVHCGSGPNR

VVVHCGSGPNRGHYITIVKSHG

GHYITIVKSHGFWLLEDDDI

FWLLEDDDIVEKIDAQAIEEFY

VEKIDAQAIEEFYGLTSDIS

GLTSDISKNSESGYILFYQSRE

KNSESGYILFYQSR

CYLD_HUMAN
68
MSSGLWSQEKVTSPYWEERIFY
179
GKKKGIQGHYNSCYLDSTLF

Ubiquitin

LLLQECSVTDKQTQKLLKVPKG

CLFAFSSVLDTVLLRPKEKN

carboxyl-

SIGQYIQDRSVGHSRIPSAKGK

DVEYYSETQELLRTEIVNPL

terminal

KNQIGLKILEQPHAVLFVDEKD

RIYGYVCATKIMKLRKILEK

hydrolase

VVEINEKFTELLLAITNCEERE

VEAASGFTSEEKDPEEFLNI

CYLD

SLFKNRNRLSKGLQIDVGCPVK

LFHHILRVEPLLKIRSAGQK

VQLRSGEEKFPGVVRERGPLLA

VQDCYFYQIFME

ERTVSGIFFGVELLEEGRGQGF

KNEKVGVPTIQQLLEWSFIN

TDGVYQGKQLFQCDEDCGVEVA

SNLKFAEAPSCLIIQMPREG

LDKLELIEDDDTALESDYAGPG

KDFKLFKKIFPSLELNITDL

DTMQVELPPLEINSRVSLKVGE

LEDTPRQCRICGGLAMYECR

TIESGTVIFCDVLPGKESLGYF

ECYDDPDISAGKIKQFCKTC

VGVDMDNPIGNWDGREDGVQLC

NTQVHLHPKRLNHKYNPVSL

SFACVESTILLHIN

PKDLPDWDWRHGCIPCQNME

DIIPALSESVTQERRPPKLAFM

LFAVLCIETSHYVAFVKYGK

SRGVGDKGSSSHNKPKATGSTS

DDSAWLFFDSMADRDGGQNG

DPGNRNRSELFYTLNGSSVDSQ

FNIPQVTPCPEVGEYLKMSL

PQSKSKNTWYIDEVAEDPAKSL

EDLHSLDSRRIQGCARRLLC

TEISTDEDRSSPPLQPPPVNSL

DAYMCMYQSPT

TTENRFHSLPFSLTKMPNINGS

IGHSPLSLSAQSVMEELNTAPV

QESPPLAMPPGNSHGLEVGSLA

EVKENPPFYGVIRWIGQPPGLN

EVLAGLELEDECAGCTDGTFRG

TRYFTCALKKALFVKLKSCRPD

SRFASLQPVSNQIERCNSLAFG

GYLSEVVEENTPPKMEKEGLEI

MIGKKKGIQGHYNS

CYLDSTLFCLFAFSSVLDTVLL

RPKEKNDVEYYSETQELLRTEI

VNPLRIYGYVCATKIMKLRKIL

EKVEAASGFTSEEKDPEEFLNI

LFHHILRVEPLLKIRSAGQKVQ

DCYFYQIFMEKNEKVGVPTIQQ

LLEWSFINSNLKFAEAPSCLII

QMPRFGKDFKLFKKIFPSLELN

ITDLLEDTPRQCRICGGLAMYE

CRECYDDPDISAGKIKQFCKTC

NTQVHLHPKRLNHKYNPVSLPK

DLPDWDWRHGCIPCQNMELFAV

LCIETSHYVAFVKYGKDDSAWL

FFDSMADRDGGQNGENIPQVTP

CPEVGEYLKMSLEDLHSLDSRR

IQGCARRLLCDAYMCMYQSPTM

SLYK

UBP16_HUMAN
69
MGKKRTKGKTVPIDDSSETLEP
180
ITVKGLSNLGNTCFFNAVMQ

Ubiquitin

VCRHIRKGLEQGNLKKALVNVE

NLSQTPVLRELLKEVKMSGT

carboxyl-

WNICQDCKTDNKVKDKAEEETE

IVKIEPPDLALTEPLEINLE

terminal

EKPSVWLCLKCGHQGCGRNSQE

PPGPLTLAMSQFLNEMQETK

hydrolase 16

QHALKHYLTPRSEPHCLVLSLD

KGVVTPKELFSQVCKKAVRE

NWSVWCYVCDNEVQYCSSNQLG

KGYQQQDSQELLRYLLDGMR

QVVDYVRKQASITTPKPAEKDN

AEEHQRVSKGILKAFGNSTE

GNIELENKKLEKESKNEQEREK

KLDEELKNKVKDYEKKKSMP

KENMAKENPPMNSPCQITVKGL

SFVDRIFGGELTSMIMCDQC

SNLGNTCFFNAVMQNLSQTPVL

RTVSLVHESFLDLSLPVLDD

RELLKEVKMSGTIVKIEPPDLA

QSGKKSVNDKNLKKTVEDED

LTEPLEINLEPPGPLTLAMSQF

QDSEEEKDNDSYIKERSDIP

LNEMQETKKGVVTPKELFSQVC

SGTSKHLQKKAKKQAKKQAK

KKAVRFKGYQQQDS

NQRRQQKIQGKVLHLNDICT

QELLRYLLDGMRAEEHQRVSKG

IDHPEDSEYEAEMSLQGEVN

ILKAFGNSTEKLDEELKNKVKD

IKSNHISQEGVMHKEYCVNQ

YEKKKSMPSFVDRIFGGELTSM

KDLNGQAKMIESVTDNQKST

IMCDQCRTVSLVHESELDLSLP

EEVDMKNINMDNDLEVLTSS

VLDDQSGKKSVNDKNLKKTVED

PTRNLNGAYLTEGSNGEVDI

EDQDSEEEKDNDSYIKERSDIP

SNGFKNLNLNAALHPDEINI

SGTSKHLQKKAKKQAKKQAKNQ

EILNDSHTPGTKVYEVVNED

RRQQKIQGKVLHLNDICTIDHP

PETAFCTLANREVENTDECS

EDSEYEAEMSLQGEVNIKSNHI

IQHCLYQFTRNEKLRDANKL

SQEGVMHKEYCVNQKDLNGQAK

LCEVCTRRQCNGPKANIKGE

MIESVTDNQKSTEEVDMKNINM

RKHVYTNAKKQMLISLAPPV

DNDLEVLTSSPTRNLNGAYLTE

LTLHLKRFQQAGFNLRKVNK

GSNGEVDISNGFKNLNLNAALH

HIKFPEIL

PDEINIEILNDSHT

DLAPFCTLKCKNVAEENTRV

PGTKVYEVVNEDPETAFCTLAN

LYSLYGVVEHSGTMRSGHYT

REVENTDECSIQHCLYQFTRNE

AYAKARTANSHLSNLVLHGD

KLRDANKLLCEVCTRRQCNGPK

IPQDFEMESKGQWFHISDTH

ANIKGERKHVYTNAKKQMLISL

VQAVPTTKVLNSQAYLLFYE

APPVLTLHLKRFQQAGENLRKV

RIL

NKHIKFPEILDLAPFCTLKCKN

VAEENTRVLYSLYGVVEHSGTM

RSGHYTAYAKARTANSHLSNLV

LHGDIPQDFEMESKGQWFHISD

THVQAVPTTKVLNSQAYLLFYE

RIL

ALG13_HUMAN
70
MKCVFVTVGTTSEDDLIACVSA
181
YRYKDSLKEDIQKADLVISH

Putative

PDSLQKIESLGYNRLILQIGRG

AGAGSCLETLEKGKPLVVVI

bifunctional

TVVPEPESTESFTLDVYRYKDS

NEKLMNNHQLELAKQLHKEG

UDP-N-

LKEDIQKADLVISHAGAGSCLE

HLFYCTCRVLTCPGQAKSIA

acetyl-

TLEKGKPLVVVINEKLMNNHQL

SAPGKCQDSAALTSTAFSGL

glucosamine

ELAKQLHKEGHLFYCTCRVLTC

DFGLLSGYLHKQALVTATHP

transferase

PGQAKSIASAPGKCQDSAALTS

TCTLLFPSCHAFFPLPLTPT

and

TAFSGLDFGLLSGYLHKQALVT

LYKMHKGWKNYCSQKSLNEA

deubiquitinase

ATHPTCTLLFPSCHAFFPLPLT

SMDEYLGSLGLFRKLTAKDA

ALG13

PTLYKMHKGWKNYCSQKSLNEA

SCLFRAISEQLFCSQVHHLE

SMDEYLGSLGLFRKLTAKDASC

IRKACVSYMRENQQTFESYV

LFRAISEQLFCSQVHHLEIRKA

EGSFEKYLERLGDPKESAGQ

CVSYMRENQQTFESYVEGSFEK

LEIRALSLIYNRDFILYREP

YLERLGDPKESAGQ

GKPPTYVTDNGYEDKILLCY

LEIRALSLIYNRDFILYREPGK

SSSGHYDSVYS

PPTYVTDNGYEDKILLCYSSSG

HYDSVYSKQFQSSAAVCQAVLY

EILYKDVFVVDEEELKTAIKLF

RSGSKKNRNNAVTGSEDAHTDY

KSSNQNRMEEWGACYNAENIPE

GYNKGTEETKSPENPSKMPFPY

KVLKALDPEIYRNVEFDVWLDS

RKELQKSDYMEYAGRQYYLGDK

CQVCLESEGRYYNAHIQEVGNE

NNSVTVFIEELAEKHVVPLANL

KPVTQVMSVPAWNAMPSRKGRG

YQKMPGGYVPEIVISEMDIKQQ

KKMFKKIRGKEVYM

TMAYGKGDPLLPPRLQHSMHYG

HDPPMHYSQTAGNVMSNEHFHP

QHPSPRQGRGYGMPRNSSRFIN

RHNMPGPKVDFYPGPGKRCCQS

YDNESYRSRSFRRSHRQMSCVN

KESQYGFTPGNGQMPRGLEETI

TFYEVEEGDETAYPTLPNHGGP

STMVPATSGYCVGRRGHSSGKQ

TLNLEEGNGQSENGRYHEEYLY

RAEPDYETSGVYSTTASTANLS

LQDRKSCSMSPQDTVTSYNYPQ

KMMGNIAAVAASCANNVPAPVL

SNGAAANQAISTTSVSSQNAIQ

PLFVSPPTHGRPVI

ASPSYPCHSAIPHAGASLPPPP

PPPPPPPPPPPPPPPPPPPPPP

PALDVGETSNLQPPPPLPPPPY

SCDPSGSDLPQDTKVLQYYENL

GLQCYYHSYWHSMVYVPQMQQQ

LHVENYPVYTEPPLVDQTVPQC

YSEVRREDGIQAEASANDTEPN

ADSSSVPHGAVYYPVMSDPYGQ

PPLPGEDSCLPVVPDYSCVPPW

HPVGTAYGGSSQIHGAINPGPI

GCIAPSPPASHYVPQGM

OTU1_HUMAN
71
MFGPAKGRHFGVHPAPGFPGGV
182
QGLSSRTRVRELQGQIAAIT

Ubiquitin

SQQAAGTKAGPAGAWPVGSRTD

GIAPGGQRILVGYPPECLDL

thioesterase

TMWRLRCKAKDGTHVLQGLSSR

SNGDTILEDLPIQSGDMLII

OTU1

TRVRELQGQIAAITGIAPGGQR

EEDQTRPRSSPAFTKRGASS

ILVGYPPECLDLSNGDTILEDL

YVRETLPVLTRTVVPADNSC

PIQSGDMLIIEEDQTRPRSSPA

LETSVYYVVEGGVLNPACAP

FTKRGASSYVRETLPVLTRTVV

EMRRLIAQIVASDPDFYSEA

PADNSCLFTSVYYVVEGGVLNP

ILGKTNQEYCDWIKRDDTWG

ACAPEMRRLIAQIVASDPDFYS

GAIEISILSKFYQCEICVVD

EAILGKTNQEYCDWIKRDDTWG

TQTVRIDRFGEDAGYTKRVL

GAIEISILSKFYQCEICVVDTQ

LIYDGIHYDPLQ

TVRIDRFGEDAGYTKRVLLIYD

GIHYDPLQRNFPDPDTPPLTIF

SSNDDIVLVQALELADEARRRR

QFTDVNRFTLRCMVCQKGLTGQ

AEAREHAKETGHTNEGEV

OTUD1_HUMAN
72
MQLYSSVCTHYPAGAPGPTAAA
183
HREAAAVPAAKMPAFSSCFE

OTU

PAPPAAATPFKVSLQPPGAAGA

VVSGAAAPASAAAGPPGASC

domain-

APEPETGECQPAAAAEHREAAA

KPPLPPHYTSTAQITVRALG

containing

VPAAKMPAFSSCFEVVSGAAAP

ADRLLLHGPDPVPGAAGSAA

protein 1

ASAAAGPPGASCKPPLPPHYTS

APRGRCLLLAPAPAAPVPPR

TAQITVRALGADRLLLHGPDPV

RGSSAWLLEELLRPDCPEPA

PGAAGSAAAPRGRCLLLAPAPA

GLDATREGPDRNFRLSEHRQ

APVPPRRGSSAWLLEELLRPDC

ALAAAKHRGPAATPGSPDPG

PEPAGLDATREGPDRNERLSEH

PGPWGEEHLAERGPRGWERG

RQALAAAKHRGPAATPGSPDPG

GDRCDAPGGDAARRPDPEAE

PGPWGEEHLAERGPRGWERGGD

APPAGSIEAAPSSAAEPVIV

RCDAPGGDAARRPDPEAEAPPA

SRSDPRDEKLALYLAEVEKQ

GSIEAAPSSAAEPVIVSRSDPR

DKYLRQRNKYRFHIIPDGNC

DEKLALYLAEVEKQ

LYRAVSKTVYGDQSLHRELR

DKYLRQRNKYRFHIIPDGNCLY

EQTVHYIADHLDHFSPLIEG

RAVSKTVYGDQSLHRELREQTV

DVGEFIIAAAQDGAWAGYPE

HYIADHLDHFSPLIEGDVGEFI

LLAMGQMLNVNIHLTTGGRL

IAAAQDGAWAGYPELLAMGQML

ESPTVSTMIHYLGPEDSLRP

NVNIHLTTGGRLESPTVSTMIH

SIWLSWLSNGHYDAV

YLGPEDSLRPSIWLSWLSNGHY

DAVEDHSYPNPEYDNWCKQTQV

QRKRDEELAKSMAISLSKMYIE

QNACS

OTU6B_HUMAN
73
MEAVLTEELDEEEQLLRRHRKE
184
QKHREELEQLKLTTKENKID

Deubiquitinase

KKELQAKIQGMKNAVPKNDKKR

SVAVNISNLVLENQPPRISK

OTUD6B

RKQLTEDVAKLEKEMEQKHREE

AQKRREKKAALEKEREERIA

LEQLKLTTKENKIDSVAVNISN

EAEIENLTGARHMESEKLAQ

LVLENQPPRISKAQKRREKKAA

ILAARQLEIKQIPSDGHCMY

LEKEREERIAEAEIENLTGARH

KAIEDQLKEKDCALTVVALR

MESEKLAQILAARQLEIKQIPS

SQTAEYMQSHVEDELPELTN

DGHCMYKAIEDQLKEKDCALTV

PNTGDMYTPEEFQKYCEDIV

VALRSQTAEYMQSHVEDELPFL

NTAAWGGQLELRALSHILQT

TNPNTGDMYTPEEFQKYCEDIV

PIEIIQADSPPIIVGEEYSK

NTAAWGGQLELRALSHILQTPI

KPLILVYMRHAYG

EIIQADSPPIIVGEEYSKKPLI

LVYMRHAYGLGEHYNSVTRLVN

IVTENCS

OTU6A_HUMAN
74
MDDPKSEQQRILRRHQRERQEL
185
QELEKFQDDSSIESVVEDLA

OTU

QAQIRSLKNSVPKTDKTKRKQL

KMNLENRPPRSSKAHRKRER

domain-

LQDVARMEAEMAQKHRQELEKF

MESEERERQESIFQAEMSEH

containing

QDDSSIESVVEDLAKMNLENRP

LAGFKREEEEKLAAILGARG

protein 6A

PRSSKAHRKRERMESEERERQE

LEMKAIPADGHCMYRAIQDQ

SIFQAEMSEHLAGFKREEEEKL

LVFSVSVEMLRCRTASYMKK

AAILGARGLEMKAIPADGHCMY

HVDEFLPFFSNPETSDSFGY

RAIQDQLVFSVSVEMLRCRTAS

DDFMIYCDNIVRTTAWGGQL

YMKKHVDEFLPFFSNPETSDSF

ELRALSHVLKTPIEVIQADS

GYDDFMIYCDNIVRTTAWGGQL

PTLIIGEEYVKKPIILVYLR

ELRALSHVLKTPIEVIQADSPT

YAYS

LIIGEEYVKKPIILVYLRYAYS

LGEHYNSVTPLEAGAAGGVLPR

LL

OTUB1_HUMAN
75
MAAEEPQQQKQEPLGSDSEGVN
75
MAAEEPQQQKQEPLGSDSEG

Ubiquitin

CLAYDEAIMAQQDRIQQEIAVQ

VNCLAYDEAIMAQQDRIQQE

thioesterase

NPLVSERLELSVLYKEYAEDDN

IAVQNPLVSERLELSVLYKE

OTUB1

IYQQKIKDLHKKYSYIRKTRPD

YAEDDNIYQQKIKDLHKKYS

GNCFYRAFGFSHLEALLDDSKE

YIRKTRPDGNCFYRAFGESH

LQRFKAVSAKSKEDLVSQGFTE

LEALLDDSKELQRFKAVSAK

FTIEDFHNTFMDLIEQVEKQTS

SKEDLVSQGFTEFTIEDFHN

VADLLASENDQSTSDYLVVYLR

TFMDLIEQVEKQTSVADLLA

LLTSGYLQRESKFFEHFIEGGR

SENDQSTSDYLVVYLRLLTS

TVKEFCQQEVEPMCKESDHIHI

GYLQRESKFFEHFIEGGRTV

IALAQALSVSIQVEYMDRGEGG

KEFCQQEVEPMCKESDHIHI

TTNPHIFPEGSEPKVYLLYRPG

IALAQALSVSIQVEYMDRGE

HYDILYK

GGTTNPHIFPEGSEPKVYLL

YRPGHYDILYK

OTU7A_HUMAN
76
MVSSVLPNPTSAECWAALLHDP
186
SDYEQLRQVHTANLPHVENE

OTU

MTLDMDAVLSDFVRSTGAEPGL

GRGPKQPEREPQPGHKVERP

domain-

ARDLLEGKNWDLTAALSDYEQL

CLQRQDDIAQEKRLSRGISH

containing

RQVHTANLPHVENEGRGPKQPE

ASSAIVSLARSHVASECNNE

protein 7A

REPQPGHKVERPCLQRQDDIAQ

QFPLEMPIYTFQLPDLSVYS

EKRLSRGISHASSAIVSLARSH

EDERSFIERDLIEQATMVAL

VASECNNEQFPLEMPIYTFQLP

EQAGRLNWWSTVCTSCKRLL

DLSVYSEDERSFIERDLIEQAT

PLATTGDGNCLLHAASLGMW

MVALEQAGRLNWWSTVCTSCKR

GFHDRDLVLRKALYTMMRTG

LLPLATTGDGNCLLHAASLGMW

AEREALKRRWRWQQTQQNKE

GFHDRDLVLRKALYTMMRTGAE

EEWEREWTELLKLASSEPRT

REALKRRWRWQQTQQNKEEEWE

HFSKNGGTGGGVDNSEDPVY

REWTELLKLASSEPRTHESKNG

ESLEEFHVEVLAHILRRPIV

GTGGGVDNSEDPVY

VVADTMLRDSGGEAFAPIPE

ESLEEFHVEVLAHILRRPIVVV

GGIYLPLEVPPNRCHCSPLV

ADTMLRDSGGEAFAPIPEGGIY

LAYDQAHFSAL

LPLEVPPNRCHCSPLVLAYDQA

HFSALVSMEQRDQQREQAVIPL

TDSEHKLLPLHFAVDPGKDWEW

GKDDNDNARLAHLILSLEAKLN

LLHSYMNVTWIRIPSETRAPLA

QPESPTASAGEDVQSLADSLDS

DRDSVCSNSNSNNGKNGKDKEK

EKQRKEKDKTRADSVANKLGSF

SKTLGIKLKKNMGGLGGLVHGK

MGRANSANGKNGDSAERGKEKK

AKSRKGSKEESGASASTSPSEK

TTPSPTDKAAGASP

AEKGGGPRGDAWKYSTDVKLSL

NILRAAMQGERKFIFAGLLLTS

HRHQFHEEMIGYYLTSAQERES

AEQEQRRRDAATAAAAAAAAAA

ATAKRPPRRPETEGVPVPERAS

PGPPTQLVLKLKERPSPGPAAG

RAARAAAGGTASPGGGARRASA

SGPVPGRSPPAPARQSVIHVQA

SGARDEACAPAVGALRPCATYP

QQNRSLSSQSYSPARAAALRTV

NTVESLARAVPGALPGAAGTAG

AAEHKSQTYTNGFGALRDGLEF

ADADAPTARSNGECGRGGPGPV

QRRCQRENCAFYGRAETEHYCS

YCYREELRRRREARGARP

OTUD4MAN_HU
77
MEAAVGVPDGGDQGGAGPREDA
187
MEAAVGVPDGGDQGGAGPRE

OTU

TPMDAYLRKLGLYRKLVAKDGS

DATPMDAYLRKLGLYRKLVA

domain-

CLFRAVAEQVLHSQSRHVEVRM

KDGSCLFRAVAEQVLHSQSR

containing

ACIHYLRENREKFEAFIEGSFE

HVEVRMACIHYLRENREKFE

protein 4

EYLKRLENPQEWVGQVEISALS

AFIEGSFEEYLKRLENPQEW

LMYRKDFIIYREPNVSPSQVTE

VGQVEISALSLMYRKDFIIY

NNFPEKVLLCESNGNHYDIVYP

REPNVSPSQVTENNFPEKVL

IKYKESSAMCQSLLYELLYEKV

LCFSNGNHYDIVYP

FKTDVSKIVMELDTLEVADEDN

SEISDSEDDSCKSKTAAAAADV

NGFKPLSGNEQLKNNGNSTSLP

LSRKVLKSLNPAVYRNVEYEIW

LKSKQAQQKRDYSIAAGLQYEV

GDKCQVRLDHNGKF

LNADVQGIHSENGPVLVEELGK

KHTSKNLKAPPPESWNTVSGKK

MKKPSTSGQNFHSDVDYRGPKN

PSKPIKAPSALPPRLQHPSGVR

QHAFSSHSSGSQSQKFSSEHKN

LSRTPSQIIRKPDRERVEDEDH

TSRESNYFGLSPEERREKQAIE

ESRLLYEIQNRDEQAFPALSSS

SVNQSASQSSNPCVQRKSSHVG

DRKGSRRRMDTEERKDKDSIHG

HSQLDKRPEPSTLENITDDKYA

TVSSPSKSKKLECPSPAEQKPA

EHVSLSNPAPLLVSPEVHLTPA

VPSLPATVPAWPSE

PTTFGPTGVPAPIPVLSVTQTL

TTGPDSAVSQAHLTPSPVPVSI

QAVNQPLMPLPQTLSLYQDPLY

PGFPCNEKGDRAIVPPYSLCQT

GEDLPKDKNILRFFENLGVKAY

SCPMWAPHSYLYPLHQAYLAAC

RMYPKVPVPVYPHNPWFQEAPA

AQNESDCTCTDAHFPMQTEASV

NGQMPQPEIGPPTFSSPLVIPP

SQVSESHGQLSYQADLESETPG

QLLHADYEESLSGKNMFPQSFG

PNPFLGPVPIAPPFFPHVWYGY

PFQGFIENPVMRQNIVLPSDEK

GELDLSLENLDLS

KDCGSVSTVDEFPEARGEHVHS

LPEASVSSKPDEGRTEQSSQTR

KADTALASIPPVAEGKAHPPTQ

ILNRERETVPVELEPKRTIQSL

KEKTEKVKDPKTAADVVSPGAN

SVDSRVQRPKEESSEDENEVSN

ILRSGRSKQFYNQTYGSRKYKS

DWGYSGRGGYQHVRSEESWKGQ

PSRSRDEGYQYHRNVRGRPFRG

DRRRSGMGDGHRGQHT

OTUB2_HUMAN
78
MSETSFNLISEKCDILSILRDH
78
MSETSENLISEKCDILSILR

Ubiquitin

PENRIYRRKIEELSKRFTAIRK

DHPENRIYRRKIEELSKRET

thioesterase

TKGDGNCFYRALGYSYLESLLG

AIRKTKGDGNCFYRALGYSY

OTUB2

KSREIFKFKERVLQTPNDLLAA

LESLLGKSREIFKFKERVLQ

GFEEHKERNFFNAFYSVVELVE

TPNDLLAAGFEEHKERNFEN

KDGSVSSLLKVENDQSASDHIV

AFYSVVELVEKDGSVSSLLK

QFLRLLTSAFIRNRADFFRHFI

VENDQSASDHIVQFLRLLTS

DEEMDIKDFCTHEVEPMATECD

AFIRNRADFFRHFIDEEMDI

HIQITALSQALSIALQVEYVDE

KDFCTHEVEPMATECDHIQI

MDTALNHHVFPEAATPSVYLLY

TALSQALSIALQVEYVDEMD

KTSHYNILYAADKH

TALNHHVFPEAATPSVYLLY

KTSHYNILYAADKH

OTUD3_HUMAN
79
MSRKQAAKSRPGSGSRKAEAER
188
MSRKQAAKSRPGSGSRKAEA

OTU

KRDERAARRALAKERRNRPESG

ERKRDERAARRALAKERRNR

domain-

GGGGCEEEFVSFANQLQALGLK

PESGGGGGCEEEFVSFANQL

containing

LREVPGDGNCLFRALGDQLEGH

QALGLKLREVPGDGNCLFRA

protein 3

SRNHLKHRQETVDYMIKQREDE

LGDQLEGHSRNHLKHRQETV

EPFVEDDIPFEKHVASLAKPGT

DYMIKQREDFEPFVEDDIPE

FAGNDAIVAFARNHQLNVVIHQ

EKHVASLAKPGTFAGNDAIV

LNAPLWQIRGTEKSSVRELHIA

AFARNHQLNVVIHQLNAPLW

YRYGEHYDSVRRINDNSEAPAH

QIRGTEKSSVRELHIAYRYG

LQTDFQMLHQDESNKREKIKTK

EHYDSVRR

GMDSEDDLRDEVEDAVQKVCNA

TGCSDENLIVQNLEAENYNIES

AIIAVLRMNQGKRNNAEENLEP

SGRVLKQCGPLWEE

GGSGARIFGNQGLNEGRTENNK

AQASPSEENKANKNQLAKVTNK

QRREQQWMEKKKRQEERHRHKA

LESRGSHRDNNRSEAEANTQVT

LVKTFAALNI

OTU7B_HUMAN
80
MTLDMDAVLSDFVRSTGAEPGL
189
MTLDMDAVLSDFVRSTGAEP

OTU

ARDLLEGKNWDVNAALSDFEQL

GLARDLLEGKNWDVNAALSD

domain-

RQVHAGNLPPSFSEGSGGSRTP

FEQLRQVHAGNLPPSESEGS

containing

EKGESDREPTRPPRPILQRQDD

GGSRTPEKGFSDREPTRPPR

protein 7B

IVQEKRLSRGISHASSSIVSLA

PILQRQDDIVQEKRLSRGIS

(Also referred

RSHVSSNGGGGGSNEHPLEMPI

HASSSIVSLARSHVSSNGGG

to herein as

CAFQLPDLTVYNEDERSFIERD

GGSNEHPLEMPICAFQLPDL

Cezanne)

LIEQSMLVALEQAGRLNWWVSV

TVYNEDERSFIERDLIEQSM

DPTSQRLLPLATTGDGNCLLHA

LVALEQAGRLNWWVSVDPTS

ASLGMWGFHDRDLMLRKALYAL

QRLLPLATTGDGNCLLHAAS

MEKGVEKEALKRRWRWQQTQQN

LGMWGFHDRDLMLRKALYAL

KESGLVYTEDEWQKEWNELIKL

MEKGVEKEALKRRWRWQQTQ

ASSEPRMHLGTNGANCGGVESS

QNKESGLVYTEDEWQKEWNE

EEPVYESLEEFHVEVLAHVLRR

LIKLASSEPRMHLGTNGANC

PIVVVADTMLRDSGGEAFAPIP

GGVESSEEPVYESLEEFHVE

FGGIYLPLEVPASQCHRSPLVL

VLAHVLRRPIVVVADTMLRD

AYDQAHFSALVSMEQKENTKEQ

SGGEAFAPIPEGGIYLPLEV

AVIPLTDSEYKLLPLHFAVDPG

PASQCHRSPLVLAYDQAHES

KGWEWGKDDSDNVRLASVILSL

AL

EVKLHLLHSYMNVKWIPLSSDA
423
PPSFSEGSGGSRTPEKGESD

QAPLAQPESPTASAGDEPRSTP

REPTRPPRPILQRQDDIVQE

ESGDSDKESVGSSSTSNEGGRR

KRLSRGISHASSSIVSLARS

KEKSKRDREKDKKRADSVANKL

HVSSNGGGGGSNEHPLEMPI

GSFGKTLGSKLKKNMGGLMHSK

CAFQLPDLTVYNEDERSFIE

GSKPGGVGTGLGGSSGTETLEK

RDLIEQSMLVALEQAGRLNW

KKKNSLKSWKGGKEEAAGDGPV

WVSVDPTSQRLLPLATTGDG

SEKPPAESVGNGGSKYSQEVMQ

NCLLHAASLGMWGFHDRDLM

SLSILRTAMQGEGKFIFVGTLK

LRKALYALMEKGVEKEALKR

MGHRHQYQEEMIQRYLSDAEER

RWRWQQTQQNKESGLVYTED

FLAEQKQKEAERKIMNGGIGGG

EWQKEWNELIKLASSEPRMH

PPPAKKPEPDAREEQPTGPPAE

LGTNGANCGGVESSEEPVYE

SRAMAFSTGYPGDFTIPRPSGG

SLEEFHVFVLAHVLRRPIVV

GVHCQEPRRQLAGGPCVGGLPP

VADTMLRDSGGEAFAPIPFG

YATFPRQCPPGRPYPHQDSIPS

GIYLPLEVPASQCHRSPLVL

LEPGSHSKDGLHRGALLPPPYR

AYDQAHFSALVSMEQKENTK

VADSYSNGYREPPEPDGWAGGL

EQAVIPLTDSEYKLLPLHFA

RGLPPTQTKCKQPNCSFYGHPE

VDPGKGWEWGKDDSDNVRLA

TNNFCSCCYREELRRREREPDG

SVILSLEVKLHLLHSYMNVK

ELLVHRE

WIPLSSDAQAPLAQ

OTUD5_HUMAN
81
MTILPKKKPPPPDADPANEPPP
190
MTILPKKKPPPPDADPANEP

OTU

PGPMPPAPRRGGGVGVGGGGTG

PPPGPMPPAPRRGGGVGVGG

domain-

VGGGDRDRDSGVVGARPRASPP

GGTGVGGGDRDRDSGVVGAR

containing

PQGPLPGPPGALHRWALAVPPG

PRASPPPQGPLPGPPGALHR

protein 5

AVAGPRPQQASPPPCGGPGGPG

WALAVPPGAVAGPRPQQASP

GGPGDALGAAAAGVGAAGVVVG

PPCGGPGGPGGGPGDALGAA

VGGAVGVGGCCSGPGHSKRRRQ

AAGVGAAGVVVGVGGAVGVG

APGVGAVGGGSPEREEVGAGYN

GCCSGPGHSKRRRQAPGVGA

SEDEYEAAAARIEAMDPATVEQ

VGGGSPEREEVGAGYNSEDE

QEHWFEKALRDKKGFIIKQMKE

YEAAAARIEAMDPATVEQQE

DGACLFRAVADQVYGDQDMHEV

HWFEKALRDKKGFIIKQMKE

VRKHCMDYLMKNADYFSNYVTE

DGACLFRAVADQVYGDQDMH

DFTTYINRKRKNNCHGNHIEMQ

EVVRKHCMDYLMKNADYFSN

AMAEMYNRPVEVYQ

YVTEDFTTYINRKRKNNCHG

YSTGTSAVEPINTFHGIHQNED

NHIEMQAMAEMYNRPVEVYQ

EPIRVSYHRNIHYNSVVNPNKA

YSTGTSAVEPINTFHGIHQN

TIGVGLGLPSFKPGFAEQSLMK

EDEPIRVSYHRNIHYNSV

NAIKTSEESWIEQQMLEDKKRA

TDWEATNEAIEEQVARESYLQW

LRDQEKQARQVRGPSQPRKASA

TCSSATAAASSGLEEWTSRSPR

QRSSASSPEHPELHAELGMKPP

SPGTVLALAKPPSPCAPGTSSQ

FSAGADRATSPLVSLYPALECR

ALIQQMSPSAFGLNDWDDDEIL

ASVLAVSQQEYLDSMKKNKVHR

DPPPDKS

TNAP3_HUMAN
82
MAEQVLPQALYLSNMRKAVKIR
191
MAEQVLPQALYLSNMRKAVK

Tumor

ERTPEDIFKPTNGIIHHFKTMH

IRERTPEDIFKPTNGIIHHF

necrosis factor

RYTLEMFRTCQFCPQFREIIHK

KTMHRYTLEMFRTCQFCPQF

alpha-induced

ALIDRNIQATLESQKKLNWCRE

REIIHKALIDRNIQATLESQ

protein 3

VRKLVALKINGDGNCLMHATSQ

KKLNWCREVRKLVALKINGD

YMWGVQDTDLVLRKALFSTLKE

GNCLMHATSQYMWGVQDTDL

TDTRNFKFRWQLESLKSQEFVE

VLRKALFSTLKETDTRNEKF

TGLCYDTRNWNDEWDNLIKMAS

RWQLESLKSQEFVETGLCYD

TDTPMARSGLQYNSLEEIHIFV

TRNWNDEWDNLIKMASTDTP

LCNILRRPIIVISDKMLRSLES

MARSGLQYNSLEEIHIFVLC

GSNFAPLKVGGIYLPLHWPAQE

NILRRPIIVISDKMLRSLES

CYRYPIVLGYDSHHFVPLVTLK

GSNFAPLKVGGIYLPLHWPA

DSGPEIRAVPLVNRDRGRFEDL

QECYRYPIVLGYDSHHFVPL

KVHELTDPENEMKE

KLLKEYLMVIEIPVQGWDHGTT

HLINAAKLDEANLPKEINLVDD

YFELVQHEYKKWQENSEQGRRE

GHAQNPMEPSVPQLSLMDVKCE

TPNCPFFMSVNTQPLCHECSER

RQKNQNKLPKLNSKPGPEGLPG

MALGASRGEAYEPLAWNPEEST

GGPHSAPPTAPSPFLESETTAM

KCRSPGCPFTLNVQHNGFCERC

HNARQLHASHAPDHTRHLDPGK

CQACLQDVTRTENGICSTCFKR

TTAEASSSLSTSLPPSCHQRSK

SDPSRLVRSPSPHSCHRAGNDA

PAGCLSQAARTPGD

RTGTSKCRKAGCVYFGTPENKG

FCTLCFIEYRENKHFAAASGKV

SPTASRFQNTIPCLGRECGTLG

STMFEGYCQKCFIEAQNQREHE

AKRTEEQLRSSQRRDVPRTTQS

TSRPKCARASCKNILACRSEEL

CMECQHPNQRMGPGAHRGEPAP

EDPPKQRCRAPACDHEGNAKCN

GYCNECFQFKQMYG

ZRAN1_HUMAN
83
MSERGIKWACEYCTYENWPSAI
192
MSERGIKWACEYCTYENWPS

Ubiquitin

KCTMCRAQRPSGTIITEDPFKS

AIKCTMCRAQRPSGTIITED

thioesterase

GSSDVGRDWDPSSTEGGSSPLI

PFKSGSSDVGRDWDPSSTEG

ZRANB1

CPDSSARPRVKSSYSMENANKW

GSSPLICPDSSARPRVKSSY

SCHMCTYLNWPRAIRCTQCLSQ

SMENANKWSCHMCTYLNWPR

RRTRSPTESPQSSGSGSRPVAF

AIRCTQCLSQRRTRSPTESP

SVDPCEEYNDRNKLNTRTQHWT

QSSGSGSRPVAFSVDPCEEY

CSVCTYENWAKAKRCVVCDHPR

NDRNKLNTRTQHWTCSVCTY

PNNIEAIELAETEEASSIINEQ

ENWAKAKRCVVCDHPRPNNI

DRARWRGSCSSGNSQRRSPPAT

EAIELAETEEASSIINEQDR

KRDSEVKMDFQRIELAGAVGSK

ARWRGSCSSGNSQRRSPPAT

EELEVDFKKLKQIKNRMKKTDW

KRDSEVKMDFQRIELAGAVG

LFLNACVGVVEGDLAAIEAYKS

SKEELEVDEKKLKQIKNRMK

SGGDIARQLTADEV

KTDWLFLNACVGVVEGDLAA

RLLNRPSAFDVGYTLVHLAIRE

IEAYKSSGGDIARQLTADEV

QRQDMLAILLTEVSQQAAKCIP

RLLNRPSAFDVGYTLVHLAI

AMVCPELTEQIRREIAASLHQR

RFQRQDMLAILLTEVSQQAA

KGDFACYFLTDLVTFTLPADIE

KCIPAMVCPELTEQIRREIA

DLPPTVQEKLFDEVLDRDVQKE

ASLHQRKGDFACYFLTDLVT

LEEESPIINWSLELATRLDSRL

FTLPADIEDLPPTVQEKLED

YALWNRTAGDCLLDSVLQATWG

EVLDRDVQKELEEESPIINW

IYDKDSVLRKALHDSLHDCSHW

SLELATRLDSRLYALWNRTA

FYTRWKDWESWYSQSFGLHESL

GDCLLDSVLQATWGIYDKDS

REEQWQEDWAFILSLASQPGAS

VLRKALHDSLHDCSHWFYTR

LEQTHIFVLAHILRRPIIVYGV

WKDWESWYSQSFGLHESLRE

KYYKSFRGETLGYTRFQGVYLP

EQWQEDWAFILSLASQPGAS

LLWEQSFCWKSPIALGYTRGHF

LEQTHIFVLAHILRRPIIVY

SALVAMENDGYGNR

GVKYYKSFRGETLGYTRFQG

GAGANLNTDDDVTITELPLVDS

VYLPLLWEQSFCWKSPIALG

ERKLLHVHELSAQELGNEEQQE

YTRGHESAL

KLLREWLDCCVTEGGVLVAMQK

SSRRRNHPLVTQMVEKWLDRYR

QIRPCTSLSDGEEDEDDEDE

VCIP1_HUMAN
84
MSQPPPPPPPLPPPPPPPEAPQ
193
PASGSVSIECTECGQRHEQQ

Deubiquitinating

TPSSLASAAASGGLLKRRDRRI

QLLGVEEVTDPDVVLHNLLR

protein

LSGSCPDPKCQARLFFPASGSV

NALLGVTGAPKKNTELVKVM

VCIP135

SIECTECGQRHEQQQLLGVEEV

GLSNYHCKLLSPILARYGMD

TDPDVVLHNLLRNALLGVTGAP

KQTGRAKLLRDMNQGELEDC

KKNTELVKVMGLSNYHCKLLSP

ALLGDRAFLIEPEHVNTVGY

ILARYGMDKQTGRAKLLRDMNQ

GKDRSGSLLYLHDTLEDIKR

GELFDCALLGDRAFLIEPEHVN

ANKSQECLIPVHVDGDGHCL

TVGYGKDRSGSLLYLHDTLEDI

VHAVSRALVGRELFWHALRE

KRANKSQECLIPVHVDGDGHCL

NLKQHFQQHLARYQALFHDE

VHAVSRALVGRELFWHALRENL

IDAAEWEDIINECDPLFVPP

KQHFQQHLARYQALFHDFIDAA

EGVPLGLRNIHIFGLANVLH

EWEDIINECDPLFVPPEGVPLG

RPIILLDSLSGMRSSGDYSA

LRNIHIFGLANVLH

TFLPGLIPAEKCTGKDGHLN

RPIILLDSLSGMRSSGDYSATE

KPICIAWSSSGRNHYIPL

LPGLIPAEKCTGKDGHLNKPIC

IAWSSSGRNHYIPLVGIKGAAL

PKLPMNLLPKAWGVPQDLIKKY

IKLEEDGGCVIGGDRSLQDKYL

LRLVAAMEEVEMDKHGIHPSLV

ADVHQYFYRRTGVIGVQPEEVT

AAAKKAVMDNRLHKCLLCGALS

ELHVPPEWLAPGGKLYNLAKST

HGQLRTDKNYSFPLNNLVCSYD

SVKDVLVPDYGMSNLTACNWCH

GTSVRKVRGDGSIVYLDGDRTN

SRSTGGKCGCGFKHFWDGKEYD

NLPEAFPITLEWGG

RVVRETVYWFQYESDSSLNSNV

YDVAMKLVTKHEPGEFGSEILV

QKVVHTILHQTAKKNPDDYTPV

NIDGAHAQRVGDVQGQESESQL

PTKIILTGQKTKTLHKEELNMS

KTERTIQQNITEQASVMQKRKT

EKLKQEQKGQPRTVSPSTIRDG

PSSAPATPTKAPYSPTTSKEKK

IRITTNDGRQSMVTLKSSTTFF

ELQESIAREFNIPPYLQCIRYG

FPPKELMPPQAGMEKEPVPLQH

GDRITIEILKSKAEGGQSAAAH

SAHTVKQEDIAVTGKLSSKELQ

EQAEKEMYSLCLLA

TLMGEDVWSYAKGLPHMFQQGG

VFYSIMKKTMGMADGKHCTFPH

LPGKTFVYNASEDRLELCVDAA

GHFPIGPDVEDLVKEAVSQVRA

EATTRSRESSPSHGLLKLGSGG

VVKKKSEQLHNVTAFQGKGHSL

GTASGNPHLDPRARETSVVRKH

NTGTDFSNSSTKTEPSVFTASS

SNSELIRIAPGVVTMRDGRQLD

PDLVEAQRKKLQEMVSSIQASM

DRHLRDQSTEQSPSDLPQRKTE

VVSSSAKSGSLQTGLPESFPLT

GGTENLNTETTDGCVADALGAA

FATRSKAQRGNSVEELEEMDSQ

DAEMTNTTEPMDHS

UCHL3_HUMAN
85
MEGQRWLPLEANPEVTNQFLKQ
194
QRWLPLEANPEVTNQFLKQL

Ubiquitin

LGLHPNWQFVDVYGMDPELLSM

GLHPNWQFVDVYGMDPELLS

carboxyl-

VPRPVCAVLLLFPITEKYEVER

MVPRPVCAVLLLFPITEKYE

terminal

TEEEEKIKSQGQDVTSSVYFMK

VFRTEEEEKIKSQGQDVTSS

hydrolase

QTISNACGTIGLIHAIANNKDK

VYFMKQTISNACGTIGLIHA

isozyme L3

MHFESGSTLKKFLEESVSMSPE

IANNKDKMHFESGSTLKKEL

ERARYLENYDAIRVTHETSAHE

EESVSMSPEERARYLENYDA

GQTEAPSIDEKVDLHFIALVHV

IRVTHETSAHEGQTEAPSID

DGHLYELDGRKPFPINHGETSD

EKVDLHFIALVHVDGHLYEL

ETLLEDAIEVCKKEMERDPDEL

DGRKPFPINHGETSDETLLE

RENAIALSAA

DAIEVCKKEMERDPDELREN

AIALSAA

UCHL1_HUMAN
86
MQLKPMEINPEMLNKVLSRLGV
86
MQLKPMEINPEMLNKVLSRL

Ubiquitin

AGQWRFVDVLGLEEESLGSVPA

GVAGQWRFVDVLGLEEESLG

carboxyl-

PACALLLLFPLTAQHENFRKKQ

SVPAPACALLLLFPLTAQHE

terminal

IEELKGQEVSPKVYFMKQTIGN

NFRKKQIEELKGQEVSPKVY

hydrolase

SCGTIGLIHAVANNQDKLGFED

FMKQTIGNSCGTIGLIHAVA

isozyme L1

GSVLKQFLSETEKMSPEDRAKC

NNQDKLGFEDGSVLKQFLSE

FEKNEAIQAAHDAVAQEGQCRV

TEKMSPEDRAKCFEKNEAIQ

DDKVNFHFILENNVDGHLYELD

AAHDAVAQEGQCRVDDKVNF

GRMPFPVNHGASSEDTLLKDAA

HFILENNVDGHLYELDGRMP

KVCREFTEREQGEVRESAVALC

FPVNHGASSEDTLLKDAAKV

KAA

CREFTEREQGEVRESAVALC

KAA

UCHL5_HUMAN
87
MTGNAGEWCLMESDPGVFTELI
195
GEWCLMESDPGVFTELIKGF

Ubiquitin

KGFGCRGAQVEEIWSLEPENFE

GCRGAQVEEIWSLEPENFEK

carboxyl-

KLKPVHGLIFLEKWQPGEEPAG

LKPVHGLIFLFKWQPGEEPA

terminal

SVVQDSRLDTIFFAKQVINNAC

GSVVQDSRLDTIFFAKQVIN

hydrolase

ATQAIVSVLLNCTHQDVHLGET

NACATQAIVSVLLNCTHQDV

isozyme L5

LSEFKEFSQSFDAAMKGLALSN

HLGETLSEFKEFSQSEDAAM

SDVIRQVHNSFARQQMFEEDTK

KGLALSNSDVIRQVHNSFAR

TSAKEEDAFHFVSYVPVNGRLY

QQMFEEDTKTSAKEEDAFHF

ELDGLREGPIDLGACNQDDWIS

VSYVPVNGRLYELDGLREGP

AVRPVIEKRIQKYSEGEIRENL

IDLGACNQDDWISAVRPVIE

MAIVSDRKMIYEQKIAELQRQL

KRIQKYSEGEIRENLMAIVS

AEEEPMDTDQGNSMLSAIQSEV

DRK

AKNQMLIEEEVQKLKRYKIENI

RRKHNYLPFIMELLKTLAEHQQ

LIPLVEKAKEKQNAKKAQETK

ATX3_HUMAN
88
MESIFHEKQEGSLCAQHCLNNL
196
ESIFHEKQEGSLCAQHCLNN

Ataxin-3

LQGEYFSPVELSSIAHQLDEEE

LLQGEYFSPVELSSIAHQLD

RMRMAEGGVTSEDYRTFLQQPS

EEERMRMAEGGVTSEDYRTF

GNMDDSGFFSIQVISNALKVWG

LQQPSGNMDDSGFFSIQVIS

LELILENSPEYQRLRIDPINER

NALKVWGLELILENSPEYQR

SFICNYKEHWFTVRKLGKQWEN

LRIDPINERSFICNYKEHWF

LNSLLTGPELISDTYLALFLAQ

TVRKLGKQWFNLNSLLTGPE

LQQEGYSIFVVKGDLPDCEADQ

LISDTYLALFLAQLQQEGYS

LLQMIRVQQMHRPKLIGEELAQ

IFVVK

LKEQRVHKTDLERVLEANDGSG

MLDEDEEDLQRALALSRQEIDM

EDEEADLRRAIQLSMQGSSRNI

SQDMTQTSGTNLTSEELRKRRE

AYFEKQQQKQQQQQQQQQQGDL

SGQSSHPCERPATSSGALGSDL

GDAMSEEDMLQAAVTMSLETVR

NDLKTEGKK

JOS2_HUMAN
89
MSQAPGAQPSPPTVYHERQRLE
197
PTVYHERQRLELCAVHALNN

Josephin-2

LCAVHALNNVLQQQLESQEAAD

VLQQQLFSQEAADEICKRLA

EICKRLAPDSRLNPHRSLLGTG

PDSRLNPHRSLLGTGNYDVN

NYDVNVIMAALQGLGLAAVWWD

VIMAALQGLGLAAVWWDRRR

RRRPLSQLALPQVLGLILNLPS

PLSQLALPQVLGLILNLPSP

PVSLGLLSLPLRRRHWVALRQV

VSLGLLSLPLRRRHWVALRQ

DGVYYNLDSKLRAPEALGDEDG

VDGVYYNLDSKLRAPEALGD

VRAFLAAALAQGLCEVLLVVTK

EDGVRAFLAAALAQGLCEVL

EVEEKGSWLRTD

LVV

JOS1_HUMAN
90
MSCVPWKGDKAKSESLELPQAA
198
PQAAPPQIYHEKQRRELCAL

Josephin-1

PPQIYHEKQRRELCALHALNNV

HALNNVFQDSNAFTRDTLQE

FQDSNAFTRDTLQEIFQRLSPN

IFQRLSPNTMVTPHKKSMLG

TMVTPHKKSMLGNGNYDVNVIM

NGNYDVNVIMAALQTKGYEA

AALQTKGYEAVWWDKRRDVGVI

VWWDKRRDVGVIALTNVMGF

ALTNVMGFIMNLPSSLCWGPLK

IMNLPSSLCWGPLKLPLKRQ

LPLKRQHWICVREVGGAYYNLD

HWICVREVGGAYYNLDSKLK

SKLKMPEWIGGESELRKFLKHH

MPEWIGGESELRKFLKHHLR

LRGKNCELLLVVPEEVEAHQSW

GKNCELLLVV

RTDV

ATX3L_HUMAN
91
MDFIFHEKQEGFLCAQHCLNNL
199
DFIFHEKQEGFLCAQHCLNN

Ataxin-

LQGEYFSPVELASIAHQLDEEE

LLQGEYFSPVELASIAHQLD

3-like protein

RMRMAEGGVTSEEYLAFLQQPS

EEERMRMAEGGVTSEEYLAF

ENMDDTGFFSIQVISNALKEWG

LQQPSENMDDTGFFSIQVIS

LEIIHENNPEYQKLGIDPINER

NALKFWGLEIIHENNPEYQK

SFICNYKQHWFTIRKEGKHWEN

LGIDPINERSFICNYKQHWE

LNSLLAGPELISDTCLANFLAR

TIRKFGKHWENLNSLLAGPE

LQQQAYSVFVVKGDLPDCEADQ

LISDTCLANFLARLQQQAYS

LLQIISVEEMDTPKLNGKKLVK

VFVVK

QKEHRVYKTVLEKVSEESDESG

TSDQDEEDFQRALELSRQETNR

EDEHLRSTIELSMQGSSGNTSQ

DLPKTSCVTPASEQPKKIKEDY

FEKHQQEQKQQQQQSDLPGHSS

YLHERPTTSSRAIESDLSDDIS

EGTVQAAVDTILEIMRKNLKIK

GEK

MINY3_HUMAN
92
MSELTKELMELVWGTKSSPGLS
200
CRWTQGFVFSESEGSALEQF

Ubiquitin

DTIFCRWTQGFVESESEGSALE

EGGPCAVIAPVQAFLLKKLL

carboxyl-

QFEGGPCAVIAPVQAFLLKKLL

FSSEKSSWRDCSEEEQKELL

terminal

FSSEKSSWRDCSEEEQKELLCH

CHTLCDILESACCDHSGSYC

hydrolase

TLCDILESACCDHSGSYCLVSW

LVSWLRGKTTEETASISGSP

MINDY-3

LRGKTTEETASISGSPAESSCQ

AESSCQVEHSSALAVEELGF

VEHSSALAVEELGFERFHALIQ

ERFHALIQKRSFRSLPELKD

KRSFRSLPELKDAVLDQYSMWG

AVLDQYSMWGNKFG

NKFGVLLFLYSVLLTKGIENIK

VLLFLYSVLLTKGIENIKNE

NEIEDASEPLIDPVYGHGSQSL

IEDASEPLIDPVYGHGSQSL

INLLLTGHAVSNVWDGDRECSG

INLLLTGHAVSNVWDGDREC

MKLLGIHEQAAVGELTLMEALR

SGMKLLGIHEQAAVGELTLM

YCKVGSYLKSPKFPIWIVGSET

EALRYCKVGSYLKSPKFPIW

HLTVFFAKDMALVA

IVGSETHLTVFFAKDMALVA

PEAPSEQARRVFQTYDPEDNGF

PEAPSEQARRVFQTYDPEDN

IPDSLLEDVMKALDLVSDPEYI

GFIPDSLLEDVMKALDLVSD

NLMKNKLDPEGLGIILLGPFLQ

PEYINLMKNKLDPEGIGIIL

EFFPDQGSSGPESFTVYHYNGL

LGPFLQEFFPDQGSSGPESF

KQSNYNEKVMYVEGTAVVMGFE

TVYHYNGLKQSNYNEKVMYV

DPMLQTDDTPIKRCLQTKWPYI

EGTAVVMGFEDPMLQTDDTP

ELLWTTDRSPSLN

IKRCLQTKWPYIELLWTTDR

SPSLN

MINY1_HUMAN
93
MEYHQPEDPAPGKAGTAEAVIP
201
YCVKWIPWKGEQTPIITQST

Ubiquitin

ENHEVLAGPDEHPQDTDARDAD

NGPCPLLAIMNILFLQWKVK

carboxyl-

GEAREREPADQALLPSQCGDNL

LPPQKEVITSDELMAHLGNC

terminal

ESPLPEASSAPPGPTLGTLPEV

LLSIKPQEKSEGLQLNFQQN

hydrolase

ETIRACSMPQELPQSPRTRQPE

VDDAMTVLPKLATGLDVNVR

MINDY-1

PDFYCVKWIPWKGEQTPIITQS

FTGVSDFEYTPECSVEDLLG

TNGPCPLLAIMNILFLQWKVKL

IPLYHGWLVDPQSPEAVRAV

PPQKEVITSDELMAHLGNCLLS

GKLSYNQLVERIITCKHSSD

IKPQEKSEGLQLNFQQNVDDAM

TNLVTEGLIAEQFLETTAAQ

TVLPKLATGLDVNVRFTGVSDF

LTYHGLCELTAAAKEGELSV

EYTPECSVEDLLGIPLYHGWLV

FFRNNHFSTMTKHKSHLYLL

DPQSPEAVRAVGKLSYNQLVER

VTDQGFLQEEQVVWESLHNV

IITCKHSSDTNLVTEGLIAEQF

DGDSCFCDSDFHLSHSLGKG

LETTAAQLTYHGLC

PGAEGGSGSPETQLQVDQDY

ELTAAAKEGELSVFFRNNHEST

LIALSLQQQQPRGPLGLTDL

MTKHKSHLYLLVTDQGELQEEQ

ELAQQLQQEEYQQQQAAQPV

VVWESLHNVDGDSCFCDSDEHL

RMRTRVLSLQGRGATSGRPA

SHSLGKGPGAEGGSGSPETQLQ

GERRQRPKHESDCILL

VDQDYLIALSLQQQQPRGPLGL

TDLELAQQLQQEEYQQQQAAQP

VRMRTRVLSLQGRGATSGRPAG

ERRQRPKHESDCILL

MINY2_HUMAN
94
MESSPESLQPLEHGVAAGPASG
202
YHIKWIQWKEENTPIITQNE

Ubiquitin

TGSSQEGLQETRLAAGDGPGVW

NGPCPLLAILNVLLLAWKVK

carboxyl-

AAETSGGNGLGAAAARRSLPDS

LPPMMEIITAEQLMEYLGDY

terminal

ASPAGSPEVPGPCSSSAGLDLK

MLDAKPKEISEIQRLNYEQN

hydrolase

DSGLESPAAAEAPLRGQYKVTA

MSDAMAILHKLQTGLDVNVR

MINDY-2

SPETAVAGVGHELGTAGDAGAR

FTGVRVFEYTPECIVEDLLD

PDLAGTCQAELTAAGSEEPSSA

IPLYHGWLVDPQIDDIVKAV

GGLSSSCSDPSPPGESPSLDSL

GNCSYNQLVEKIISCKQSDN

ESFSNLHSFPSSCEENSEEGAE

SELVSEGFVAEQFLNNTATQ

NRVPEEEEGAAVLPGAVPLCKE

LTYHGLCELTSTVQEGELCV

EEGEETAQVLAASKERFPGQSV

FFRNNHFSTMTKYKGQLYLL

YHIKWIQWKEENTPIITQNENG

VTDQGFLTEEKVVWESLHNV

PCPLLAILNVLLLAWKVKLPPM

DGDGNFCDSEFHLRPPSDPE

MEIITAEQLMEYLG

TVYKGQQDQIDQDYLMALSL

DYMLDAKPKEISEIQRLNYEQN

QQEQQSQEINWEQIPEGISD

MSDAMAILHKLQTGLDVNVRFT

LELAKKLQEEEDRRASQYYQ

GVRVFEYTPECIVEDLLDIPLY

EQEQAAAAAAAASTQAQQGQ

HGWLVDPQIDDIVKAVGNCSYN

PAQASPSSGRQSGNSERKRK

QLVEKIISCKQSDNSELVSEGF

EPREKDKEKEKEKNSCVIL

VAEQFLNNTATQLTYHGLCELT

STVQEGELCVFFRNNHESTMTK

YKGQLYLLVTDQGELTEEKVVW

ESLHNVDGDGNFCDSEFHLRPP

SDPETVYKGQQDQIDQDYLMAL

SLQQEQQSQEINWEQIPEGISD

LELAKKLQEEEDRRASQYYQEQ

EQAAAAAAAASTQAQQGQPAQA

SPSSGRQSGNSERKRKEPREKD

KEKEKEKNSCVIL

MINY4_HUMAN
95
MDSLFVEEVAASLVREFLSRKG
203
FCCFNEEWKLQSESESNTAS

Probable

LKKTCVTMDQERPRSDLSINNR

LKYGIVQNKGGPCGVLAAVQ

ubiquitin

NDLRKVLHLEFLYKENKAKENP

GCVLQKLLFEGDSKADCAQG

carboxyl-

LKTSLELITRYFLDHEGNTANN

LQPSDAHRTRCLVLALADIV

terminal

FTQDTPIPALSVPKKNNKVPSR

WRAGGRERAVVALASRTQQF

hydrolase

CSETTLVNIYDLSDEDAGWRTS

SPTGKYKADGVLETLTLHSL

MINDY-4

LSETSKARHDNLDGDVLGNFVS

TCYEDLVTFLQQSIHQFEVG

SKRPPHKSKPMQTVPGETPVLT

PYGCILLTLSAILSRSTELI

SAWEKIDKLHSEPSLDVKRMGE

RQDFDVPTSHLIGAHGYCTQ

NSRPKSGLIVRGMMSGPIASSP

ELVNLLLTGKAVSNVENDVV

QDSFHRHYLRRSSPSSSSTQPQ

ELDSGDGNITLLRGIAARSD

EESRKVPELFVCTQQDILASSN

IGFLSLFEHYNMCQVGCFLK

SSPSRTSLGQLSELTVERQKTT

TPRFPIWVVCSESHESILES

ASSPPHLPSKRLPP

LQPGLLRDWRTERLEDLYYY

WDRARPRDPSEDTPAVDGSTDT

DGLANQQEQIRLTIDTTQTI

DRMPLKLYLPGGNSRMTQERLE

SEDTDNDLVPPLELCIRTKW

RAFKRQGSQPAPVRKNQLLPSD

KGASVNWNGSDPIL

KVDGELGALRLEDVEDELIREE

VILSPVPSVLKLQTASKPIDLS

VAKEIKTLLFGSSFCCENEEWK

LQSFSFSNTASLKYGIVQNKGG

PCGVLAAVQGCVLQKLLFEGDS

KADCAQGLQPSDAHRTRCLVLA

LADIVWRAGGRERAVVALASRT

QQFSPTGKYKADGVLETLTLHS

LTCYEDLVTFLQQSIHQFEVGP

YGCILLTLSAILSRSTELIRQD

FDVPTSHLIGAHGY

CTQELVNLLLTGKAVSNVENDV

VELDSGDGNITLLRGIAARSDI

GFLSLFEHYNMCQVGCFLKTPR

FPIWVVCSESHESILFSLQPGL

LRDWRTERLEDLYYYDGLANQQ

EQIRLTIDTTQTISEDTDNDLV

PPLELCIRTKWKGASVNWNGSD

PIL

STABP_HUMAN
96
MSDHGDVSLPPEDRVRALSQLG
204
VVPGRLCPQFLQLASANTAR

STAM-

SAVEVNEDIPPRRYFRSGVEII

GVETCGILCGKLMRNEFTIT

binding

RMASIYSEEGNIEHAFILYNKY

HVLIPKQSAGSDYCNTENEE

protein

ITLFIEKLPKHRDYKSAVIPEK

ELFLIQDQQGLITLGWIHTH

KDTVKKLKEIAFPKAEELKAEL

PTQTAFLSSVDLHTHCSYQM

LKRYTKEYTEYNEEKKKEAEEL

MLPESVAIVCSPKFQETGFF

ARNMAIQQELEKEKQRVAQQKQ

KLTDHGLEEISSCRQKGFHP

QQLEQEQFHAFEEMIRNQELEK

HSKDPPLFCSCSHVTVVDRA

ERLKIVQEFGKVDPGLGGPLVP

VTITDLR

DLEKPSLDVEPTLTVSSIQPSD

CHTTVRPAKPPVVDRSLKPGAL

SNSESIPTIDGLRHVVVPGRLC

PQFLQLASANTARGVETCGILC

GKLMRNEFTITHVL

IPKQSAGSDYCNTENEEELFLI

QDQQGLITLGWIHTHPTQTAFL

SSVDLHTHCSYQMMLPESVAIV

CSPKFQETGFFKLTDHGLEEIS

SCRQKGFHPHSKDPPLFCSCSH

VTVVDRAVTITDLR

MPND_HUMAN
97
MAAPEPLSPAGGAGEEAPEEDE
205
VAVSSNVLFLLDFHSHLTRS

MPN

DEAEAEDPERPNAGAGGGRSGG

EVVGYLGGRWDVNSQMLTVL

domain-

GGSSVSGGGGGGGAGAGGCGGP

RAFPCRSRLGDAETAAAIEE

containing

GGALTRRAVTLRVLLKDALLEP

EIYQSLFLRGLSLVGWYHSH

protein

GAGVLSIYYLGKKELGDLQPDG

PHSPALPSLQDIDAQMDYQL

RIMWQETGQTENSPSAWATHCK

RLQGSSNGFQPCLALLCSPY

KLVNPAKKSGCGWASVKYKGQK

YSGNPGPESKISPFWVMPPP

LDKYKATWLRLHQLHTPATAAD

EMLLVEFYKGSPDLVRLQEP

ESPASEGEEEELLMEEEEEDVL

WSQEHTYLDKLKISLASRTP

AGVSAEDKSRRPLGKSPSEPAH

KDQSLCHVLEQVCGVLKQGS

PEATTPGKRVDSKIRVPVRYCM

LGSRDLARNPHTLVEVTSFAAI

NKFQPFNVAVSSNVLELLDEHS

HLTRSEVVGYLGGR

WDVNSQMLTVLRAFPCRSRLGD

AETAAAIEEEIYQSLFLRGLSL

VGWYHSHPHSPALPSLQDIDAQ

MDYQLRLQGSSNGFQPCLALLC

SPYYSGNPGPESKISPFWVMPP

PEMLLVEFYKGSPDLVRLQEPW

SQEHTYLDKLKISLASRTPKDQ

SLCHVLEQVCGVLKQGS

EMC9_HUMAN
98
MGEVEISALAYVKMCLHAARYP
206
ALAYVKMCLHAARYPHAAVN

ER

HAAVNGLFLAPAPRSGECLCLT

GLFLAPAPRSGECLCLTDCV

membrane

DCVPLFHSHLALSVMLEVALNQ

PLFHSHLALSVMLEVALNQV

protein

VDVWGAQAGLVVAGYYHANAAV

DVWGAQAGLVVAGYYHANAA

complex

NDQSPGPLALKIAGRIAEFFPD

VNDQSPGPLALKIAGRIAEF

subunit 9

AVLIMLDNQKLVPQPRVPPVIV

FPDAVLIMLDNQKLVPQPRV

LENQGLRWVPKDKNLVMWRDWE

PPVIVLENQGLRWVPKDKNL

ESRQMVGALLEDRAHQHLVDED

VMWRDWEESRQMVGALLEDR

CHLDDIRQDWTNQRLNTQITQW

AHQHLVDEDCHLDDIRQDWT

VGPTNGNGNA

NQRLNTQITQWVGPTNGNGN

A

PSDE_HUMAN
99
MDRLLRLGGGMPGLGQGPPTDA
207
QVYISSLALLKMLKHGRAGV

26S

PAVDTAEQVYISSLALLKMLKH

PMEVMGLMLGEFVDDYTVRV

proteasome

GRAGVPMEVMGLMLGEFVDDYT

IDVFAMPQSGTGVSVEAVDP

non-ATPase

VRVIDVFAMPQSGTGVSVEAVD

VFQAKMLDMLKQTGRPEMVV

regulatory

PVFQAKMLDMLKQTGRPEMVVG

GWYHSHPGFGCWLSGVDINT

subunit 14

WYHSHPGFGCWLSGVDINTQQS

QQSFEALSERAVAVVVDPIQ

FEALSERAVAVVVDPIQSVKGK

SVKGKVVIDAFRLINANMMV

VVIDAFRLINANMMVLGHEPRQ

LGHEPRQTTSNLGHLNKPSI

TTSNLGHLNKPSIQALIHGLNR

QALIHGLNRHYYSITINYRK

HYYSITINYRKNELEQKMLLNL

NELEQKMLLNLHKKSWMEGL

HKKSWMEGLTLQDYSEHCKHNE

TLQDYSEHCKHNESVVKEML

SVVKEMLELAKNYNKAVEEEDK

ELAKNYNKAVEEEDKMTPEQ

MTPEQLAIKNVGKQDPKRHLEE

LAIKNVGKQDPKRHLEEHVD

HVDVLMTSNIVQCLAAMLDTVV

VLMTSNIVQCLAAMLDTVVE

FK

K

MYSM1_HUMAN
100
MAAEEADVDIEGDVVAAAGAQP
208
QVKVASEALLIMDLHAHVSM

Histone

GSGENTASVLQKDHYLDSSWRT

AEVIGLLGGRYSEVDKVVEV

H2A

ENGLIPWTLDNTISEENRAVIE

CAAEPCNSLSTGLQCEMDPV

deubiquitinase

KMLLEEEYYLSKKSQPEKVWLD

SQTQASETLAVRGESVIGWY

MYSM1

QKEDDKKYMKSLQKTAKIMVHS

HSHPAFDPNPSLRDIDTQAK

PTKPASYSVKWTIEEKELFEQG

YQSYFSRGGAKFIGMIVSPY

LAKFGRRWTKISKLIGSRTVLQ

NRNNPLPYSQITCLVISEEI

VKSYARQYFKNKVKCGLDKETP

SPDGSYRLPYKFEVQQMLEE

NQKTGHNLQVKNEDKGTKAWTP

PQWGLVFEKTRWIIEKYRLS

SCLRGRADPNLNAVKIEKLSDD

HSSVPMDKIFRRDSDLTCLQ

EEVDITDEVDELSSQTPQKNSS

KLLECMRKTLSKVTNCFMAE

SDLLLDFPNSKMHETNQGEFIT

EFLTEIENLFLSNYKSNQEN

SDSQEALESKSSRGCLQNEKQD

GVTEENCTKELLM

ETLSSSEITLWTEK

QSNGDKKSIELNDQKENELIKN

CNKHDGRGIIVDARQLPSPEPC

EIQKNLNDNEMLFHSCQMVEES

HEEEELKPPEQEIEIDRNIIQE

EEKQAIPEFFEGRQAKTPERYL

KIRNYILDQWEICKPKYLNKTS

VRPGLKNCGDVNCIGRIHTYLE

LIGAINFGCEQAVYNRPQTVDK

VRIRDRKDAVEAYQLAQRLQSM

RTRRRRVRDPWGNWCDAKDLEG

QTFEHLSAEELAKRREEEKGRP

VKSLKVPRPTKSSFDPFQLIPC

NFFSEEKQEPFQVKVASEALLI

MDLHAHVSMAEVIG

LLGGRYSEVDKVVEVCAAEPCN

SLSTGLQCEMDPVSQTQASETL

AVRGFSVIGWYHSHPAFDPNPS

LRDIDTQAKYQSYFSRGGAKFI

GMIVSPYNRNNPLPYSQITCLV

ISEEISPDGSYRLPYKFEVQQM

LEEPQWGLVFEKTRWIIEKYRL

SHSSVPMDKIFRRDSDLTCLQK

LLECMRKTLSKVINCEMAEEFL

TEIENLELSNYKSNQENGVTEE

NCTKELLM

ABRX2_HUMAN
101
MAASISGYTFSAVCFHSANSNA
209
AVCFHSANSNADHEGELLGE

BRISC

DHEGELLGEVRQEETFSISDSQ

VRQEETFSISDSQISNTEFL

complex

ISNTEFLQVIEIHNHQPCSKLE

QVIEIHNHQPCSKLESFYDY

subunit

SFYDYASKVNEESLDRILKDRR

ASKVNEESLDRILKDRRKKV

Abraxas 2

KKVIGWYRFRRNTQQQMSYREQ

IGWYRFRRNTQQQMSYREQV

VLHKQLTRILGVPDLVELLESF

LHKQLTRIL

ISTANNSTHALEYVLERPNRRY

GVPDLVELLESFISTANNST

NQRISLAIPNLGNTSQQEYKVS

HALEYVLERPNRRYNQRISL

SVPNTSQSYAKVIKEHGTDFFD

AIPNLGNTSQQEYKVSSVPN

KDGVMKDIRAIYQVYNALQEKV

TSQSYAKVIKEHGTDFEDKD

QAVCADVEKSERVVESCQAEVN

GVMKDIRAIYQVYNALQEKV

KLRRQITQRKNEKEQERRLQQA

QAVCADVEKSERVVESCQAE

VLSRQMPSESLDPAFSPRMPSS

VNKLRRQITQRKNEKEQERR

GFAAEGRSTLGDAE

LQQAVLSRQMPSESLDPAFS

ASDPPPPYSDFHPNNQESTLSH

PRMPSSGFAAEGRSTLGDAE

SRMERSVEMPRPQAVGSSNYAS

ASDPPPPYSDFHPNNQESTL

TSAGLKYPGSGADLPPPQRAAG

SHSRMERSVEMPRPQAVGSS

DSGEDSDDSDYENLIDPTEPSN

NYASTSAGLKYPGSGADLPP

SEYSHSKDSRPMAHPDEDPRNT

PQRAAGDSGEDSDDSDYENL

QTSQI

IDPTEPSNSEYSHSKDSRPM

AHPDEDPRNTQTSQI

PRP8_HUMAN
102
MAGVFPYRGPGNPVPGPLAPLP
210
FNPRTGQLELKIIHTSVWAG

Pre-mRNA-

DYMSEEKLQEKARKWQQLQAKR

QKRLGQLAKWKTAEEVAALI

processing-

YAEKRKFGFVDAQKEDMPPEHV

RSLPVEEQPKQIIVTRKGML

splicing factor

RKIIRDHGDMTNRKFRHDKRVY

DPLEVHLLDEPNIVIKGSEL

8

LGALKYMPHAVLKLLENMPMPW

QLPFQACLKVEKFGDLILKA

EQIRDVPVLYHITGAISFVNEI

TEPQMVLENLYDDWLKTISS

PWVIEPVYISQWGSMWIMMRRE

YTAFSRLILILRALHVNNDR

KRDRRHFKRMRFPPEDDEEPPL

AKVILKPDKTTITEPHHIWP

DYADNILDVEPLEAIQLELDPE

TLTDEEWIKVEVQLKDLILA

EDAPVLDWFYDHQPLRDSRKYV

DYGKKNNVNVASLTQSEIRD

NGSTYQRWQFTLPMMSTLYRLA

IILGMEISAPSQQRQQIAEI

NQLLTDLVDDNYFYLFDLKAFF

EKQTKEQSQLTATQTRTVNK

TSKALNMAIPGGPKFEPLVRDI

HGDEIITSTTSNYETQTESS

NLQDEDWNEENDIN

KTEWRVRAISAANLHLRTNH

KIIIRQPIRTEYKIAFPYLYNN

IYVSSDDIKETGYTYILPKN

LPHHVHLTWYHTPNVVFIKTED

VLKKFICISDLRAQIAGYLY

PDLPAFYFDPLINPISHRHSVK

GVSPPDNPQVKEIRCIVMVP

SQEPLPDDDEEFELPEFVEPEL

QWGTHQTVHLPGQLPQHEYL

KDTPLYTDNTANGIALLWAPRP

KEMEPLGWIHTQPNESPQLS

FNLRSGRTRRALDIPLVKNWYR

PQDVTTHAKIMADNPSWDGE

EHCPAGQPVKVRVSYQKLLKYY

KTIIITCSFTPGSCTLTAYK

VLNALKHRPPKAQKKRYLFRSF

LTPSGYEWGRQNTDKGNNPK

KATKFFQSTKLDWVEVGLQVCR

GYLPSHYERVOMLLSDRELG

QGYNMLNLLIHRKNLNYLHLDY

FFMVPAQSSWNYNEMGVRHD

NFNLKPVKTLTTKERKKSREGN

PNMKYELQLANPKEFYHEVH

AFHLCREVLRLTKLVVDSHVQY

RPSHELNFALLQEGEVYSAD

RLGNVDAFQLADGLQYIFAHVG

REDLYA

QLTGMYRYKYKLMR

QIRMCKDLKHLIYYRENTGPVG

KGPGCGFWAAGWRVWLFFMRGI

TPLLERWLGNLLARQFEGRHSK

GVAKTVTKQRVESHEDLELRAA

VMHDILDMMPEGIKQNKARTIL

QHLSEAWRCWKANIPWKVPGLP

TPIENMILRYVKAKADWWTNTA

HYNRERIRRGATVDKTVCKKNL

GRLTRLYLKAEQERQHNYLKDG

PYITAEEAVAVYTTTVHWLESR

RESPIPFPPLSYKHDTKLLILA

LERLKEAYSVKSRLNQSQREEL

GLIEQAYDNPHEALSRIKRHLL

TQRAFKEVGIEFMD

LYSHLVPVYDVEPLEKITDAYL

DQYLWYEADKRRLFPPWIKPAD

TEPPPLLVYKWCQGINNLQDVW

ETSEGECNVMLESRFEKMYEKI

DLTLLNRLLRLIVDHNIADYMT

AKNNVVINYKDMNHTNSYGIIR

GLQFASFIVQYYGLVMDLLVLG

LHRASEMAGPPQMPNDFLSFQD

IATEAAHPIRLFCRYIDRIHIF

FRFTADEARDLIQRYLTEHPDP

NNENIVGYNNKKCWPRDARMRL

MKHDVNLGRAVEWDIKNRLPRS

VTTVQWENSFVSVYSKDNPNLL

FNMCGFECRILPKC

RTSYEEFTHKDGVWNLQNEVTK

ERTAQCFLRVDDESMQRFHNRV

RQILMASGSTTFTKIVNKWNTA

LIGLMTYFREAVVNTQELLDLL

VKCENKIQTRIKIGLNSKMPSR

FPPVVFYTPKELGGLGMLSMGH

VLIPQSDLRWSKQTDVGITHER

SGMSHEEDQLIPNLYRYIQPWE

SEFIDSQRVWAEYALKRQEAIA

QNRRLTLEDLEDSWDRGIPRIN

TLFQKDRHTLAYDKGWRVRTDE

KQYQVLKQNPFWWTHQRHDGKL

WNLNNYRTDMIQALGGVEGILE

HTLFKGTYFPTWEG

LFWEKASGFEESMKWKKLTNAQ

RSGLNQIPNRRFTLWWSPTINR

ANVYVGFQVQLDLTGIFMHGKI

PTLKISLIQIFRAHLWQKIHES

IVMDLCQVEDQELDALEIETVQ

KETIHPRKSYKMNSSCADILLE

ASYKWNVSRPSLLADSKDVMDS

TTTQKYWIDIQLRWGDYDSHDI

ERYARAKFLDYTTDNMSIYPSP

TGVLIAIDLAYNLHSAYGNWFP

GSKPLIQQAMAKIMKANPALYV

LRERIRKGLQLYSSEPTEPYLS

SQNYGELFSNQIIWFVDDTNVY

RVTIHKTFEGNLTT

KPINGAIFIENPRTGQLELKII

HTSVWAGQKRLGQLAKWKTAEE

VAALIRSLPVEEQPKQIIVTRK

GMLDPLEVHLLDEPNIVIKGSE

LQLPFQACLKVEKFGDLILKAT

EPQMVLFNLYDDWLKTISSYTA

FSRLILILRALHVNNDRAKVIL

KPDKTTITEPHHIWPTLTDEEW

IKVEVQLKDLILADYGKKNNVN

VASLTQSEIRDIILGMEISAPS

QQRQQIAEIEKQTKEQSQLTAT

QTRTVNKHGDEIITSTTSNYET

QTFSSKTEWRVRAISAANLHLR

TNHIYVSSDDIKET

GYTYILPKNVLKKFICISDLRA

QIAGYLYGVSPPDNPQVKEIRC

IVMVPQWGTHQTVHLPGQLPQH

EYLKEMEPLGWIHTQPNESPQL

SPQDVTTHAKIMADNPSWDGEK

TIIITCSFTPGSCTLTAYKLTP

SGYEWGRQNTDKGNNPKGYLPS

HYERVQMLLSDRELGFFMVPAQ

SSWNYNEMGVRHDPNMKYELQL

ANPKEFYHEVHRPSHELNFALL

QEGEVYSADREDLYA

NPL4_HUMAN
103
MAESIIIRVQSPDGVKRITATK
211
QPSAITLNRQKYRHVDNIME

Nuclear

RETAATFLKKVAKEFGFQNNGE

ENHTVADRFLDFWRKTGNQH

protein

SVYINRNKTGEITASSNKSLNL

FGYLYGRYTEHKDIPLGIRA

localization

LKIKHGDLLFLFPSSLAGPSSE

EVAAIYEPPQIGTQNSLELL

protein 4

METSVPPGFKVEGAPNVVEDEI

EDPKAEVVDEIAAKLGLRKV

homolog

DQYLSKQDGKIYRSRDPQLCRH

GWIFTDLVSEDTRKGTVRYS

GPLGKCVHCVPLEPFDEDYLNH

RNKDTYFLSSEECITAGDFQ

LEPPVKHMSFHAYIRKLTGGAD

NKHPNMCRLSPDGHFGSKFV

KGKFVALENISCKIKSGCEGHL

TAVATGGPDNQVHFEGYQVS

PWPNGICTKCQPSAITLNRQKY

NQCMALVRDECLLPCKDAPE

RHVDNIMFENHTVADRELDEWR

LGYAKESSSEQYVPDVFYKD

KTGNQHFGYLYGRYTEHKDIPL

VDKFGNEITQLARPLPVEYL

GIRAEVAAIYEPPQIGTQNSLE

IIDITTTFPKDPVYTESISQ

LLEDPKAEVVDEIA

NPFPIENRDVLGETQDFHSL

AKLGLRKVGWIFTDLVSEDTRK

ATYLSQNTSSVELDTISDFH

GTVRYSRNKDTYFLSSEECITA

LLLFLVTNEVMPLQDSISLL

GDFQNKHPNMCRLSPDGHFGSK

LEAVRTRNEELAQTWKRSEQ

FVTAVATGGPDNQVHFEGYQVS

WATIEQLCSTVGGQLPGLHE

NQCMALVRDECLLPCKDAPELG

YGAVGGSTHTATAAMWACQH

YAKESSSEQYVPDVFYKDVDKF

CTFMNQPGTGHCEMCSLPRT

GNEITQLARPLPVEYLIIDITT

TFPKDPVYTESISQNPFPIENR

DVLGETQDFHSLATYLSQNTSS

VELDTISDFHLLLFLVTNEVMP

LQDSISLLLEAVRTRNEELAQT

WKRSEQWATIEQLCSTVGGQLP

GLHEYGAVGGSTHTATAAMWAC

QHCTFMNQPGTGHCEMCSLPRT

EMC8_HUMAN
104
MPGVKLTTQAYCKMVLHGAKYP
212
TQAYCKMVLHGAKYPHCAVN

ER

HCAVNGLLVAEKQKPRKEHLPL

GLLVAEKQKPRKEHLPLGGP

membrane

GGPGAHHTLFVDCIPLFHGTLA

GAHHTLFVDCIPLFHGTLAL

protein

LAPMLEVALTLIDSWCKDHSYV

APMLEVALTLIDSWCKDHSY

complex

IAGYYQANERVKDASPNQVAEK

VIAGYYQANERVKDASPNQV

subunit 8

VASRIAEGFSDTALIMVDNTKF

AEKVASRIAEGFSDTALIMV

TMDCVAPTIHVYEHHENRWRCR

DNTKFTMDCVAPTIHVYEHH

DPHHDYCEDWPEAQRISASLLD

ENRWRCRDPHHDYCEDWPEA

SRSYETLVDEDNHLDDIRNDWT

QRISASLLDSRSYETLVDED

NPEINKAVLHLC

NHLDDIRNDWTNPEINKAVL

HLC

ABRX1_HUMAN
105
MEGESTSAVLSGFVLGALAFQH
213
GFVLGALAFQHLNTDSDTEG

BRCA1-A

LNTDSDTEGELLGEVKGEAKNS

FLLGEVKGEAKNSITDSQMD

complex

ITDSQMDDVEVVYTIDIQKYIP

DVEVVYTIDIQKYIPCYQLF

subunit

CYQLFSFYNSSGEVNEQALKKI

SFYNSSGEVNEQALKKILSN

Abraxas 1

LSNVKKNVVGWYKFRRHSDQIM

VKKNVVGWYKFRRHSDQIMT

TFRERLLHKNLQEHFSNQDLVE

FRERLLHKNLQEHFSNQDLV

LLLTPSIITESCSTHRLEHSLY

FLLLTPSIITESCSTHRLEH

KPQKGLFHRVPLVVANLGMSEQ

SLYKPQKGLFHRVPLVVANL

LGYKTVSGSCMSTGFSRAVQTH

GMSEQLGYKTVSGSCMSTGF

SSKFFEEDGSLKEVHKINEMYA

SRAVQTHSSKFFEEDGSLKE

SLQEELKSICKKVEDSEQAVDK

VHKINEMYASLQEELKSICK

LVKDVNRLKREIEKRRGAQIQA

KVEDSEQAVDKLVKDVNRLK

AREKNIQKDPQENIFLCQALRT

REIEKRRGAQIQAAREKNIQ

FFPNSEFLHSCVMS

KDPQENIFLCQALRTFFPNS

LKNRHVSKSSCNYNHHLDVVDN

EFLHSCVMSLKNRHVSKSSC

LTLMVEHTDIPEASPASTPQII

NYNHHLDVVDNLTLMVEHTD

KHKALDLDDRWQFKRSRLLDTQ

IPEASPASTPQIIKHKALDL

DKRSKADTGSSNQDKASKMSSP

DDRWQFKRSRLLDTQDKRSK

ETDEEIEKMKGFGEYSRSPTF

ADTGSSNQDKASKMSSPETD

EEIEKMKGFGEYSRSPTF

STALP_HUMAN
106
MDQPFTVNSLKKLAAMPDHTDV
214
VVLPEDLCHKELQLAESNTV

AMSH-

SLSPEERVRALSKLGCNITISE

RGIETCGILCGKLTHNEFTI

like protease

DITPRRYFRSGVEMERMASVYL

THVIVPKQSAGPDYCDMENV

EEGNLENAFVLYNKFITLFVEK

EELFNVQDQHDLLTLGWIHT

LPNHRDYQQCAVPEKQDIMKKL

HPTQTAFLSSVDLHTHCSYQ

KEIAFPRTDELKNDLLKKYNVE

LMLPEAIAIVCSPKHKDTGI

YQEYLQSKNKYKAEILKKLEHQ

FRLTNAGMLEVSACKKKGFH

RLIEAERKRIAQMRQQQLESEQ

PHTKEPRLFSICKHVLVKDI

FLFFEDQLKKQELARGQMRSQQ

KIIVLDLR

TSGLSEQIDGSALSCFSTHQNN

SLLNVFADQPNKSDATNYASHS

PPVNRALTPAATLSAVQNLVVE

GLRCVVLPEDLCHKELQLAESN

TVRGIETCGILCGK

LTHNEFTITHVIVPKQSAGPDY

CDMENVEELFNVQDQHDLLTLG

WIHTHPTQTAFLSSVDLHTHCS

YQLMLPEAIAIVCSPKHKDTGI

FRLTNAGMLEVSACKKKGFHPH

TKEPRLFSICKHVLVKDIKIIV

LDLR

CSN6_HUMAN
107
MAAAAAAAAATNGTGGSSGMEV
215
VALHPLVILNISDHWIRMRS

COP9

DAAVVPSVMACGVTGSVSVALH

QEGRPVQVIGALIGKQEGRN

signalosome

PLVILNISDHWIRMRSQEGRPV

IEVMNSFELLSHTVEEKIII

complex

QVIGALIGKQEGRNIEVMNSFE

DKEYYYTKEEQFKQVFKELE

subunit 6

LLSHTVEEKIIIDKEYYYTKEE

FLGWYTTGGPPDPSDIHVHK

QFKQVFKELEFLGWYTTGGPPD

QVCEIIESPLFLKLNPMTKH

PSDIHVHKQVCEIIESPLELKL

TDLPVSVFESVIDIINGEAT

NPMTKHTDLPVSVFESVIDIIN

MLFAELTYTLATEEAERIGV

GEATMLFAELTYTLATEEAERI

DHVARMTATGSGENSTVAEH

GVDHVARMTATGSGENSTVAEH

LIAQHSAIKMLHSRVKLILE

LIAQHSAIKMLHSRVKLILEYV

YVKASEAGEVPFNHEILREA

KASEAGEVPFNHEILREAYALC

YALCHCLPVLSTDKFKTDFY

HCLPVLSTDKFKTDFYDQCNDV

DQCNDVGLMAYLGTITKTCN

GLMAYLGTITKTCNTMNQFVNK

TMNQFVNKFNVLYDRQGIGR

FNVLYDRQGIGRRMRGLFF

RMRGLFF

EIF3F_HUMAN
108
MATPAVPVSAPPATPTPVPAAA
216
VRLHPVILASIVDSYERRNE

Eukaryotic

PASVPAPTPAPAAAPVPAAAPA

GAARVIGTLLGTVDKHSVEV

translation

SSSDPAAAAAATAAPGQTPASA

TNCFSVPHNESEDEVAVDME

initiation

QAPAQTPAPALPGPALPGPFPG

FAKNMYELHKKVSPNELILG

factor 3

GRVVRLHPVILASIVDSYERRN

WYATGHDITEHSVLIHEYYS

subunit F

EGAARVIGTLLGTVDKHSVEVT

REAPNPIHLTVDTSLQNGRM

NCFSVPHNESEDEVAVDMEFAK

SIKAYVSTLMGVPGRTMGVM

NMYELHKKVSPNELILGWYATG

FTPLTVKYAYYDTERIGVDL

HDITEHSVLIHEYYSREAPNPI

IMKTCFSPNRVIGLSSDLQQ

HLTVDTSLQNGRMSIKAYVSTL

VGGASARIQDALSTVLQYAE

MGVPGRTMGVMFTPLTVKYAYY

DVLSGKVSADNTVGRFLMSL

DTERIGVDLIMKTCFSPNRVIG

VNQVPKIVPDDFETMLNSNI

LSSDLQQVGGASARIQDALSTV

NDLLMVTYLANLTQSQIALN

LQYAEDVLSGKVSADNTVGREL

EKLVNL

MSLVNQVPKIVPDDFETMLNSN

INDLLMVTYLANLTQSQIALNE

KLVNL

PSMD7_HUMAN
109
MPELAVQKVVVHPLVLLSVVDH
217
VVVHPLVLLSVVDHENRIGK

26S

FNRIGKVGNQKRVVGVLLGSWQ

VGNQKRVVGVLLGSWQKKVL

proteasome

KKVLDVSNSFAVPFDEDDKDDS

DVSNSFAVPFDEDDKDDSVW

non-ATPase

VWFLDHDYLENMYGMFKKVNAR

FLDHDYLENMYGMFKKVNAR

regulatory

ERIVGWYHTGPKLHKNDIAINE

ERIVGWYHTGPKLHKNDIAI

subunit 7

LMKRYCPNSVLVIIDVKPKDLG

NELMKRYCPNSVLVIIDVKP

LPTEAYISVEEVHDDGTPTSKT

KDLGLPTEAYISVEEVHDDG

FEHVTSEIGAEEAEEVGVEHLL

TPTSKTFEHVTSEIGAEEAE

RDIKDTTVGTLSQRITNQVHGL

EVGVEHLLRDIKDTTVGTLS

KGLNSKLLDIRSYLEKVATGKL

QRITNQVHGLKGLNSKLLDI

PINHQIIYQLQDVENLLPDVSL

RSYLEKVATGKLPINHQIIY

QEFVKAFYLKTNDQMVVVYLAS

QLQDVFNLLPDVSLQEFVKA

LIRSVVALHNLINNKIANRDAE

FYLKTNDQMVVVYLASLIRS

KKEGQEKEESKKDRKEDKEKDK

VVALHNLINNKIANRDAEKK

DKEKSDVKKEEKKEKK

EGQEKEESKKDRKEDKEKDK

DKEKSDVKKEEKKEKK

EIF3H_HUMAN
110
MASRKEGTGSTATSSSSTAGAA
218
VQIDGLVVLKIIKHYQEEGQ

Eukaryotic

GKGKGKGGSGDSAVKQVQIDGL

GTEVVQGVLLGLVVEDRLEI

translation

VVLKIIKHYQEEGQGTEVVQGV

TNCFPFPQHTEDDADEDEVQ

initiation

LLGLVVEDRLEITNCFPFPQHT

YQMEMMRSLRHVNIDHLHVG

factor 3

EDDADEDEVQYQMEMMRSLRHV

WYQSTYYGSFVTRALLDSQF

subunit H

NIDHLHVGWYQSTYYGSFVTRA

SYQHAIEESVVLIYDPIKTA

LLDSQFSYQHAIEESVVLIYDP

QGSLSLKAYRLTPKLMEVCK

IKTAQGSLSLKAYRLTPKLMEV

EKDESPEALKKANITFEYME

CKEKDFSPEALKKANITFEYME

EEVPIVIKNSHLINVLMWEL

EEVPIVIKNSHLINVLMWELEK

EKKSAVADKHELLSLASSNH

KSAVADKHELLSLASSNHLG

LGKNLQLLMDRVDEMSQDIV

KNLQLLMDRVDEMSQDIVKYNT

KYNTYMRNTSKQQQQKHQYQ

YMRNTSKQQQQKHQYQQRRQQE

QRRQQENMQRQSRGEPPLPE

NMQRQSRGEPPLPEEDLSKLFK

EDLSKLFKPPQPPARMDSLL

PPQPPARMDSLLIAGQINTYCQ

IAGQINTYCQNIKEFTAQNL

NIKEFTAQNLGKLEMAQALQEY

GKLFMAQALQEYNN

NN

CSN5_HUMAN
111
MAASGSGMAQKTWELANNMQEA
219
YCKISALALLKMVMHARSGG

COP9

QSIDEIYKYDKKQQQEILAAKP

NLEVMGLMLGKVDGETMIIM

signalosome

WTKDHHYFKYCKISALALLKMV

DSFALPVEGTETRVNAQAAA

complex

MHARSGGNLEVMGLMLGKVDGE

YEYMAAYIENAKQVGRLENA

subunit 5

TMIIMDSFALPVEGTETRVNAQ

IGWYHSHPGYGCWLSGIDVS

AAAYEYMAAYIENAKQVGRLEN

TQMLNQQFQEPFVAVVIDPT

AIGWYHSHPGYGCWLSGIDVST

RTISAGKVNLGAFRTYPKGY

QMLNQQFQEPFVAVVIDPTRTI

KPPDEGPSEYQTIPLNKIED

SAGKVNLGAFRTYPKGYKPPDE

FGVHCKQYYALEVSYFKSSL

GPSEYQTIPLNKIEDFGVHCKQ

DRKLLELLWNKYWVNTLSSS

YYALEVSYFKSSLDRKLLELLW

SLLTNADYTTGQVEDLSEKL

NKYWVNTLSSSSLLTNADYTTG

EQSEAQLGRGSFMLGLETHD

QVEDLSEKLEQSEAQLGRGSEM

RKSEDKLAKATRDSCKTTIE

LGLETHDRKSEDKLAKATRDSC

AIHGLMSQVIKDKLENQINI

KTTIEAIHGLMSQVIKDKLENQ

S

INIS

BRCC3_HUMAN
112
MAVQVVQAVQAVHLESDAFLVC
220
VHLESDAFLVCLNHALSTEK

Lys-63-

LNHALSTEKEEVMGLCIGELND

EEVMGLCIGELNDDTRSDSK

specific

DTRSDSKFAYTGTEMRTVAEKV

FAYTGTEMRTVAEKVDAVRI

deubiquitinase

DAVRIVHIHSVIILRRSDKRKD

VHIHSVIILRRSDKRKDRVE

BRCC36

RVEISPEQLSAASTEAERLAEL

ISPEQLSAASTEAERLAELT

TGRPMRVVGWYHSHPHITVWPS

GRPMRVVGWYHSHPHITVWP

HVDVRTQAMYQMMDQGEVGLIF

SHVDVRTQAMYQMMDQGFVG

SCFIEDKNTKTGRVLYTCFQSI

LIFSCFIEDKNTKTGRVLYT

QAQKSSESLHGPRDEWSSSQHI

CFQSIQAQKSSESLHGPRDE

SIEGQKEEERYERIEIPIHIVP

WSSSQHISIEGQKEEERYER

HVTIGKVCLESAVELPKILCQE

IEIPIHIVPHVTIGKVCLES

EQDAYRRIHSLTHLDSVIKIHN

AVELPKILCQEEQDAYRRIH

GSVFTKNLCSQMSAVSGPLLQW

SLTHLDSVTKIHNGSVETKN

LEDRLEQNQQHLQELQQEKEEL

LCSQMSAVSGPLLQWLEDRL

MQELSSLE

EQNQQHLQELQQEKEELMQE

LSSLE

5.3.2 Targeting Domain

In some embodiments, the targeting domain comprises a targeting moiety that specifically binds to a target nuclear protein. In some embodiments, the targeting moiety comprises an antibody (or antigen binding fragment thereof). In some embodiments, the antibody is a full-length antibody, a single chain variable fragment (scFv), a (scFv)₂, a scFv-Fc, a Fab, a Fab′, a (Fab′)₂, a F(v), a single domain antibody, a single chain antibody, a VHH, or a (VHH)₂. In some embodiments the targeting moiety comprises a VHH. In some embodiments the targeting moiety comprises a (VHH)₂.

In some embodiments, the targeting moiety specifically binds to a wild type target nuclear protein. In some embodiments, the targeting moiety specifically binds to a wild type target nuclear protein, but does not specifically binds to a variant of the target nuclear protein associated with a genetic disease. In some embodiments, the targeting moiety specifically binds to a naturally occurring variant of a target nuclear protein. In some embodiments, the targeting moiety specifically binds to a naturally occurring variant of a target nuclear protein that is associated with a genetic disease (e.g., a genetic disease described herein). In some embodiments, the targeting moiety specifically binds to a naturally occurring variant of a target nuclear protein that is a cause of a genetic disease (e.g., a genetic disease described herein). In some embodiments, the targeting moiety specifically binds a naturally occurring variant of a target nuclear protein that is a loss of a function variant. In some embodiments, the targeting moiety specifically binds a naturally occurring variant of a target nuclear protein that is a loss of a function variant associated with a genetic disease (e.g., a genetic disease described herein). In some embodiments, the targeting moiety specifically binds a naturally occurring variant of a target nuclear protein that is a loss of a function variant that causes a genetic disease (e.g., a genetic disease described herein).

5.3.2.1 Exemplary Target Nuclear Proteins

In some embodiments, targeting moiety specifically binds a target nuclear protein (e.g., a nuclear protein described herein). Exemplary target nuclear proteins include, but are not limited to, chromodomain-helicase-DNA-binding protein 2 (CHD2), arginine-glutamic acid dipeptide repeats protein (RERE), cyclin-dependent kinase-like 5 (CDKL5), methyl-CpG-binding protein 2 (MECP2), histone-lysine N-methyltransferase 2D (KMT2D), histone-lysine N-methyltransferase SETD5 (SETD5), zinc finger E-box-binding homeobox 2 (ZEB2), and calmodulin-binding transcription activator 1 (CAMTA1), synaptic functional regulator FMR1 (FMR1), pre-mRNA-processing-splicing factor 8 (PRPF8), retinoic acid-induced protein 1 (RAI1), CREB-binding protein (CREBBP), neurofibromin 1 (NF1), histone-lysine N-methyltransferase 2A (KMT2A), chromodomain-helicase-DNA-binding protein 4 (CHD4), histone-lysine N-methyltransferase, H3 lysine-36 specific (NSD1), mediator of RNA polymerase II transcription subunit 13-like (MED13L), structural maintenance of chromosomes protein 1A (SMC1A), probable global transcription activator SNF2L2 (SMARCA2), AT-rich interactive domain-containing protein 1B (ARID1B), pogo transposable element with ZNF domain (POGZ), histone acetyltransferase KAT6B (KAT6B), AT-hook DNA-binding motif-containing protein 1 (AHDC1), histone acetyltransferase p300 (EP300), IQ motif and SEC7 domain-containing protein 2 (IQSEC2), transcription factor 20 (TCF20), putative polycomb group protein ASXL3(ASXL3), and histone acetyltransferase KAT6A (KAT6A). In some embodiments, the target nuclear protein is CHD2. In some embodiments, the target nuclear protein is RERE. In some embodiments, the target nuclear protein is CDKL5. In some embodiments, the target nuclear protein is MECP2. In some embodiments, the target nuclear protein is KMT2D. In some embodiments, the target nuclear protein is SETD5. In some embodiments, the target nuclear protein is ZEB2. In some embodiments, the target nuclear protein is CAMTA1. In some embodiments, the target nuclear protein is FMR1. In some embodiments, the target nuclear protein is PRPF8. In some embodiments, the target nuclear protein is RAI1. In some embodiments, the target nuclear protein is CREBBP. In some embodiments, the target nuclear protein is NF1. In some embodiments, the target nuclear protein is KMT2A. In some embodiments, the target nuclear protein is CHD4. In some embodiments, the target nuclear protein is NSD1. In some embodiments, the target nuclear protein is MED13L. In some embodiments, the target nuclear protein is SMC1A. In some embodiments, the target nuclear protein is SMARCA2. In some embodiments, the target nuclear protein is ARID1B. In some embodiments, the target nuclear protein is POGZ. In some embodiments, the target nuclear protein is KAT6B. In some embodiments, the target nuclear protein is AHDC1. In some embodiments, the target nuclear protein is EP300. In some embodiments, the target nuclear protein is IQSEC2. In some embodiments, the target nuclear protein is TCF20. In some embodiments, the target nuclear protein is ASXL3. In some embodiments, the target nuclear protein is KAT6A.

In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 221. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 222. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 223. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 224. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 225. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 226. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 227. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 228. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 229. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 230. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 231. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 232. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 233. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 234. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 235. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 236. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 237. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 238. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 239. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 240. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 241. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 242. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 243. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 245. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 246. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 247. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 248. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 424. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 425. In some embodiments, the target nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 426.

Table 2 below, provides the wild type amino acid sequence of exemplary proteins to target for deubiquitination utilizing the fusion proteins described herein.

TABLE 2

The amino acid sequence of exemplary nuclear proteins to target for deubiquitination

utilizing the fusion proteins described herein and exemplary disease associations

Disease
SEQ

Description
Associations
ID NO
WT Amino Acid Sequence

Chromodomain-
Epileptic
221
MMRNKDKSQEEDSSLHSNASSHSASEEASGSDSGSQS

helicase-DNA-
encephalopathy,

ESEQGSDPGSGHGSESNSSSESSESQSESESESAGSK

binding protein
childhood-

SQPVLPEAKEKPASKKERIADVKKMWEEYPDVYGVRR

2 (CHD2)
onset

SNRSRQEPSRENIKEEASSGSESGSPKRRGQRQLKKQ

EKWKQEPSEDEQEQGTSAESEPEQKKVKARRPVPRRT

VPKPRVKKQPKTQRGKRKKQDSSDEDDDDDEAPKRQT

RRRAAKNVSYKEDDDFETDSDDLIEMTGEGVDEQQDN

SETIEKVLDSRLGKKGATGASTTVYAIEANGDPSGDE

DTEKDEGEIQYLIKWKGWSYIHSTWESEESLQQQKVK

GLKKLENFKKKEDEIKQWLGKVSPEDVEYENCQQELA

SELNKQYQIVERVIAVKTSKSTLGQTDFPAHSRKPAP

SNEPEYLCKWMGLPYSECSWEDEALIGKKFQNCIDSF

HSRNNSKTIPTRECKALKQRPRFVALKKQPAYLGGEN

LELRDYQLEGLNWLAHSWCKNNSVILADEMGLGKTIQ

TISFLSYLFHQHQLYGPFLIVVPLSTLTSWQREFEIW

APEINVVVYIGDLMSRNTIREYEWIHSQTKRLKENAL

ITTYEILLKDKTVLGSINWAFLGVDEAHRLKNDDSLL

YKTLIDFKSNHRLLITGTPLQNSLKELWSLLHFIMPE

KFEFWEDFEEDHGKGRENGYQSLHKVLEPFLLRRVKK

DVEKSLPAKVEQILRVEMSALQKQYYKWILTRNYKAL

AKGTRGSTSGELNIVMELKKCCNHCYLIKPPEENERE

NGQEILLSLIRSSGKLILLDKLLTRLRERGNRVLIES

QMVRMLDILAEYLTIKHYPFQRLDGSIKGEIRKQALD

HFNADGSEDFCFLLSTRAGGLGINLASADTVVIFDSD

WNPQNDLQAQARAHRIGQKKQVNIYRLVTKGTVEEEI

IERAKKKMVLDHLVIQRMDTTGRTILENNSGRSNSNP

FNKEELTAILKFGAEDLFKELEGEESEPQEMDIDEIL

RLAETRENEVSTSATDELLSQFKVANFATMEDEEELE

ERPHKDWDEIIPEEQRKKVEEEERQKELEEIYMLPRI

RSSTKKAQTNDSDSDTESKRQAQRSSASESETEDSDD

DKKPKRRGRPRSVRKDLVEGETDAEIRRFIKAYKKFG

LPLERLECIARDAELVDKSVADLKRLGELIHNSCVSA

MQEYEEQLKENASEGKGPGKRRGPTIKISGVQVNVKS

IIQHEEEFEMLHKSIPVDPEEKKKYCLTCRVKAAHED

VEWGVEDDSRLLLGIYEHGYGNWELIKTDPELKLTDK

ILPVETDKKPQGKQLQTRADYLLKLLRKGLEKKGAVT

GGEEAKLKKRKPRVKKENKVPRLKEEHGIELSSPRHS

DNPSEEGEVKDDGLEKSPMKKKQKKKENKENKEKQMS

SRKDKEGDKERKKSKDKKEKPKSGDAKSSSKSKRSQG

PVHITAGSEPVPIGEDEDDDLDQETFSICKERMRPVK

KALKQLDKPDKGLNVQEQLEHTRNCLLKIGDRIAECL

KAYSDQEHIKLWRRNLWIFVSKFTEFDARKLHKLYKM

AHKKRSQEEEEQKKKDDVTGGKKPFRPEASGSSRDSL

ISQSHTSHNLHPQKPHLPASHGPQMHGHPRDNYNHPN

KRHFSNADRGDWQRERKENYGGGNNNPPWGSDRHHQY

EQHWYKDHHYGDRRHMDAHRSGSYRPNNMSRKRPYDQ

YSSDRDHRGHRDYYDRHHHDSKRRRSDEFRPQNYHQQ

DERRMSDHRPAMGYHGQGPSDHYRSFHTDKLGEYKQP

LPPLHPAVSDPRSPPSQKSPHDSKSPLDHRSPLERSL

EQKNNPDYNWNVRKT

Arginine-
1p36 Deletion
222
MTADKDKDKDKEKDRDRDRDREREKRDKARESENSRP

glutamic acid
Syndrome

RRSCTLEGGAKNYAESDHSEDEDNDNNSATAEESTKK

dipeptide

NKKKPPKKKSRYERTDTGEITSYITEDDVVYRPGDCV

repeats protein

YIESRRPNTPYFICSIQDFKLVHNSQACCRSPTPALC

(RERE)

DPPACSLPVASQPPQHLSEAGRGPVGSKRDHLLMNVK

WYYRQSEVPDSVYQHLVQDRHNENDSGRELVITDPVI

KNRELFISDYVDTYHAAALRGKCNISHESDIFAAREF

KARVDSFFYILGYNPETRRLNSTQGEIRVGPSHQAKL

PDLQPFPSPDGDTVTQHEELVWMPGVNDCDLLMYLRA

ARSMAAFAGMCDGGSTEDGCVAASRDDTTLNALNTLH

ESGYDAGKALQRLVKKPVPKLIEKCWTEDEVKRFVKG

LRQYGKNFFRIRKELLPNKETGELITFYYYWKKTPEA

ASSRAHRRHRRQAVFRRIKTRTASTPVNTPSRPPSSE

FLDLSSASEDDFDSEDSEQELKGYACRHCFTTTSKDW

HHGGRENILLCTDCRIHFKKYGELPPIEKPVDPPPEM

FKPVKEEDDGLSGKHSMRTRRSRGSMSTLRSGRKKQP

ASPDGRTSPINEDIRSSGRNSPSAASTSSNDSKAETV

KKSAKKVKEEASSPLKSNKRQREKVASDTEEADRTSS

KKTKTQEISRPNSPSEGEGESSDSRSVNDEGSSDPKD

IDQDNRSTSPSIPSPQDNESDSDSSAQQQMLQAQPPA

LQAPTGVTPAPSSAPPGTPQLPTPGPTPSATAVPPQG

SPTASQAPNQPQAPTAPVPHTHIQQAPALHPQRPPSP

HPPPHPSPHPPLQPLTGSAGQPSAPSHAQPPLHGQGP

PGPHSLQAGPLLQHPGPPQPFGLPPQASQGQAPLGTS

PAAAYPHTSLQLPASQSALQSQQPPREQPLPPAPLAM

PHIKPPPTTPIPQLPAPQAHKHPPHLSGPSPESMNAN

LPPPPALKPLSSLSTHHPPSAHPPPLQLMPQSQPLPS

SPAQPPGLTQSQNLPPPPASHPPTGLHQVAPQPPFAQ

HPFVPGGPPPITPPTCPSTSTPPAGPGTSAQPPCSGA

AASGGSIAGGSSCPLPTVQIKEEALDDAEEPESPPPP

PRSPSPEPTVVDTPSHASQSARFYKHLDRGYNSCART

DLYFMPLAGSKLAKKREEAIEKAKREAEQKAREERER

EKEKEKEREREREREREAERAAKASSSAHEGRLSDPQ

LSGPGHMRPSFEPPPTTIAAVPPYIGPDTPALRTLSE

YARPHVMSPTNRNHPFYMPLNPTDPLLAYHMPGLYNV

DPTIRERELREREIREREIRERELRERMKPGFEVKPP

ELDPLHPAANPMEHFARHSALTIPPTAGPHPFASEHP

GLNPLERERLALAGPQLRPEMSYPDRLAAERIHAERM

ASLTSDPLARLQMENVTPHHHQHSHIHSHLHLHQQDP

LHQGSAGPVHPLVDPLTAGPHLARFPYPPGTLPNPLL

GQPPHEHEMLRHPVFGTPYPRDLPGAIPPPMSAAHQL

QAMHAQSAELQRLAMEQQWLHGHPHMHGGHLPSQEDY

YSRLKKEGDKQL

Cyclin-
Epileptic
223
MKIPNIGNVMNKFEILGVVGEGAYGVVLKCRHKETHE

dependent
encephalopathy,

IVAIKKFKDSEENEEVKETTLRELKMLRTLKQENIVE

kinase-like 5
early infantile

LKEAFRRRGKLYLVFEYVEKNMLELLEEMPNGVPPEK

(CDKL5)
Type 2

VKSYIYQLIKAIHWCHKNDIVHRDIKPENLLISHNDV

LKLCDFGFARNLSEGNNANYTEYVATRWYRSPELLLG

APYGKSVDMWSVGCILGELSDGQPLEPGESEIDQLET

IQKVLGPLPSEQMKLFYSNPRFHGLRFPAVNHPQSLE

RRYLGILNSVLLDLMKNLLKLDPADRYLTEQCLNHPT

FQTQRLLDRSPSRSAKRKPYHVESSTLSNRNQAGKST

ALQSHHRSNSKDIQNLSVGLPRADEGLPANESFLNGN

LAGASLSPLHTKTYQASSQPGSTSKDLINNNIPHLLS

PKEAKSKTEFDFNIDPKPSEGPGTKYLKSNSRSQQNR

HSFMESSQSKAGTLQPNEKQSRHSYIDTIPQSSRSPS

YRTKAKSHGALSDSKSVSNLSEARAQIAEPSTSRYFP

SSCLDLNSPTSPTPTRHSDTRTLLSPSGRNNRNEGTL

DSRRTTTRHSKTMEELKLPEHMDSSHSHSLSAPHESE

SYGLGYTSPESSQQRPHRHSMYVTRDKVRAKGLDGSL

SIGQGMAARANSLQLLSPQPGEQLPPEMTVARSSVKE

TSREGTSSFHTRQKSEGGVYHDPHSDDGTAPKENRHL

YNDPVPRRVGSFYRVPSPRPDNSFHENNVSTRVSSLP

SESSSGTNHSKRQPAFDPWKSPENISHSEQLKEKEKQ

GFFRSMKKKKKKSQTVPNSDSPDLLTLQKSIHSASTP

SSRPKEWRPEKISDLQTQSQPLKSLRKLLHLSSASNH

PASSDPRFQPLTAQQTKNSFSEIRIHPLSQASGGSSN

IRQEPAPKGRPALQLPGQMDPGWHVSSVTRSATEGPS

YSEQLGAKSGPNGHPYNRTNRSRMPNLNDLKETAL

Methyl-CpG-
Rett syndrome
224
MVAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKE

binding protein

EKEGKHEPVQPSAHHSAEPAEAGKAETSEGSGSAPAV

2 (MECP2)

PEASASPKQRRSIIRDRGPMYDDPTLPEGWTRKLKQR

KSGRSAGKYDVYLINPQGKAFRSKVELIAYFEKVGDT

SLDPNDFDFTVTGRGSPSRREQKPPKKPKSPKAPGTG

RGRGRPKGSGTTRPKAATSEGVQVKRVLEKSPGKLLV

KMPFQTSPGGKAEGGGATTSTQVMVIKRPGRKRKAEA

DPQAIPKKRGRKPGSVVAAAAAEAKKKAVKESSIRSV

QETVLPIKKRKTRETVSIEVKEVVKPLLVSTLGEKSG

KGLKTCKSPGRKSKESSPKGRSSSASSPPKKEHHHHH

HHSESPKAPVPLLPPLPPPPPEPESSEDPTSPPEPQD

LSSSVCKEEKMPRGGSLESDGCPKEPAKTQPAVATAA

TAAEKYKHRGEGERKDIVSSSMPRPNREEPVDSRTPV

TERVS

Histone-lysine
Kabuki
225
MDSQKLAGEDKDSEPAADGPAASEDPSATESDLPNPH

N-
syndrome 1

VGEVSVLSSGSPRLQETPQDCSGGPVRRCALCNCGEP

methyltransferase

SLHGQRELRRFELPFDWPRCPVVSPGGSPGPNEAVLP

2D (KMT2D)

SEDLSQIGFPEGLTPAHLGEPGGSCWAHHWCAAWSAG

VWGQEGPELCGVDKAIFSGISQRCSHCTRLGASIPCR

SPGCPRLYHFPCATASGSELSMKTLQLLCPEHSEGAA

YLEEARCAVCEGPGELCDLFFCTSCGHHYHGACLDTA

LTARKRAGWQCPECKVCQACRKPGNDSKMLVCETCDK

GYHTFCLKPPMEELPAHSWKCKACRVCRACGAGSAEL

NPNSEWFENYSLCHRCHKAQGGQTIRSVAEQHTPVCS

RESPPEPGDTPTDEPDALYVACQGQPKGGHVTSMQPK

EPGPLQCEAKPLGKAGVQLEPQLEAPLNEEMPLLPPP

EESPLSPPPEESPTSPPPEASRLSPPPEELPASPLPE

ALHLSRPLEESPLSPPPEESPLSPPPESSPESPLEES

PLSPPEESPPSPALETPLSPPPEASPLSPPFEESPLS

PPPEELPTSPPPEASRLSPPPEESPMSPPPEESPMSP

PPEASRLFPPFEESPLSPPPEESPLSPPPEASRLSPP

PEDSPMSPPPEESPMSPPPEVSRLSPLPVVSRLSPPP

EESPLSPPPEESPTSPPPEASRLSPPPEDSPTSPPPE

DSPASPPPEDSLMSLPLEESPLLPLPEEPQLCPRSEG

PHLSPRPEEPHLSPRPEEPHLSPQAEEPHLSPQPEEP

CLCAVPEEPHLSPQAEGPHLSPQPEELHLSPQTEEPH

LSPVPEEPCLSPQPEESHLSPQSEEPCLSPRPEESHL

SPELEKPPLSPRPEKPPEEPGQCPAPEELPLFPPPGE

PSLSPLLGEPALSEPGEPPLSPLPEELPLSPSGEPSL

SPQLMPPDPLPPPLSPIITAAAPPALSPLGELEYPFG

AKGDSDPESPLAAPILETPISPPPEANCTDPEPVPPM

ILPPSPGSPVGPASPILMEPLPPQCSPLLQHSLVPQN

SPPSQCSPPALPLSVPSPLSPIGKVVGVSDEAELHEM

ETEKVSEPECPALEPSATSPLPSPMGDLSCPAPSPAP

ALDDESGLGEDTAPLDGIDAPGSQPEPGQTPGSLASE

LKGSPVLLDPEELAPVTPMEVYPECKQTAGQGSPCEE

QEEPRAPVAPTPPTLIKSDIVNEISNLSQGDASASFP

GSEPLLGSPDPEGGGSLSMELGVSTDVSPARDEGSLR

LCTDSLPETDDSLLCDAGTAISGGKAEGEKGRRRSSP

ARSRIKQGRSSSFPGRRRPRGGAHGGRGRGRARLKST

ASSIETLVVADIDSSPSKEEEEEDDDTMQNTVVLESN

TDKFVLMQDMCVVCGSFGRGAEGHLLACSQCSQCYHP

YCVNSKITKVMLLKGWRCVECIVCEVCGQASDPSRLL

LCDDCDISYHTYCLDPPLLTVPKGGWKCKWCVSCMQC

GAASPGFHCEWQNSYTHCGPCASLVTCPICHAPYVEE

DLLIQCRHCERWMHAGCESLFTEDDVEQAADEGEDCV

SCQPYVVKPVAPVAPPELVPMKVKEPEPQYFRFEGVW

LTETGMALLRNLTMSPLHKRRQRRGRLGLPGEAGLEG

SEPSDALGPDDKKDGDLDTDELLKGEGGVEHMECEIK

LEGPVSPDVEPGKEETEESKKRKRKPYRPGIGGFMVR

QRKSHTRTKKGPAAQAEVLSGDGQPDEVIPADLPAEG

AVEQSLAEGDEKKKQQRRGRKKSKLEDMFPAYLQEAF

FGKELLDLSRKALFAVGVGRPSFGLGTPKAKGDGGSE

RKELPTSQKGDDGPDIADEESRGLEGKADTPGPEDGG

VKASPVPSDPEKPGTPGEGMLSSDLDRISTEELPKME

SKDLQQLFKDVLGSEREQHLGCGTPGLEGSRTPLQRP

FLQGGLPLGNLPSSSPMDSYPGLCQSPFLDSRERGGE

FSPEPGEPDSPWTGSGGTTPSTPTTPTTEGEGDGLSY

NQRSLQRWEKDEELGQLSTISPVLYANINFPNLKQDY

PDWSSRCKQIMKLWRKVPAADKAPYLQKAKDNRAAHR

INKVQKQAESQINKQTKVGDIARKTDRPALHLRIPPQ

PGALGSPPPAAAPTIFIGSPTTPAGLSTSADGELKPP

AGSVPGPDSPGELFLKLPPQVPAQVPSQDPFGLAPAY

PLEPRFPTAPPTYPPYPSPTGAPAQPPMLGASSRPGA

GQPGEFHTTPPGTPRHQPSTPDPFLKPRCPSLDNLAV

PESPGVGGGKASEPLLSPPPFGESRKALEVKKEELGA

SSPSYGPPNLGFVDSPSSGTHLGGLELKTPDVFKAPL

TPRASQVEPQSPGLGLRPQEPPPAQALAPSPPSHPDI

FRPGSYTDPYAQPPLTPRPQPPPPESCCALPPRSLPS

DPFSRVPASPQSQSSSQSPLTPRPLSAEAFCPSPVTP

RFQSPDPYSRPPSRPQSRDPFAPLHKPPRPQPPEVAF

KAGSLAHTSLGAGGFPAALPAGPAGELHAKVPSGQPP

NFVRSPGTGAFVGTPSPMRFTFPQAVGEPSLKPPVPQ

PGLPPPHGINSHFGPGPTLGKPQSTNYTVATGNFHPS

GSPLGPSSGSTGESYGLSPLRPPSVLPPPAPDGSLPY

LSHGASQRSGITSPVEKREDPGTGMGSSLATAELPGT

QDPGMSGLSQTELEKQRQRQRLRELLIRQQIQRNTLR

QEKETAAAAAGAVGPPGSWGAEPSSPAFEQLSRGQTP

FAGTQDKSSLVGLPPSKLSGPILGPGSFPSDDRLSRP

PPPATPSSMDVNSRQLVGGSQAFYQRAPYPGSLPLQQ

QQQQLWQQQQATAATSMRFAMSARFPSTPGPELGRQA

LGSPLAGISTRLPGPGEPVPGPAGPAQFIELRHNVQK

GLGPGGTPFPGQGPPQRPRFYPVSEDPHRLAPEGLRG

LAVSGLPPQKPSAPPAPELNNSLHPTPHTKGPTLPTG

LELVNRPPSSTELGRPNPLALEAGKLPCEDPELDDDE

DAHKALEDDEELAHLGLGVDVAKGDDELGTLENLETN

DPHLDDLLNGDEFDLLAYTDPELDTGDKKDIFNEHLR

LVESANEKAEREALLRGVEPGPLGPEERPPPAADASE

PRLASVLPEVKPKVEEGGRHPSPCQFTIATPKVEPAP

AANSLGLGLKPGQSMMGSRDTRMGTGPFSSSGHTAEK

ASFGATGGPPAHLLTPSPLSGPGGSSLLEKFELESGA

LTLPGGPAASGDELDKMESSLVASELPLLIEDLLEHE

KKELQKKQQLSAQLQPAQQQQQQQQQHSLLSAPGPAQ

AMSLPHEGSSPSLAGSQQQLSLGLAGARQPGLPQPLM

PTQPPAHALQQRLAPSMAMVSNQGHMLSGQHGGQAGL

VPQQSSQPVLSQKPMGTMPPSMCMKPQQLAMQQQLAN

SFFPDTDLDKFAAEDIIDPIAKAKMVALKGIKKVMAQ

GSIGVAPGMNRQQVSLLAQRLSGGPSSDLQNHVAAGS

GQERSAGDPSQPRPNPPTFAQGVINEADQRQYEEWLF

HTQQLLQMQLKVLEEQIGVHRKSRKALCAKQRTAKKA

GREFPEADAEKLKLVTEQQSKIQKQLDQVRKQQKEHT

NLMAEYRNKQQQQQQQQQQQQQQHSAVLALSPSQSPR

LLTKLPGQLLPGHGLQPPQGPPGGQAGGLRLTPGGMA

LPGQPGGPFLNTALAQQQQQQHSGGAGSLAGPSGGFF

PGNLALRSLGPDSRLLQERQLQLQQQRMQLAQKLQQQ

QQQQQQQQHLLGQVAIQQQQQQGPGVQTNQALGPKPQ

GLMPPSSHQGLLVQQLSPQPPQGPQGMLGPAQVAVLQ

QQHPGALGPQGPHRQVLMTQSRVLSSPQLAQQGQGLM

GHRLVTAQQQQQQQQHQQQGSMAGLSHLQQSLMSHSG

QPKLSAQPMGSLQQLQQQQQLQQQQQLQQQQQQQLQQ

QQQQQQFQQQQQQQQMGLLNQSRTLLSPQQQQQQQVA

LGPGMPAKPLQHFSSPGALGPTLLLTGKEQNTVDPAV

SSEATEGPSTHQGGPLAIGTTPESMATEPGEVKPSLS

GDSQLLLVQPQPQPQPSSLQLQPPLRLPGQQQQQVSL

LHTAGGGSHGQLGSGSSSEASSVPHLLAQPSVSLGDQ

PGSMTQNLLGPQQPMLERPMQNNTGPQPPKPGPVLQS

GQGLPGVGIMPTVGQLRAQLQGVLAKNPQLRHLSPQQ

QQQLQALLMQRQLQQSQAVRQTPPYQEPGTQTSPLQG

LLGCQPQLGGFPGPQTGPLQELGAGPRPQGPPRLPAP

PGALSTGPVLGPVHPTPPPSSPQEPKRPSQLPSPSSQ

LPTEAQLPPTHPGTPKPQGPTLEPPPGRVSPAAAQLA

DTLESKGLGPWDPPDNLAETQKPEQSSLVPGHLDQVN

GQVVPEASQLSIKQEPREEPCALGAQSVKREANGEPI

GAPGTSNHLLLAGPRSEAGHLLLQKLLRAKNVQLSTG

RGSEGLRAEINGHIDSKLAGLEQKLQGTPSNKEDAAA

RKPLTPKPKRVQKASDRLVSSRKKLRKEDGVRASEAL

LKQLKQELSLLPLTEPAITANFSLFAPFGSGCPVNGQ

SQLRGAFGSGALPTGPDYYSQLLTKNNLSNPPTPPSS

LPPTPPPSVQQKMVNGVTPSEELGEHPKDAASARDSE

RALRDTSEVKSLDLLAALPTPPHNQTEDVRMESDEDS

DSPDSIVPASSPESILGEEAPRFPHLGSGRWEQEDRA

LSPVIPLIPRASIPVFPDTKPYGALGLEVPGKLPVTT

WEKGKGSEVSVMLTVSAAAAKNLNGVMVAVAELLSMK

IPNSYEVLFPESPARAGTEPKKGEAEGPGGKEKGLEG

KSPDTGPDWLKQFDAVLPGYTLKSQLDILSLLKQESP

APEPPTQHSYTYNVSNLDVRQLSAPPPEEPSPPPSP

LAPSPASPPTEPLVELPTEPLAEPPVPSPLPLASSPE

SARPKPRARPPEEGEDSRPPRLKKWKGVRWKRLRLLL

TIQKGSGRQEDEREVAEFMEQLGTALRPDKVPRDMRR

CCFCHEEGDGATDGPARLLNLDLDLWVHLNCALWSTE

VYETQGGALMNVEVALHRGLLTKCSLCQRTGATSSCN

RMRCPNVYHFACAIRAKCMFFKDKTMLCPMHKIKGPC

EQELSSFAVERRVYIERDEVKQIASIIQRGERLHMER

VGGLVFHAIGQLLPHQMADFHSATALYPVGYEATRIY

WSLRTNNRRCCYRCSIGENNGRPEFVIKVIEQGLEDL

VFTDASPQAVWNRIIEPVAAMRKEADMLRLFPEYLKG

EELFGLTVHAVLRIAESLPGVESCQNYLFRYGRHPLM

ELPLMINPTGCARSEPKILTHYKRPHTLNSTSMSKAY

QSTFTGETNTPYSKQFVHSKSSQYRRLRTEWKNNVYL

ARSRIQGLGLYAAKDLEKHTMVIEYIGTIIRNEVANR

REKIYEEQNRGIYMFRINNEHVIDATLTGGPARYINH

SCAPNCVAEVVTEDKEDKIIIISSRRIPKGEELTYDY

QFDFEDDQHKIPCHCGAWNCRKWMN

Histone-lysine
Mental
226
MSIAIPLGVTTSDTSYSDMAAGSDPESVEASPAVNEK

N-
retardation,

SVYSTHNYGTTQRHGCRGLPYATIIPRSDLNGLPSPV

methyltransferase
autosomal

EERCGDSPNSEGETVPTWCPCGLSQDGELLNCDKCRG

SETD5
dominant 23

MSRGKVIRLHRRKQDNISGGDSSATESWDEELSPSTV

(SETD5)

LYTATQHTPTSITLTVRRTKPKKRKKSPEKGRAAPKT

KKIKNSPSEAQNLDENTTEGWENRIRLWTDQYEEAFT

NQYSADVQNALEQHLHSSKEFVGKPTILDTINKTELA

CNNTVIGSQMQLQLGRVTRVQKHRKILRAARDLALDT

LIIEYRGKVMLRQQFEVNGHFFKKPYPFVLFYSKENG

VEMCVDARTEGNDARFIRRSCTPNAEVRHMIADGMIH

LCIYAVSAITKDAEVTIAFDYEYSNCNYKVDCACHKG

NRNCPIQKRNPNATELPLLPPPPSLPTIGAETRRRKA

RRKELEMEQQNEASEENNDQQSQEVPEKVTVSSDHEE

VDNPEEKPEEEKEEVIDDQENLAHSRRTREDRKVEAI

MHAFENLEKRKKRRDQPLEQSNSDVEITTTTSETPVG

EETKTEAPESEVSNSVSNVTIPSTPQSVGVNTRRSSQ

AGDIAAEKLVPKPPPAKPSRPRPKSRISRYRTSSAQR

LKRQKQANAQQAELSQAALEEGGSNSLVTPTEAGSLD

SSGENRPLTGSDPTVVSITGSHVNRAASKYPKTKKYL

VTEWLNDKAEKQECPVECPLRITTDPTVLATTLNMLP

GLIHSPLICTTPKHYIRFGSPFIPERRRRPLLPDGTF

SSCKKRWIKQALEEGMTQTSSVPQETRTQHLYQSNEN

SSSSSICKDNADLLSPLKKWKSRYLMEQNVTKLLRPL

SPVTPPPPNSGSKSPQLATPGSSHPGEEECRNGYSLM

FSPVTSLTTASRCNTPLQFELCHRKDLDLAKVGYLDS

NTNSCADRPSLLNSGHSDLAPHPSLGPTSETGFPSRS

GDGHQTLVRNSDQAFRTEENLMYAYSPLNAMPRADGL

YRGSPLVGDRKPLHLDGGYCSPAEGESSRYEHGLMKD

LSRGSLSPGGERACEGVPSAPQNPPQRKKVSLLEYRK

RKQEAKENSAGGGGDSAQSKSKSAGAGQGSSNSVSDT

GAHGVQGSSARTPSSPHKKESPSHSSMSHLEAVSPSD

SRGTSSSHCRPQENISSRWMVPTSVERLREGGSIPKV

LRSSVRVAQKGEPSPTWESNITEKDSDPADGEGPETL

SSALSKGATVYSPSRYSYQLLQCDSPRTESQSLLQQS

SSPFRGHPTQSPGYSYRTTALRPGNPPSHGSSESSLS

STSYSSPAHPVSTDSLAPFTGTPGYFSSQPHSGNSTG

SNLPRRSCPSSAASPTLQGPSDSPTSDSVSQSSTGTL

SSTSFPQNSRSSLPSDLRTISLPSAGQSAVYQASRVS

AVSNSQHYPHRGSGGVHQYRLQPLQGSGVKTQTGLS

Zinc finger E-
Mowat-Wilson
227
MKQPIMADGPRCKRRKQANPRRKNVVNYDNVVDTGSE

box-binding
syndrome

TDEEDKLHIAEDDGIANPLDQETSPASVPNHESSPHV

homeobox 2

SQALLPREEEEDEIREGGVEHPWHNNEILQASVDGPE

(ZEB2)

EMKEDYDTMGPEATIQTAINNGTVKNANCTSDFEEYF

AKRKLEERDGHAVSIEEYLQRSDTAITYPEAPEELSR

LGTPEANGQEENDLPPGTPDAFAQLLTCPYCDRGYKR

LTSLKEHIKYRHEKNEENFSCPLCSYTFAYRTQLERH

MVTHKPGTDQHQMLTQGAGNRKFKCTECGKAFKYKHH

LKEHLRIHSGEKPYECPNCKKRFSHSGSYSSHISSKK

CIGLISVNGRMRNNIKTGSSPNSVSSSPTNSAITQLR

NKLENGKPLSMSEQTGLLKIKTEPLDENDYKVLMATH

GFSGTSPFMNGGLGATSPLGVHPSAQSPMQHLGVGME

APLLGFPTMNSNLSEVQKVLQIVDNTVSRQKMDCKAE

EISKLKGYHMKDPCSQPEEQGVTSPNIPPVGLPVVSH

NGATKSIIDYTLEKVNEAKACLQSLTTDSRRQISNIK

KEKLRTLIDLVTDDKMIENHNISTPFSCQFCKESFPG

PIPLHQHERYLCKMNEEIKAVLQPHENIVPNKAGVFV

DNKALLLSSVLSEKGMTSPINPYKDHMSVLKAYYAMN

MEPNSDELLKISIAVGLPQEFVKEWFEQRKVYQYSNS

RSPSLERSSKPLAPNSNPPTKDSLLPRSPVKPMDSIT

SPSIAELHNSVTNCDPPLRLTKPSHFTNIKPVEKLDH

SRSNTPSPLNLSSTSSKNSHSSSYTPNSESSEELQAE

PLDLSLPKQMKEPKSIIATKNKTKASSISLDHNSVSS

SSENSDEPLNLTFIKKEFSNSNNLDNKSTNPVESMNP

FSAKPLYTALPPQSAFPPATEMPPVQTSIPGLRPYPG

LDQMSFLPHMAYTYPTGAATFADMQQRRKYQRKQGFQ

GELLDGAQDYMSGLDDMTDSDSCLSRKKIKKTESGMY

ACDLCDKTFQKSSSLLRHKYEHTGKRPHQCQICKKAF

KHKHHLIEHSRLHSGEKPYQCDKCGKRFSHSGSYSQH

MNHRYSYCKREAEEREAAEREAREKGHLEPTELLMNR

AYLQSITPQGYSDSEERESMPRDGESEKEHEKEGEDG

YGKLGRQDGDEEFEEEEEESENKSMDTDPETIRDEEE

TGDHSMDDSSEDGKMETKSDHEEDNMEDGM

Calmodulin-
CAMTA1
228
MWRAEGKWLPKTSRKSVSQSVFCGTSTYCVLNTVPPI

binding
Syndrome;

EDDHGNSNSSHVKIFLPKKLLECLPKCSSLPKERHRW

transcription
Cerebellar

NTNEEIAAYLITFEKHEEWLTTSPKTRPQNGSMILYN

activator 1
ataxia,

RKKVKYRKDGYCWKKRKDGKTTREDHMKLKVQGVECL

(CAMTA1)
nonprogressive,

YGCYVHSSIIPTFHRRCYWLLQNPDIVLVHYLNVPAI

with mental

EDCGKPCGPILCSINTDKKEWAKWTKEELIGQLKPMF

retardation

HGIKWTCSNGNSSSGFSVEQLVQQILDSHQTKPQPRT

HNCLCTGSLGAGGSVHHKCNSAKHRIISPKVEPRTGG

YGSHSEVQHNDVSEGKHEHSHSKGSSREKRNGKVAKP

VLLHQSSTEVSSTNQVEVPDTTQSSPVSISSGLNSDP

DMVDSPVVTGVSGMAVASVMGSLSQSATVEMSEVTNE

AVYTMSPTAGPNHHLLSPDASQGLVLAVSSDGHKFAF

PTTGSSESLSMLPTNVSEELVLSTTLDGGRKIPETTM

NFDPDCFLNNPKQGQTYGGGGLKAEMVSSNIRHSPPG

ERSESFTTVLTKEIKTEDTSFEQQMAKEAYSSSAAAV

AASSLTLTAGSSLLPSGGGLSPSTTLEQMDFSAIDSN

KDYTSSFSQTGHSPHIHQTPSPSFFLQDASKPLPVEQ

NTHSSLSDSGGTFVMPTVKTEASSQTSSCSGHVETRI

ESTSSLHLMQFQANFQAMTAEGEVTMETSQAAEGSEV

LLKSGELQACSSEHYLQPETNGVIRSAGGVPILPGNV

VQGLYPVAQPSLGNASNMELSLDHFDISESNQFSDLI

NDFISVEGGSSTIYGHQLVSGDSTALSQSEDGARAPF

TQAEMCLPCCSPQQGSLQLSSSEGGASTMAYMHVAEV

VSAASAQGTLGMLQQSGRVEMVTDYSPEWSYPEGGVK

VLITGPWQEASNNYSCLFDQISVPASLIQPGVLRCYC

PAHDTGLVTLQVAFNNQIISNSVVFEYKARALPTLPS

SQHDWLSLDDNQFRMSILERLEQMERRMAEMTGSQQH

KQASGGGSSGGGSGSGNGGSQAQCASGTGALGSCFES

RVVVVCEKMMSRACWAKSKHLIHSKTFRGMTLLHLAA

AQGYATLIQTLIKWRTKHADSIDLELEVDPLNVDHES

CTPLMWACALGHLEAAVVLYKWDRRAISIPDSLGRLP

LGIARSRGHVKLAECLEHLQRDEQAQLGQNPRIHCPA

SEEPSTESWMAQWHSEAISSPEIPKGVTVIASTNPEL

RRPRSEPSNYYSSESHKDYPAPKKHKLNPEYFQTRQE

KLLPTALSLEEPNIRKQSPSSKQSVPETLSPSEGVRD

FSRELSPPTPETAAFQASGSQPVGKWNSKDLYIGVST

VQVTGNPKGTSVGKEAAPSQVRPREPMSVLMMANREV

VNTELGSYRDSAENEECGQPMDDIQVNMMTLAEHIIE

ATPDRIKQENFVPMESSGLERTDPATISSTMSWLASY

LADADCLPSAAQIRSAYNEPLTPSSNTSLSPVGSPVS

EIAFEKPNLPSAADWSEFLSASTSEKVENEFAQLTLS

DHEQRELYEAARLVQTAFRKYKGRPLREQQEVAAAVI

QRCYRKYKQYALYKKMTQAAILIQSKERSYYEQKKFQ

QSRRAAVLIQKYYRSYKKCGKRRQARRTAVIVQQKLR

SSLLTKKQDQAARKIMRFLRRCRHSPLVDHRLYKRSE

RIEKGQGT

Synaptic
Fragile X
229
MEELVVEVRGSNGAFYKAFVKDVHEDSITVAFENNWQ

functional
syndrome

PDRQIPFHDVREPPPVGYNKDINESDEVEVYSRANEK

regulator FMR1

EPCCWWLAKVRMIKGEFYVIEYAACDATYNEIVTIER

(FMR1)

LRSVNPNKPATKDTFHKIKLDVPEDLRQMCAKEAAHK

DFKKAVGAFSVTYDPENYQLVILSINEVTSKRAHMLI

DMHFRSLRTKLSLIMRNEEASKQLESSRQLASRFHEQ

FIVREDLMGLAIGTHGANIQQARKVPGVTAIDLDEDT

CTFHIYGEDQDAVKKARSFLEFAEDVIQVPRNLVGKV

IGKNGKLIQEIVDKSGVVRVRIEAENEKNVPQEEEIM

PPNSLPSNNSRVGPNAPEEKKHLDIKENSTHESQPNS

TKVQRVLVASSVVAGESQKPELKAWQGMVPFVFVGTK

DSIANATVLLDYHLNYLKEVDQLRLERLQIDEQLRQI

GASSRPPPNRTDKEKSYVTDDGQGMGRGSRPYRNRGH

GRRGPGYTSGTNSEASNASETESDHRDELSDWSLAPT

EEERESFLRRGDGRRRGGGGRGQGGRGRGGGFKGNDD

HSRTDNRPRNPREAKGRTTDGSLQIRVDCNNERSVHT

KTLQNTSSEGSRLRTGKDRNQKKEKPDSVDGQQPLVN

GVP

Pre-mRNA-
Retinitis
230
MAGVFPYRGPGNPVPGPLAPLPDYMSEEKLQEKARKW

processing-
pigmentosa 13

QQLQAKRYAEKRKFGFVDAQKEDMPPEHVRKIIRDHG

splicing factor 8

DMTNRKFRHDKRVYLGALKYMPHAVLKLLENMPMPWE

(PRPF8)

QIRDVPVLYHITGAISFVNEIPWVIEPVYISQWGSMW

IMMRREKRDRRHFKRMRFPPEDDEEPPLDYADNILDV

EPLEAIQLELDPEEDAPVLDWFYDHQPLRDSRKYVNG

STYQRWQFTLPMMSTLYRLANQLLTDLVDDNYFYLED

LKAFFTSKALNMAIPGGPKFEPLVRDINLQDEDWNEF

NDINKIIIRQPIRTEYKIAFPYLYNNLPHHVHLTWYH

TPNVVFIKTEDPDLPAFYEDPLINPISHRHSVKSQEP

LPDDDEEFELPEFVEPFLKDTPLYTDNTANGIALLWA

PRPENLRSGRTRRALDIPLVKNWYREHCPAGQPVKVR

VSYQKLLKYYVLNALKHRPPKAQKKRYLFRSFKATKF

FQSTKLDWVEVGLQVCRQGYNMLNLLIHRKNLNYLHL

DYNFNLKPVKTLTTKERKKSREGNAFHLCREVLRLTK

LVVDSHVQYRLGNVDAFQLADGLQYIFAHVGQLTGMY

RYKYKLMRQIRMCKDLKHLIYYRENTGPVGKGPGCGF

WAAGWRVWLFFMRGITPLLERWLGNLLARQFEGRHSK

GVAKTVTKQRVESHEDLELRAAVMHDILDMMPEGIKQ

NKARTILQHLSEAWRCWKANIPWKVPGLPTPIENMIL

RYVKAKADWWTNTAHYNRERIRRGATVDKTVCKKNLG

RLTRLYLKAEQERQHNYLKDGPYITAEEAVAVYTTTV

HWLESRRESPIPFPPLSYKHDTKLLILALERLKEAYS

VKSRLNQSQREELGLIEQAYDNPHEALSRIKRHLLTQ

RAFKEVGIEFMDLYSHLVPVYDVEPLEKITDAYLDQY

LWYEADKRRLFPPWIKPADTEPPPLLVYKWCQGINNL

QDVWETSEGECNVMLESRFEKMYEKIDLTLLNRLLRL

IVDHNIADYMTAKNNVVINYKDMNHTNSYGIIRGLQF

ASFIVQYYGLVMDLLVLGLHRASEMAGPPQMPNDELS

FQDIATEAAHPIRLFCRYIDRIHIFFRFTADEARDLI

QRYLTEHPDPNNENIVGYNNKKCWPRDARMRLMKHDV

NLGRAVEWDIKNRLPRSVTTVQWENSFVSVYSKDNPN

LLENMCGFECRILPKCRTSYEEFTHKDGVWNLQNEVT

KERTAQCFLRVDDESMQRFHNRVRQILMASGSTTFTK

IVNKWNTALIGLMTYFREAVVNTQELLDLLVKCENKI

QTRIKIGLNSKMPSRFPPVVFYTPKELGGLGMLSMGH

VLIPQSDLRWSKQTDVGITHERSGMSHEEDQLIPNLY

RYIQPWESEFIDSQRVWAEYALKRQEAIAQNRRLTLE

DLEDSWDRGIPRINTLFQKDRHTLAYDKGWRVRTDEK

QYQVLKQNPFWWTHQRHDGKLWNLNNYRTDMIQALGG

VEGILEHTLFKGTYFPTWEGLFWEKASGFEESMKWKK

LTNAQRSGLNQIPNRRFTLWWSPTINRANVYVGFQVQ

LDLTGIFMHGKIPTLKISLIQIFRAHLWQKIHESIVM

DLCQVFDQELDALEIETVQKETIHPRKSYKMNSSCAD

ILLFASYKWNVSRPSLLADSKDVMDSTTTQKYWIDIQ

LRWGDYDSHDIERYARAKFLDYTTDNMSIYPSPTGVL

IAIDLAYNLHSAYGNWFPGSKPLIQQAMAKIMKANPA

LYVLRERIRKGLQLYSSEPTEPYLSSQNYGELFSNQI

IWFVDDTNVYRVTIHKTFEGNLTTKPINGAIFIENPR

TGQLELKIIHTSVWAGQKRLGQLAKWKTAEEVAALIR

SLPVEEQPKQIIVTRKGMLDPLEVHLLDEPNIVIKGS

ELQLPFQACLKVEKFGDLILKATEPQMVLENLYDDWL

KTISSYTAFSRLILILRALHVNNDRAKVILKPDKTTI

TEPHHIWPTLTDEEWIKVEVQLKDLILADYGKKNNVN

VASLTQSEIRDIILGMEISAPSQQRQQIAEIEKQTKE

QSQLTATQTRTVNKHGDEIITSTTSNYETQTESSKTE

WRVRAISAANLHLRTNHIYVSSDDIKETGYTYILPKN

VLKKFICISDLRAQIAGYLYGVSPPDNPQVKEIRCIV

MVPQWGTHQTVHLPGQLPQHEYLKEMEPLGWIHTQPN

ESPQLSPQDVTTHAKIMADNPSWDGEKTIIITCSFTP

GSCTLTAYKLTPSGYEWGRQNTDKGNNPKGYLPSHYE

RVQMLLSDRFLGFFMVPAQSSWNYNEMGVRHDPNMKY

ELQLANPKEFYHEVHRPSHELNFALLQEGEVYSADRE

DLYA

Retinoic acid-
Smith-Magenis
231
MQSFRERCGFHGKQQNYQQTSQETSRLENYRQPSQAG

induced protein
syndrome

LSCDRQRLLAKDYYNPQPYPSYEGGAGTPSGTAAAVA

1 (RAI1)

ADKYHRGSKALPTQQGLQGRPAFPGYGVQDSSPYPGR

YAGEESLQAWGAPQPPPPQPQPLPAGVAKYDENLMKK

TAVPPSRQYAEQGAQVPFRTHSLHVQQPPPPQQPLAY

PKLQRQKLQNDIASPLPFPQGTHEPQHSQSFPTSSTY

SSSVQGGGQGAHSYKSCTAPTAQPHDRPLTASSSLAP

GQRVQNLHAYQSGRLSYDQQQQQQQQQQQQQQALQSR

HHAQETLHYQNLAKYQHYGQQGQGYCQPDAAVRTPEQ

YYQTFSPSSSHSPARSVGRSPSYSSTPSPLMPNLENF

PYSQQPLSTGAFPAGITDHSHEMPLLNPSPTDATSSV

DTQAGNCKPLQKDKLPENLLSDLSLQSLTALTSQVEN

ISNTVQQLLLSKAAVPQKKGVKNLVSRTPEQHKSQHC

SPEGSGYSAEPAGTPLSEPPSSTPQSTHAEPQEADYL

SGSEDPLERSFLYCNQARGSPARVNSNSKAKPESVST

CSVTSPDDMSTKSDDSFQSLHGSLPLDSESKEVAGER

DCPRLLLSALAQEDLASEILGLQEAIGEKADKAWAEA

PSLVKDSSKPPFSLENHSACLDSVAKSAWPRPGEPEA

LPDSLQLDKGGNAKDESPGLFEDPSVAFATPDPKKTT

GPLSFGTKPTLGVPAPDPTTAAFDCFPDTTAASSADS

ANPFAWPEENLGDACPRWGLHPGELTKGLEQGGKASD

GISKGDTHEASACLGFQEEDPPGEKVASLPGDEKQEE

VGGVKEEAGGLLQCPEVAKADRWLEDSRHCCSTADFG

DLPLLPPTSRKEDLEAEEEYSSLCELLGSPEQRPGMQ

DPLSPKAPLICTKEEVEEVLDSKAGWGSPCHLSGESV

ILLGPTVGTESKVQSWFESSLSHMKPGEEGPDGERAP

GDSTTSDASLAQKPNKPAVPEAPIAKKEPVPRGKSLR

SRRVHRGLPEAEDSPCRAPVLPKDLLLPESCTGPPQG

QMEGAGAPGRGASEGLPRMCTRSLTALSEPRTPGPPG

LTTTPAPPDKLGGKQRAAFKSGKRVGKPSPKAASSPS

NPAALPVASDSSPMGSKTKETDSPSTPGKDQRSMILR

SRTKTQEIFHSKRRRPSEGRLPNCRATKKLLDNSHLP

ATFKVSSSPQKEGRVSQRARVPKPGAGSKLSDRPLHA

LKRKSAFMAPVPTKKRNLVLRSRSSSSSNASGNGGDG

KEERPEGSPTLFKRMSSPKKAKPTKGNGEPATKLPPP

ETPDACLKLASRAAFQGAMKTKVLPPRKGRGLKLEAI

VQKITSPSLKKFACKAPGASPGNPLSPSLSDKDRGLK

GAGGSPVGVEEGLVNVGTGQKLPTSGADPLCRNPTNR

SLKGKLMNSKKLSSTDCFKTEAFTSPEALQPGGTALA

PKKRSRKGRAGAHGLSKGPLEKRPYLGPALLLTPRDR

ASGTQGASEDNSGGGGKKPKMEELGLASQPPEGRPCQ

PQTRAQKQPGHTNYSSYSKRKRLTRGRAKNTTSSPCK

GRAKRRRQQQVLPLDPAEPEIRLKYISSCKRLRSDSR

TPAFSPFVRVEKRDAFTTICTVVNSPGDAPKPHRKPS

SSASSSSSSSSESLDAAGASLATLPGGSILQPRPSLP

LSSTMHLGPVVSKALSTSCLVCCLCQNPANEKDLGDL

CGPYYPEHCLPKKKPKLKEKVRPEGTCEEASLPLERT

LKGPECAAAATAGKPPRPDGPADPAKQGPLRTSARGL

SRRLQSCYCCDGREDGGEEAAPADKGRKHECSKEAPA

EPGGEAQEHWVHEACAVWTGGVYLVAGKLFGLQEAMK

VAVDMMCSSCQEAGATIGCCHKGCLHTYHYPCASDAG

CIFIEENFSLKCPKHKRLP

CREB-binding
Rubinstein-
232
MAENLLDGPPNPKRAKLSSPGFSANDSTDEGSLEDLE

protein
Taybi

NDLPDELIPNGGELGLLNSGNLVPDAASKHKQLSELL

(CREBBP)
syndrome

RGGSGSSINPGIGNVSASSPVQQGLGGQAQGQPNSAN

MASLSAMGKSPLSQGDSSAPSLPKQAASTSGPTPAAS

QALNPQAQKQVGLATSSPATSQTGPGICMNANENQTH

PGLLNSNSGHSLINQASQGQAQVMNGSLGAAGRGRGA

GMPYPTPAMQGASSSVLAETLTQVSPQMTGHAGLNTA

QAGGMAKMGITGNTSPFGQPFSQAGGQPMGATGVNPQ

LASKQSMVNSLPTFPTDIKNTSVTNVPNMSQMQTSVG

IVPTQAIATGPTADPEKRKLIQQQLVLLLHAHKCQRR

EQANGEVRACSLPHCRTMKNVLNHMTHCQAGKACQVA

HCASSRQIISHWKNCTRHDCPVCLPLKNASDKRNQQT

ILGSPASGIQNTIGSVGTGQQNATSLSNPNPIDPSSM

QRAYAALGLPYMNQPQTQLQPQVPGQQPAQPQTHQQM

RTLNPLGNNPMNIPAGGITTDQQPPNLISESALPTSL

GATNPLMNDGSNSGNIGTLSTIPTAAPPSSTGVRKGW

HEHVTQDLRSHLVHKLVQAIFPTPDPAALKDRRMENL

VAYAKKVEGDMYESANSRDEYYHLLAEKIYKIQKELE

EKRRSRLHKQGILGNQPALPAPGAQPPVIPQAQPVRP

PNGPLSLPVNRMQVSQGMNSFNPMSLGNVQLPQAPMG

PRAASPMNHSVQMNSMGSVPGMAISPSRMPQPPNMMG

AHTNNMMAQAPAQSQFLPQNQFPSSSGAMSVGMGQPP

AQTGVSQGQVPGAALPNPLNMLGPQASQLPCPPVTQS

PLHPTPPPASTAAGMPSLQHTTPPGMTPPQPAAPTQP

STPVSSSGQTPTPTPGSVPSATQTQSTPTVQAAAQAQ

VTPQPQTPVQPPSVATPQSSQQQPTPVHAQPPGTPLS

QAAASIDNRVPTPSSVASAETNSQQPGPDVPVLEMKT

ETQAEDTEPDPGESKGEPRSEMMEEDLQGASQVKEET

DIAEQKSEPMEVDEKKPEVKVEVKEEEESSSNGTASQ

STSPSQPRKKIFKPEELRQALMPTLEALYRQDPESLP

FRQPVDPQLLGIPDYFDIVKNPMDLSTIKRKLDTGQY

QEPWQYVDDVWLMENNAWLYNRKTSRVYKFCSKLAEV

FEQEIDPVMQSLGYCCGRKYEFSPQTLCCYGKQLCTI

PRDAAYYSYQNRYHFCEKCFTEIQGENVTLGDDPSQP

QTTISKDQFEKKKNDTLDPEPFVDCKECGRKMHQICV

LHYDIIWPSGFVCDNCLKKTGRPRKENKFSAKRLQTT

RLGNHLEDRVNKELRRQNHPEAGEVFVRVVASSDKTV

EVKPGMKSRFVDSGEMSESFPYRTKALFAFEEIDGVD

VCFFGMHVQEYGSDCPPPNTRRVYISYLDSIHFFRPR

CLRTAVYHEILIGYLEYVKKLGYVTGHIWACPPSEGD

DYIFHCHPPDQKIPKPKRLQEWYKKMLDKAFAERIIH

DYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIK

ELEQEEEERKKEESTAASETTEGSQGDSKNAKKKNNK

KTNKNKSSISRANKKKPSMPNVSNDLSQKLYATMEKH

KEVFFVIHLHAGPVINTLPPIVDPDPLLSCDLMDGRD

AFLTLARDKHWEFSSLRRSKWSTLCMLVELHTQGQDR

FVYTCNECKHHVETRWHCTVCEDYDLCINCYNTKSHA

HKMVKWGLGLDDEGSSQGEPQSKSPQESRRLSIQRCI

QSLVHACQCRNANCSLPSCQKMKRVVQHTKGCKRKTN

GGCPVCKQLIALCCYHAKHCQENKCPVPFCLNIKHKL

RQQQIQHRLQQAQLMRRRMATMNTRNVPQQSLPSPTS

APPGTPTQQPSTPQTPQPPAQPQPSPVSMSPAGEPSV

ARTQPPTTVSTGKPTSQVPAPPPPAQPPPAAVEAARQ

IEREAQQQQHLYRVNINNSMPPGRTGMGTPGSQMAPV

SLNVPRPNQVSGPVMPSMPPGQWQQAPLPQQQPMPGL

PRPVISMQAQAAVAGPRMPSVQPPRSISPSALQDLLR

TLKSPSSPQQQQQVLNILKSNPQLMAAFIKQRTAKYV

ANQPGMQPQPGLQSQPGMQPQPGMHQQPSLQNLNAMQ

AGVPRPGVPPQQQAMGGLNPQGQALNIMNPGHNPNMA

SMNPQYREMLRRQLLQQQQQQQQQQQQQQQQQQGSAG

MAGGMAGHGQFQQPQGPGGYPPAMQQQQRMQQHLPLQ

GSSMGQMAAQMGQLGQMGQPGLGADSTPNIQQALQQR

ILQQQQMKQQIGSPGQPNPMSPQQHMLSGQPQASHLP

GQQIATSLSNQVRSPAPVQSPRPQSQPPHSSPSPRIQ

PQPSPHHVSPQTGSPHPGLAVTMASSIDQGHLGNPEQ

SAMLPQLNTPSRSALSSELSLVGDTTGDTLEKFVEGL

Neurofibromin
Neurofibromatosis,
233
MAAHRPVEWVQAVVSRFDEQLPIKTGQQNTHTKVSTE

(NF1)
type 1

HNKECLINISKYKESLVISGLTTILKNVNNMRIFGEA

AEKNLYLSQLIILDTLEKCLAGQPKDTMRLDETMLVK

QLLPEICHELHTCREGNQHAAELRNSASGVLESLSCN

NFNAVESRISTRLQELTVCSEDNVDVHDIELLQYINV

DCAKLKRLLKETAFKFKALKKVAQLAVINSLEKAFWN

WVENYPDEFTKLYQIPQTDMAECAEKLEDLVDGFAES

TKRKAAVWPLQIILLILCPEIIQDISKDVVDENNMNK

KLFLDSLRKALAGHGGSRQLTESAAIACVKLCKASTY

INWEDNSVIFLLVQSMVVDLKNLLENPSKPFSRGSQP

ADVDLMIDCLVSCFRISPHNNQHFKICLAQNSPSTEH

YVLVNSLHRIITNSALDWWPKIDAVYCHSVELRNMEG

ETLHKAVQGCGAHPAIRMAPSLTFKEKVTSLKFKEKP

TDLETRSYKYLLLSMVKLIHADPKLLLCNPRKQGPET

QGSTAELITGLVQLVPQSHMPEIAQEAMEALLVLHQL

DSIDLWNPDAPVETFWEISSQMLFYICKKLTSHQMLS

STEILKWLREILICRNKELLKNKQADRSSCHELLFYG

VGCDIPSSGNTSQMSMDHEELLRTPGASLRKGKGNSS

MDSAAGCSGTPPICRQAQTKLEVALYMFLWNPDTEAV

LVAMSCFRHLCEEADIRCGVDEVSVHNLLPNYNTEME

FASVSNMMSTGRAALQKRVMALLRRIEHPTAGNTEAW

EDTHAKWEQATKLILNYPKAKMEDGQAAESLHKTIVK

RRMSHVSGGGSIDLSDTDSLQEWINMTGFLCALGGVC

LQQRSNSGLATYSPPMGPVSERKGSMISVMSSEGNAD

TPVSKEMDRLLSLMVCNHEKVGLQIRTNVKDLVGLEL

SPALYPMLENKLKNTISKFFDSQGQVLLTDTNTQFVE

QTIAIMKNLLDNHTEGSSEHLGQASIETMMLNLVRYV

RVLGNMVHAIQIKTKLCQLVEVMMARRDDLSFCQEMK

FRNKMVEYLTDWVMGTSNQAADDDVKCLTRDLDQASM

EAVVSLLAGLPLQPEEGDGVELMEAKSQLFLKYFTLE

MNLLNDCSEVEDESAQTGGRKRGMSRRLASLRHCTVL

AMSNLLNANVDSGLMHSIGLGYHKDLQTRATFMEVLT

KILQQGTEFDTLAETVLADRFERLVELVTMMGDQGEL

PIAMALANVVPCSQWDELARVLVTLEDSRHLLYQLLW

NMFSKEVELADSMQTLFRGNSLASKIMTFCFKVYGAT

YLQKLLDPLLRIVITSSDWQHVSFEVDPTRLEPSESL

EENQRNLLQMTEKFFHAIISSSSEFPPQLRSVCHCLY

QATCHSLLNKATVKEKKENKKSVVSQRFPQNSIGAVG

SAMFLRFINPAIVSPYEAGILDKKPPPRIERGLKLMS

KILQSIANHVLFTKEEHMRPENDEVKSNEDAARRFEL

DIASDCPTSDAVNHSLSFISDGNVLALHRLLWNNQEK

IGQYLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKPV

ADTHWSSLNLTSSKFEEFMTRHQVHEKEEFKALKTLS

IFYQAGTSKAGNPIFYYVARREKTGQINGDLLIYHVL

LTLKPYYAKPYEIVVDLTHTGPSNRFKTDELSKWFVV

FPGFAYDNVSAVYIYNCNSWVREYTKYHERLLTGLKG

SKRIVFIDCPGKLAEHIEHEQQKLPAATLALEEDLKV

FHNALKLAHKDTKVSIKVGSTAVQVTSAERTKVLGQS

VFLNDIYYASEIEEICLVDENQFTLTIANQGTPLTEM

HQECEAIVQSIIHIRTRWELSQPDSIPQHTKIRPKDV

PGTLLNIALLNLGSSDPSLRSAAYNLLCALTCTENLK

IEGQLLETSGLCIPANNTLFIVSISKTLAANEPHLTL

EFLEECISGFSKSSIELKHLCLEYMTPWLSNLVRECK

HNDDAKRQRVTAILDKLITMTINEKQMYPSIQAKIWG

SLGQITDLLDVVLDSFIKTSATGGLGSIKAEVMADTA

VALASGNVKLVSSKVIGRMCKIIDKTCLSPTPTLEQH

LMWDDIAILARYMLMLSENNSLDVAAHLPYLFHVVTF

LVATGPLSLRASTHGLVINIIHSLCTCSQLHFSEETK

QVLRLSLTEFSLPKFYLLFGISKVKSAAVIAFRSSYR

DRSESPGSYERETFALTSLETVTEALLEIMEACMRDI

PTCKWLDQWTELAQRFAFQYNPSLQPRALVVFGCISK

RVSHGQIKQIIRILSKALESCLKGPDTYNSQVLIEAT

VIALTKLQPLLNKDSPLHKALFWVAVAVLQLDEVNLY

SAGTALLEQNLHTLDSLRIENDKSPEEVEMAIRNPLE

WHCKQMDHFVGLNENSNENFALVGHLLKGYRHPSPAI

VARTVRILHTLLTLVNKHRNCDKFEVNTQSVAYLAAL

LTVSEEVRSRCSLKHRKS

LLLTDISMENVPMDTYPIHHGDPSYRTLKETQPWSSP

KGSEGYLAATYPTVGQTSPRARKSMSLDMGQPSQANT

KKLLGTRKSFDHLISDTKAPKRQEMESGITTPPKMRR

VAETDYEMETQRISSSQQHPHLRKVSVSESNVLLDEE

VLTDPKIQALLLTVLATLVKYTTDEFDQRILYEYLAE

ASVVFPKVFPVVHNLLDSKINTLLSLCQDPNLLNPIH

GIVQSVVYHEESPPQYQTSYLQSFGENGLWRFAGPES

KQTQIPDYAELIVKELDALIDTYLPGIDEETSEESLL

TPTSPYPPALQSQLSITANLNLSNSMTSLATSQHSPG

IDKENVELSPTTGHCNSGRTRHGSASQVQKORSAGSF

KRNSIKKIV

Histone-lysine
Wiedmann-
234
MAHSCRWRFPARPGTTGGGGGGGRRGLGGAPRQRVPA

N-
Steiner

LLLPPGPPVGGGGPGAPPSPPAVAAAAAAAGSSGAGV

methyltransferase
Syndrome

PGGAAAASAASSSSASSSSSSSSSASSGPALLRVGPG

2A

FDAALQVSAAIGTNLRRFRAVFGESGGGGGSGEDEQF

(KMT2A)

LGFGSDEEVRVRSPTRSPSVKTSPRKPRGRPRSGSDR

NSAILSDPSVESPLNKSETKSGDKIKKKDSKSIEKKR

GRPPTFPGVKIKITHGKDISELPKGNKEDSLKKIKRT

PSATFQQATKIKKLRAGKLSPLKSKFKTGKLQIGRKG

VQIVRRRGRPPSTERIKTPSGLLINSELEKPQKVRKD

KEGTPPLTKEDKTVVRQSPRRIKPVRIIPSSKRTDAT

IAKQLLQRAKKGAQKKIEKEAAQLQGRKVKTQVKNIR

QFIMPVVSAISSRIIKTPRRFIEDEDYDPPIKIARLE

STPNSRESAPSCGSSEKSSAASQHSSQMSSDSSRSSS

PSVDTSTDSQASEEIQVLPEERSDTPEVHPPLPISQS

PENESNDRRSRRYSVSERSFGSRTTKKLSTLQSAPQQ

QTSSSPPPPLLTPPPPLQPASSISDHTPWLMPPTIPL

ASPFLPASTAPMQGKRKSILREPTFRWTSLKHSRSEP

QYFSSAKYAKEGLIRKPIFDNERPPPLTPEDVGFASG

FSASGTAASARLFSPLHSGTREDMHKRSPLLRAPRFT

PSEAHSRIFESVTLPSNRTSAGTSSSGVSNRKRKRKV

FSPIRSEPRSPSHSMRTRSGRLSSSELSPLTPPSSVS

SSLSISVSPLATSALNPTFTFPSHSLTQSGESAEKNQ

RPRKQTSAPAEPFSSSSPTPLFPWFTPGSQTERGRNK

DKAPEELSKDRDADKSVEKDKSRERDREREKENKRES

RKEKRKKGSEIQSSSALYPVGRVSKEKVVGEDVATSS

SAKKATGRKKSSSHDSGTDITSVTLGDTTAVKTKILI

KKGRGNLEKTNLDLGPTAPSLEKEKTLCLSTPSSSTV

KHSTSSIGSMLAQADKLPMTDKRVASLLKKAKAQLCK

IEKSKSLKQTDQPKAQGQESDSSETSVRGPRIKHVCR

RAAVALGRKRAVFPDDMPTLSALPWEEREKILSSMGN

DDKSSIAGSEDAEPLAPPIKPIKPVTRNKAPQEPPVK

KGRRSRRCGQCPGCQVPEDCGVCTNCLDKPKFGGRNI

KKQCCKMRKCQNLQWMPSKAYLQKQAKAVKKKEKKSK

TSEKKDSKESSVVKNVVDSSQKPTPSAREDPAPKKSS

SEPPPRKPVEEKSEEGNVSAPGPESKQATTPASRKSS

KQVSQPALVIPPQPPTTGPPRKEVPKTTPSEPKKKQP

PPPESGPEQSKQKKVAPRPSIPVKQKPKEKEKPPPVN

KQENAGTLNILSTLSNGNSSKQKIPADGVHRIRVDEK

EDCEAENVWEMGGLGILTSVPITPRVVCFLCASSGHV

EFVYCQVCCEPFHKFCLEENERPLEDQLENWCCRRCK

FCHVCGRQHQATKQLLECNKCRNSYHPECLGPNYPTK

PTKKKKVWICTKCVRCKSCGSTTPGKGWDAQWSHDES

LCHDCAKLFAKGNFCPLCDKCYDDDDYESKMMQCGKC

DRWVHSKCENLSDEMYEILSNLPESVAYTCVNCTERH

PAEWRLALEKELQISLKQVLTALLNSRTTSHLLRYRQ

AAKPPDLNPETEESIPSRSSPEGPDPPVLTEVSKQDD

QQPLDLEGVKRKMDQGNYTSVLEFSDDIVKIIQAAIN

SDGGQPEIKKANSMVKSFFIRQMERVFPWFSVKKSRF

WEPNKVSSNSGMLPNAVLPPSLDHNYAQWQEREENSH

TEQPPLMKKIIPAPKPKGPGEPDSPTPLHPPTPPILS

TDRSREDSPELNPPPGIEDNRQCALCLTYGDDSANDA

GRLLYIGQNEWTHVNCALWSAEVFEDDDGSLKNVHMA

VIRGKQLRCEFCQKPGATVGCCLTSCTSNYHFMCSRA

KNCVFLDDKKVYCQRHRDLIKGEVVPENGFEVERRVE

VDFEGISLRRKELNGLEPENIHMMIGSMTIDCLGILN

DLSDCEDKLFPIGYQCSRVYWSTTDARKRCVYTCKIV

ECRPPVVEPDINSTVEHDENRTIAHSPTSFTESSSKE

SQNTAEIISPPSPDRPPHSQTSGSCYYHVISKVPRIR

TPSYSPTQRSPGCRPLPSAGSPTPTTHEIVTVGDPLL

SSGLRSIGSRRHSTSSLSPQRSKLRIMSPMRTGNTYS

RNNVSSVSTTGTATDLESSAKVVDHVLGPLNSSTSLG

QNTSTSSNLQRTVVTVGNKNSHLDGSSSSEMKQSSAS

DLVSKSSSLKGEKTKVLSSKSSEGSAHNVAYPGIPKL

APQVHNTTSRELNVSKIGSFAEPSSVSFSSKEALSFP

HLHLRGQRNDRDQHTDSTQSANSSPDEDTEVKTLKLS

GMSNRSSIINEHMGSSSRDRRQKGKKSCKETFKEKHS

SKSFLEPGQVTTGEEGNLKPEFMDEVLTPEYMGQRPC

NNVSSDKIGDKGLSMPGVPKAPPMQVEGSAKELQAPR

KRTVKVTLTPLKMENESQSKNALKESSPASPLQIEST

SPTEPISASENPGDGPVAQPSPNNTSCQDSQSNNYQN

LPVQDRNLMLPDGPKPQEDGSFKRRYPRRSARARSNM

FFGLTPLYGVRSYGEEDIPFYSSSTGKKRGKRSAEGQ

VDGADDLSTSDEDDLYYYNFTRTVISSGGEERLASHN

LFREEEQCDLPKISQLDGVDDGTESDTSVTATTRKSS

QIPKRNGKENGTENLKIDRPEDAGEKEHVTKSSVGHK

NEPKMDNCHSVSRVKTQGQDSLEAQLSSLESSRRVHT

STPSDKNLLDTYNTELLKSDSDNNNSDDCGNILPSDI

MDFVLKNTPSMQALGESPESSSSELLNLGEGLGLDSN

REKDMGLFEVESQQLPTTEPVDSSVSSSISAEEQFEL

PLELPSDLSVLTTRSPTVPSQNPSRLAVISDSGEKRV

TITEKSVASSESDPALLSPGVDPTPEGHMTPDHFIQG

HMDADHISSPPCGSVEQGHGNNQDLTRNSSTPGLQVP

VSPTVPIQNQKYVPNSTDSPGPSQISNAAVQTTPPHL

KPATEKLIVVNQNMQPLYVLQTLPNGVTQKIQLTSSV

SSTPSVMETNTSVLGPMGGGLTLTTGLNPSLPTSQSL

FPSASKGLLPMSHHQHLHSFPAATQSSFPPNISNPPS

GLLIGVQPPPDPQLLVSESSQRTDLSTTVATPSSGLK

KRPISRLQTRKNKKLAPSSTPSNIAPSDVVSNMTLIN

FTPSQLPNHPSLLDLGSLNTSSHRTVPNIIKRSKSSI

MYFEPAPLLPQSVGGTAATAAGTSTISQDTSHLTSGS

VSGLASSSSVLNVVSMQTTTTPTSSASVPGHVTLTNP

RLLGTPDIGSISNLLIKASQQSLGIQDQPVALPPSSG

MFPQLGTSQTPSTAAITAASSICVLPSTQTTGITAAS

PSGEADEHYQLQHVNQLLASKTGIHSSQRDLDSASGP

QVSNFTQTVDAPNSMGLEQNKALSSAVQASPTSPGGS

PSSPSSGQRSASPSVPGPTKPKPKTKRFQLPLDKGNG

KKHKVSHLRTSSSEAHIPDQETTSLTSGTGTPGAEAE

QQDTASVEQSSQKECGQPAGQVAVLPEVQVTQNPANE

QESAEPKTVEEEESNESSPLMLWLQQEQKRKESITEK

KPKKGLVFEISSDDGFQICAESIEDAWKSLTDKVQEA

RSNARLKQLSFAGVNGLRMLGILHDAVVFLIEQLSGA

KHCRNYKFRFHKPEEANEPPLNPHGSARAEVHLRKSA

FDMENFLASKHRQPPEYNPNDEEEEEVQLKSARRATS

MDLPMPMRFRHLKKTSKEAVGVYRSPIHGRGLFCKRN

IDAGEMVIEYAGNVIRSIQTDKREKYYDSKGIGCYME

RIDDSEVVDATMHGNAARFINHSCEPNCYSRVINIDG

QKHIVIFAMRKIYRGEELTYDYKFPIEDASNKLPCNC

GAKKCRKELN

Chromodomain-
Sifrim-Hitz-
235
MASGLGSPSPCSAGSEEEDMDALLNNSLPPPHPENEE

helicase-DNA-
Weiss

DPEEDLSETETPKLKKKKKPKKPRDPKIPKSKRQKKE

binding protein
Syndrome

RMLLCRQLGDSSGEGPEFVEEEEEVALRSDSEGSDYT

4

PGKKKKKKLGPKKEKKSKSKRKEEEEEEDDDDDSKEP

(CHD4)

KSSAQLLEDWGMEDIDHVESEEDYRTLTNYKAFSQFV

RPLIAAKNPKIAVSKMMMVLGAKWREFSTNNPFKGSS

GASVAAAAAAAVAVVESMVTATEVAPPPPPVEVPIRK

AKTKEGKGPNARRKPKGSPRVPDAKKPKPKKVAPLKI

KLGGFGSKRKRSSSEDDDLDVESDEDDASINSYSVSD

GSTSRSSRSRKKLRTTKKKKKGEEEVTAVDGYETDHQ

DYCEVCQQGGEIILCDTCPRAYHMVCLDPDMEKAPEG

KWSCPHCEKEGIQWEAKEDNSEGEEILEEVGGDLEEE

DDHHMEFCRVCKDGGELLCCDTCPSSYHIHCLNPPLP

EIPNGEWLCPRCTCPALKGKVQKILIWKWGQPPSPTP

VPRPPDADPNTPSPKPLEGRPERQFFVKWQGMSYWHC

SWVSELQLELHCQVMERNYQRKNDMDEPPSGDEGGDE

EKSRKRKNKDPKFAEMEERFYRYGIKPEWMMIHRILN

HSVDKKGHVHYLIKWRDLPYDQASWESEDVEIQDYDL

FKQSYWNHRELMRGEEGRPGKKLKKVKLRKLERPPET

PTVDPTVKYERQPEYLDATGGTLHPYQMEGLNWLRES

WAQGTDTILADEMGLGKTVQTAVFLYSLYKEGHSKGP

FLVSAPLSTIINWEREFEMWAPDMYVVTYVGDKDSRA

IIRENEFSFEDNAIRGGKKASRMKKEASVKFHVLLTS

YELITIDMAILGSIDWACLIVDEAHRLKNNQSKFFRV

LNGYSLQHKLLLTGTPLQNNLEELFHLLNELTPERFH

NLEGFLEEFADIAKEDQIKKLHDMLGPHMLRRLKADV

FKNMPSKTELIVRVELSPMQKKYYKYILTRNFEALNA

RGGGNQVSLLNVVMDLKKCCNHPYLFPVAAMEAPKMP

NGMYDGSALIRASGKLLLLQKMLKNLKEGGHRVLIES

QMTKMLDLLEDFLEHEGYKYERIDGGITGNMRQEAID

RFNAPGAQQFCFLLSTRAGGLGINLATADTVIIYDSD

WNPHNDIQAFSRAHRIGQNKKVMIYREVTRASVEERI

TQVAKKKMMLTHLVVRPGLGSKTGSMSKQELDDILKF

GTEELFKDEATDGGGDNKEGEDSSVIHYDDKAIERLL

DRNQDETEDTELQGMNEYLSSFKVAQYVVREEEMGEE

EEVEREIIKQEESVDPDYWEKLLRHHYEQQQEDLARN

LGKGKRIRKQVNYNDGSQEDRDWQDDQSDNQSDYSVA

SEEGDEDFDERSEAPRRPSRKGLRNDKDKPLPPLLAR

VGGNIEVLGFNARQRKAFLNAIMRYGMPPQDAFTTQW

LVRDLRGKSEKEFKAYVSLFMRHLCEPGADGAETFAD

GVPREGLSRQHVLTRIGVMSLIRKKVQEFEHVNGRWS

MPELAEVEENKKMSQPGSPSPKTPTPSTPGDTQPNTP

APVPPAEDGIKIEENSLKEEESIEGEKEVKSTAPETA

IECTQAPAPASEDEKVVVEPPEGEEKVEKAEVKERTE

EPMETEPKGAADVEKVEEKSAIDLTPIVVEDKEEKKE

EEEKKEVMLQNGETPKDLNDEKQKKNIKQRFMENIAD

GGFTELHSLWQNEERAATVTKKTYEIWHRRHDYWLLA

GIINHGYARWQDIQNDPRYAILNEPFKGEMNRGNFLE

IKNKFLARRFKLLEQALVIEEQLRRAAYLNMSEDPSH

PSMALNTRFAEVECLAESHQHLSKESMAGNKPANAVL

HKVLKQLEELLSDMKADVTRLPATIARIPPVAVRLQM

SERNILSRLANRAPEPTPQQVAQQQ

Histone-lysine
Sotos
236
MDQTCELPRRNCLLPFSNPVNLDAPEDKDSPEGNGQS

N-
Syndrome

NFSEPLNGCTMQLSTVSGTSQNAYGQDSPSCYIPLRR

methyltransferase,

LQDLASMINVEYLNGSADGSESFQDPEKSDSRAQTPI

H3 lysine-36

VCTSLSPGGPTALAMKQEPSCNNSPELQVKVTKTIKN

specific

GFLHFENFTCVDDADVDSEMDPEQPVTEDESIEEIFE

(NSD1)

ETQTNATCNYETKSENGVKVAMGSEQDSTPESRHGAV

KSPFLPLAPQTETQKNKQRNEVDGSNEKAALLPAPES

LGDTNITIEEQLNSINLSFQDDPDSSTSTLGNMLELP

GTSSSSTSQELPFCQPKKKSTPLKYEVGDLIWAKEKR

RPWWPCRICSDPLINTHSKMKVSNRRPYRQYYVEAFG

DPSERAWVAGKAIVMFEGRHQFEELPVLRRRGKQKEK

GYRHKVPQKILSKWEASVGLAEQYDVPKGSKNRKCIP

GSIKLDSEEDMPFEDCTNDPESEHDLLLNGCLKSLAF

DSEHSADEKEKPCAKSRARKSSDNPKRTSVKKGHIQF

EAHKDERRGKIPENLGLNFISGDISDTQASNELSRIA

NSLTGSNTAPGSFLFSSCGKNTAKKEFETSNGDSLLG

LPEGALISKCSREKNKPQRSLVCGSKVKLCYIGAGDE

EKRSDSISICTTSDDGSSDLDPIEHSSESDNSVLEIP

DAFDRTENMLSMQKNEKIKYSRFAATNTRVKAKQKPL

ISNSHTDHLMGCTKSAEPGTETSQVNLSDLKASTLVH

KPQSDFTNDALSPKENLSSSISSENSLIKGGAANQAL

LHSKSKQPKFRSIKCKHKENPVMAEPPVINEECSLKC

CSSDTKGSPLASISKSGKVDGLKLLNNMHEKTRDSSD

IETAVVKHVLSELKELSYRSLGEDVSDSGTSKPSKPL

LFSSASSQNHIPIEPDYKFSTLLMMLKDMHDSKTKEQ

RLMTAQNLVSYRSPGRGDCSTNSPVGVSKVLVSGGST

HNSEKKGDGTQNSANPSPSGGDSALSGELSASLPGLL

SDKRDLPASGKSRSDCVTRRNCGRSKPSSKLRDAFSA

QMVKNTVNRKALKTERKRKLNQLPSVTLDAVLQGDRE

RGGSLRGGAEDPSKEDPLQIMGHLTSEDGDHFSDVHF

DSKVKQSDPGKISEKGLSFENGKGPELDSVMNSENDE

LNGVNQVVPKKRWQRLNQRRTKPRKRMNREKEKENSE

CAFRVLLPSDPVQEGRDEFPEHRTPSASILEEPLTEQ

NHADCLDSAGPRLNVCDKSSASIGDMEKEPGIPSLTP

QAELPEPAVRSEKKRLRKPSKWLLEYTEEYDQIFAPK

KKQKKVQEQVHKVSSRCEEESLLARGRSSAQNKQVDE

NSLISTKEEPPVLEREAPFLEGPLAQSELGGGHAELP

QLTLSVPVAPEVSPRPALESEELLVKTPGNYESKRQR

KPTKKLLESNDLDPGEMPKKGDLGLSKKCYEAGHLEN

GITESCATSYSKDFGGGTTKIFDKPRKRKRQRHAAAK

MQCKKVKNDDSSKEIPGSEGELMPHRTATSPKETVEE

GVEHDPGMPASKKMQGERGGGAALKENVCQNCEKLGE

LLLCEAQCCGAFHLECLGLTEMPRGKFICNECRTGIH

TCFVCKQSGEDVKRCLLPLCGKFYHEECVQKYPPTVM

QNKGFRCSLHICITCHAANPANVSASKGRLMRCVRCP

VAYHANDFCLAAGSKILASNSIICPNHFTPRRGCRNH

EHVNVSWCFVCSEGGSLLCCDSCPAAFHRECLNIDIP

EGNWYCNDCKAGKKPHYREIVWVKVGRYRWWPAEICH

PRAVPSNIDKMRHDVGEFPVLFFGSNDYLWTHQARVE

PYMEGDVSSKDKMGKGVDGTYKKALQEAAARFEELKA

QKELRQLQEDRKNDKKPPPYKHIKVNRPIGRVQIFTA

DLSEIPRCNCKATDENPCGIDSECINRMLLYECHPTV

CPAGGRCQNQCFSKRQYPEVEIFRTLQRGWGLRTKTD

IKKGEFVNEYVGELIDEEECRARIRYAQEHDITNFYM

LTLDKDRIIDAGPKGNYARFMNHCCQPNCETQKWSVN

GDTRVGLFALSDIKAGTELTENYNLECLGNGKTVCKC

GAPNCSGFLGVRPKNQPIATEEKSKKFKKKQQGKRRT

QGEITKEREDECFSCGDAGQLVSCKKPGCPKVYHADC

LNLTKRPAGKWECPWHQCDICGKEAASFCEMCPSSFC

KQHREGMLFISKLDGRLSCTEHDPCGPNPLEPGEIRE

YVPPPVPLPPGPSTHLAEQSTGMAAQAPKMSDKPPAD

TNQMLSLSKKALAGTCQRPLLPERPLERTDSRPQPLD

KVRDLAGSGTKSQSLVSSQRPLDRPPAVAGPRPQLSD

KPSPVTSPSSSPSVRSQPLERPLGTADPRLDKSIGAA

SPRPQSLEKTSVPTGLRLPPPDRLLITSSPKPQTSDR

PTDKPHASLSQRLPPPEKVLSAVVQTLVAKEKALRPV

DQNTQSKNRAALVMDLIDLTPRQKERAASPHQVTPQA

DEKMPVLESSSWPASKGLGHMPRAVEKGCVSDPLQTS

GKAAAPSEDPWQAVKSLTQARLLSQPPAKAFLYEPTT

QASGRASAGAEQTPGPLSQSPGLVKQAKQMVGGQQLP

ALAAKSGQSFRSLGKAPASLPTEEKKLVTTEQSPWAL

GKASSRAGLWPIVAGQTLAQSCWSAGSTQTLAQTCWS

LGRGQDPKPEQNTLPALNQAPSSHKCAESEQK

Mediator of
MED13L
237
MTAAANWVANGASLEDCHSNLESLAELTGIKWRRYNF

RNA
Syndrome

GGHGDCGPIISAPAQDDPILLSFIRCLQANLLCVWRR

polymerase II

DVKPDCKELWIFWWGDEPNLVGVIHHELQVVEEGLWE

transcription

NGLSYECRTLLFKAIHNLLERCLMDKNFVRIGKWFVR

subunit 13-like

PYEKDEKPVNKSEHLSCAFTFELHGESNVCTSVEIAQ

(MED13L)

HQPIYLINEEHIHMAQSSPAPFQVLVSPYGLNGTLTG

QAYKMSDPATRKLIEEWQYFYPMVLKKKEESKEEDEL

GYDDDFPVAVEVIVGGVRMVYPSAFVLISQNDIPVPQ

SVASAGGHIAVGQQGLGSVKDPSNCGMPLTPPTSPEQ

AILGESGGMQSAASHLVSQDGGMITMHSPKRSGKIPP

KLHNHMVHRVWKECILNRTQSKRSQMSTPTLEEEPAS

NPATWDFVDPTQRVSCSCSRHKLLKRCAVGPNRPPTV

SQPGFSAGPSSSSSLPPPASSKHKTAERQEKGDKLQK

RPLIPFHHRPSVAEELCMEQDTPGQKLGLAGIDSSLE

VSSSRKYDKQMAVPSRNTSKQMNLNPMDSPHSPISPL

PPTLSPQPRGQETESLDPPSVPVNPALYGNGLELQQL

STLDDRTVLVGQRLPLMAEVSETALYCGIRPSNPESS

EKWWHSYRLPPSDDAEFRPPELQGERCDAKMEVNSES

TALQRLLAQPNKRFKIWQDKQPQLQPLHELDPLPLSQ

QPGDSLGEVNDPYTFEDGDIKYIFTANKKCKQGTEKD

SLKKNKSEDGFGTKDVTTPGHSTPVPDGKNAMSIFSS

ATKTDVRQDNAAGRAGSSSLTQVTDLAPSLHDLDNIE

DNSDDDELGAVSPALRSSKMPAVGTEDRPLGKDGRAA

VPYPPTVADLQRMFPTPPSLEQHPAFSPVMNYKDGIS

SETVTALGMMESPMVSMVSTQLTEFKMEVEDGLGSPK

PEEIKDFSYVHKVPSFQPFVGSSMFAPLKMLPSHCLL

PLKIPDACLFRPSWAIPPKIEQLPMPPAATFIRDGYN

NVPSVGSLADPDYLNTPQMNTPVTLNSAAPASNSGAG

VLPSPATPRFSVPTPRTPRTPRTPRGGGTASGQGSVK

YDSTDQGSPASTPSTTRPLNSVEPATMQPIPEAHSLY

VTLILSDSVMNIFKDRNEDSCCICACNMNIKGADVGL

YIPDSSNEDQYRCTCGFSAIMNRKLGYNSGLFLEDEL

DIFGKNSDIGQAAERRLMMCQSTELPQVEGTKKPQEP

PISLLLLLQNQHTQPFASLNFLDYISSNNRQTLPCVS

WSYDRVQADNNDYWTECFNALEQGRQYVDNPTGGKVD

EALVRSATVHSWPHSNVLDISMLSSQDVVRMLLSLQP

FLQDAIQKKRTGRTWENIQHVQGPLTWQQFHKMAGRG

TYGSEESPEPLPIPTLLVGYDKDELTISPESLPFWER

LLLDPYGGHRDVAYIVVCPENEALLEGAKTFERDLSA

VYEMCRLGQHKPICKVLRDGIMRVGKTVAQKLTDELV

SEWFNQPWSGEENDNHSRLKLYAQVCRHHLAPYLATL

QLDSSLLIPPKYQTPPAAAQGQATPGNAGPLAPNGSA

APPAGSAFNPTSNSSSTNPAASSSASGSSVPPVSSSA

SAPGISQISTTSSSGFSGSVGGQNPSTGGISADRTQG

NIGCGGDTDPGQSSSQPSQDGQESVTERERIGIPTEP

DSADSHAHPPAVVIYMVDPFTYAAEEDSTSGNEWLLS

LMRCYTEMLDNLPEHMRNSFILQIVPCQYMLQTMKDE

QVFYIQYLKSMAFSVYCQCRRPLPTQIHIKSLTGFGP

AASIEMTLKNPERPSPIQLYSPPFILAPIKDKQTELG

ETFGEASQKYNVLFVGYCLSHDQRWLLASCTDLHGEL

LETCVVNIALPNRSRRSKVSARKIGLQKLWEWCIGIV

QMTSLPWRVVIGRLGRLGHGELKDWSILLGECSLQTI

SKKLKDVCRMCGISAADSPSILSACLVAMEPQGSFVV

MPDAVTMGSVFGRSTALNMQSSQLNTPQDASCTHILV

FPTSSTIQVAPANYPNEDGESPNNDDMFVDLPFPDDM

DNDIGILMTGNLHSSPNSSPVPSPGSPSGIGVGSHFQ

HSRSQGERLLSREAPEELKQQPLALGYFVSTAKAENL

PQWFWSSCPQAQNQCPLFLKASLHHHISVAQTDELLP

ARNSQRVPHPLDSKTTSDVLRFVLEQYNALSWLTCNP

ATQDRTSCLPVHFVVLTQLYNAIMNIL

Structural
SMC1A
238
MGFLKLIEIENFKSYKGRQIIGPFQRFTAIIGPNGSG

maintenance of
Syndrome

KSNLMDAISFVLGEKTSNLRVKTLRDLIHGAPVGKPA

chromosomes

ANRAFVSMVYSEEGAEDRTFARVIVGGSSEYKINNKV

protein 1A

VQLHEYSEELEKLGILIKARNFLVFQGAVESIAMKNP

(SMC1A)

KERTALFEEISRSGELAQEYDKRKKEMVKAEEDTQEN

YHRKKNIAAERKEAKQEKEEADRYQRLKDEVVRAQVQ

LQLFKLYHNEVEIEKLNKELASKNKEIEKDKKRMDKV

EDELKEKKKELGKMMREQQQIEKEIKEKDSELNQKRP

QYIKAKENTSHKIKKLEAAKKSLQNAQKHYKKRKGDM

DELEKEMLSVEKARQEFEERMEEESQSQGRDLTLEEN

QVKKYHRLKEEASKRAATLAQELEKENRDQKADQDRL

DLEERKKVETEAKIKQKLREIEENQKRIEKLEEYITT

SKQSLEEQKKLEGELTEEVEMAKRRIDEINKELNQVM

EQLGDARIDRQESSRQQRKAEIMESIKRLYPGSVYGR

LIDLCQPTQKKYQIAVTKVLGKNMDAIIVDSEKTGRD

CIQYIKEQRGEPETFLPLDYLEVKPTDEKLRELKGAK

LVIDVIRYEPPHIKKALQYACGNALVCDNVEDARRIA

FGGHQRHKTVALDGTLFQKSGVISGGASDLKAKARRW

DEKAVDKLKEKKERLTEELKEQMKAKRKEAELRQVQS

QAHGLQMRLKYSQSDLEQTKTRHLALNLQEKSKLESE

LANFGPRINDIKRIIQSREREMKDLKEKMNQVEDEVE

EEFCREIGVRNIREFEEEKVKRQNEIAKKRLEFENQK

TRLGIQLDFEKNQLKEDQDKVHMWEQTVKKDENEIEK

LKKEEQRHMKIIDETMAQLQDLKNQHLAKKSEVNDKN

HEMEEIRKKLGGANKEMTHLQKEVTAIETKLEQKRSD

RHNLLQACKMQDIKLPLSKGTMDDISQEEGSSQGEDS

VSGSQRISSIYAREALIEIDYGDLCEDLKDAQAEEEI

KQEMNTLQQKLNEQQSVLQRIAAPNMKAMEKLESVRD

KFQETSDEFEAARKRAKKAKQAFEQIKKERFDRENAC

FESVATNIDEIYKALSRNSSAQAFLGPENPEEPYLDG

INYNCVAPGKRFRPMDNLSGGEKTVAALALLFAIHSY

KPAPFFVLDEIDAALDNTNIGKVANYIKEQSTCNFQA

IVISLKEEFYTKAESLIGVYPEQGDCVISKVLTEDLT

KYPDANPNPNEQ

Probable global
Nicolaides-
239
MSTPTDPGAMPHPGPSPGPGPSPGPILGPSPGPGPSP

transcription
Baraitser

GSVHSMMGPSPGPPSVSHPMPTMGSTDFPQEGMHQMH

activator
Syndrome

KPIDGIHDKGIVEDIHCGSMKGTGMRPPHPGMGPPQS

SNF2L2

PMDQHSQGYMSPHPSPLGAPEHVSSPMSGGGPTPPQM

(SMARCA2)

PPSQPGALIPGDPQAMSQPNRGPSPFSPVQLHQLRAQ

ILAYKMLARGQPLPETLQLAVQGKRTLPGLQQQQQQQ

QQQQQQQQQQQQQQQQPQQQPPQPQTQQQQQPALVNY

NRPSGPGPELSGPSTPQKLPVPAPGGRPSPAPPAAAQ

PPAAAVPGPSVPQPAPGQPSPVLQLQQKQSRISPIQK

PQGLDPVEILQEREYRLQARIAHRIQELENLPGSLPP

DLRTKATVELKALRLLNFQRQLRQEVVACMRRDTTLE

TALNSKAYKRSKRQTLREARMTEKLEKQQKIEQERKR

RQKHQEYLNSILQHAKDFKEYHRSVAGKIQKLSKAVA

TWHANTEREQKKETERIEKERMRRLMAEDEEGYRKLI

DQKKDRRLAYLLQQTDEYVANLTNLVWEHKQAQAAKE

KKKRRRRKKKAEENAEGGESALGPDGEPIDESSQMSD

LPVKVTHTETGKVLFGPEAPKASQLDAWLEMNPGYEV

APRSDSEESDSDYEEEDEEEESSRQETEEKILLDPNS

EEVSEKDAKQIIETAKQDVDDEYSMQYSARGSQSYYT

VAHAISERVEKQSALLINGTLKHYQLQGLEWMVSLYN

NNLNGILADEMGLGKTIQTIALITYLMEHKRINGPYL

IIVPLSTLSNWTYEFDKWAPSVVKISYKGTPAMRRSL

VPQLRSGKENVLLTTYEYIIKDKHILAKIRWKYMIVD

EGHRMKNHHCKLTQVLNTHYVAPRRILLTGTPLQNKL

PELWALLNFLLPTIFKSCSTFEQWENAPFAMTGERVD

LNEEETILIIRRLHKVLRPELLRRLKKEVESQLPEKV

EYVIKCDMSALQKILYRHMQAKGILLTDGSEKDKKGK

GGAKTLMNTIMQLRKICNHPYMFQHIEESFAEHLGYS

NGVINGAELYRASGKFELLDRILPKLRATNHRVLLFC

QMTSLMTIMEDYFAFRNFLYLRLDGTTKSEDRAALLK

KENEPGSQYFIFLLSTRAGGLGLNLQAADTVVIEDSD

WNPHQDLQAQDRAHRIGQQNEVRVLRLCTVNSVEEKI

LAAAKYKLNVDQKVIQAGMEDQKSSSHERRAFLQAIL

EHEEENEEEDEVPDDETLNQMIARREEEFDLFMRMDM

DRRREDARNPKRKPRLMEEDELPSWIIKDDAEVERLT

CEEEEEKIFGRGSRQRRDVDYSDALTEKQWLRAIEDG

NLEEMEEEVRLKKRKRRRNVDKDPAKEDVEKAKKRRG

RPPAEKLSPNPPKLTKQMNAIIDTVINYKDRCNVEKV

PSNSQLEIEGNSSGRQLSEVFIQLPSRKELPEYYELI

RKPVDFKKIKERIRNHKYRSLGDLEKDVMLLCHNAQT

FNLEGSQIYEDSIVLQSVEKSARQKIAKEEESEDESN

EEEEEEDEEESESEAKSVKVKIKLNKKDDKGRDKGKG

KKRPNRGKAKPVVSDFDSDEEQDEREQSEGSGTDDE

AT-rich
ARID1B-
240
MAHNAGAAAAAGTHSAKSGGSEAALKEGGSAAALSSS

interactive
Related

SSSSAAAAAASSSSSSGPGSAMETGLLPNHKLKTVGE

domain-
Disorder

APAAPPHQQHHHHHHAHHHHHHAHHLHHHHALQQQLN

containing

QFQQQQQQQQQQQQQQQQQQHPISNNNSLGGAGGGAP

protein 1B

QPGPDMEQPQHGGAKDSAAGGQADPPGPPLLSKPGDE

(ARID1B)

DDAPPKMGEPAGGRYEHPGLGALGTQQPPVAVPGGGG

GPAAVPEFNNYYGSAAPASGGPGGRAGPCFDQHGGQQ

SPGMGMMHSASAAAAGAPGSMDPLQNSHEGYPNSQCN

HYPGYSRPGAGGGGGGGGGGGGGSGGGGGGGGAGAGG

AGAGAVAAAAAAAAAAAGGGGGGGYGGSSAGYGVLSS

PRQQGGGMMMGPGGGGAASLSKAAAGSAAGGFQRFAG

QNQHPSGATPTLNQLLTSPSPMMRSYGGSYPEYSSPS

APPPPPSQPQSQAAAAGAAAGGQQAAAGMGLGKDMGA

QYAAASPAWAAAQQRSHPAMSPGTPGPTMGRSQGSPM

DPMVMKRPQLYGMGSNPHSQPQQSSPYPGGSYGPPGP

QRYPIGIQGRTPGAMAGMQYPQQQMPPQYGQQGVSGY

CQQGQQPYYSQQPQPPHLPPQAQYLPSQSQQRYQPQQ

DMSQEGYGTRSQPPLAPGKPNHEDLNLIQQERPSSLP

DLSGSIDDLPTGTEATLSSAVSASGSTSSQGDQSNPA

QSPFSPHASPHLSSIPGGPSPSPVGSPVGSNQSRSGP

ISPASIPGSQMPPQPPGSQSESSSHPALSQSPMPQER

GFMAGTQRNPQMAQYGPQQTGPSMSPHPSPGGQMHAG

ISSFQQSNSSGTYGPQMSQYGPQGNYSRPPAYSGVPS

ASYSGPGPGMGISANNQMHGQGPSQPCGAVPLGRMPS

AGMQNRPFPGNMSSMTPSSPGMSQQGGPGMGPPMPTV

NRKAQEAAAAVMQAAANSAQSRQGSFPGMNQSGLMAS

SSPYSQPMNNSSSLMNTQAPPYSMAPAMVNSSAASVG

LADMMSPGESKLPLPLKADGKEEGTPQPESKSKKSSS

STTTGEKITKVYELGNEPERKLWVDRYLTEMEERGSP

VSSLPAVGKKPLDLFRLYVCVKEIGGLAQVNKNKKWR

ELATNLNVGTSSSAASSLKKQYIQYLFAFECKIERGE

EPPPEVESTGDTKKQPKLQPPSPANSGSLQGPQTPQS

TGSNSMAEVPGDLKPPTPASTPHGQMTPMQGGRSSTI

SVHDPFSDVSDSSFPKRNSMTPNAPYQQGMSMPDVMG

RMPYEPNKDPFGGMRKVPGSSEPFMTQGQMPNSSMQD

MYNQSPSGAMSNLGMGQRQQFPYGASYDRRHEPYGQQ

YPGQGPPSGQPPYGGHQPGLYPQQPNYKRHMDGMYGP

PAKRHEGDMYNMQYSSQQQEMYNQYGGSYSGPDRRPI

QGQYPYPYSRERMQGPGQIQTHGIPPQMMGGPLQSSS

SEGPQQNMWAARNDMPYPYQNRQGPGGPTQAPPYPGM

NRTDDMMVPDQRINHESQWPSHVSQRQPYMSSSASMQ

PITRPPQPSYQTPPSLPNHISRAPSPASFQRSLENRM

SPSKSPFLPSMKMQKVMPTVPTSQVTGPPPQPPPIRR

EITFPPGSVEASQPVLKQRRKITSKDIVTPEAWRVMM

SLKSGLLAESTWALDTINILLYDDSTVATENLSQLSG

FLELLVEYERKCLIDIFGILMEYEVGDPSQKALDHNA

ARKDDSQSLADDSGKEEEDAECIDDDEEDEEDEEEDS

EKTESDEKSSIALTAPDAAADPKEKPKQASKEDKLPI

KIVKKNNLFVVDRSDKLGRVQEFNSGLLHWQLGGGDT

TEHIQTHFESKMEIPPRRRPPPPLSSAGRKKEQEGKG

DSEEQQEKSIIATIDDVLSARPGALPEDANPGPQTES

SKFPFGIQQAKSHRNIKLLEDEPRSRDETPLCTIAHW

QDSLAKRCICVSNIVRSLSFVPGNDAEMSKHPGLVLI

LGKLILLHHEHPERKRAPQTYEKEEDEDKGVACSKDE

WWWDCLEVLRDNTLVTLANISGQLDLSAYTESICLPI

LDGLLHWMVCPSAEAQDPFPTVGPNSVLSPQRLVLET

LCKLSIQDNNVDLILATPPFSRQEKFYATLVRYVGDR

KNPVCREMSMALLSNLAQGDALAARAIAVQKGSIGNL

ISFLEDGVTMAQYQQSQHNLMHMQPPPLEPPSVDMMC

RAAKALLAMARVDENRSEFLLHEGRLLDISISAVLNS

LVASVICDVLFQIGQL

Pogo
White-Sutton
241
MADTDLFMECEEEELEPWQKISDVIEDSVVEDYNSVD

transposable
Syndrome

KTTTVSVSQQPVSAPVPIAAHASVAGHLSTSTTVSSS

element with

GAQNSDSTKKTLVTLIANNNAGNPLVQQGGQPLILTQ

ZNF domain

NPAPGLGTMVTQPVLRPVQVMQNANHVTSSPVASQPI

(POGZ)

FITTQGFPVRNVRPVQNAMNQVGIVLNVQQGQTVRPI

TLVPAPGTQFVKPTVGVPQVFSQMTPVRPGSTMPVRP

TTNTFTTVIPATLTIRSTVPQSQSQQTKSTPSTSTTP

TATQPTSLGQLAVQSPGQSNQTTNPKLAPSFPSPPAV

SIASFVTVKRPGVTGENSNEVAKLVNTLNTIPSLGQS

PGPVVVSNNSSAHGSQRTSGPESSMKVTSSIPVEDLQ

DGGRKICPRCNAQFRVTEALRGHMCYCCPEMVEYQKK

GKSLDSEPSVPSAAKPPSPEKTAPVASTPSSTPIPAL

SPPTKVPEPNENVGDAVQTKLIMLVDDFYYGRDGGKV

AQLTNFPKVATSFRCPHCTKRLKNNIRFMNHMKHHVE

LDQQNGEVDGHTICQHCYRQFSTPFQLQCHLENVHSP

YESTTKCKICEWAFESEPLFLQHMKDTHKPGEMPYVC

QVCQYRSSLYSEVDVHERMIHEDTRHLLCPYCLKVEK

NGNAFQQHYMRHQKRNVYHCNKCRLQFLFAKDKIEHK

LQHHKTFRKPKQLEGLKPGTKVTIRASRGQPRTVPVS

SNDTPPSALQEAAPLTSSMDPLPVFLYPPVQRSIQKR

AVRKMSVMGRQTCLECSFEIPDFPNHFPTYVHCSLCR

YSTCCSRAYANHMINNHVPRKSPKYLALFKNSVSGIK

LACTSCTFVTSVGDAMAKHLVENPSHRSSSILPRGLT

WIAHSRHGQTRDRVHDRNVKNMYPPPSEPTNKAATVK

SAGATPAEPEELLTPLAPALPSPASTATPPPTPTHPQ

ALALPPLATEGAECLNVDDQDEGSPVTQEPELASGGG

GSGGVGKKEQLSVKKLRVVLFALCCNTEQAAEHERNP

QRRIRRWLRRFQASQGENLEGKYLSFEAEEKLAEWVL

TQREQQLPVNEETLFQKATKIGRSLEGGEKISYEWAV

RFMLRHHLTPHARRAVAHTLPKDVAENAGLFIDEVQR

QIHNQDLPLSMIVAIDEISLFLDTEVLSSDDRKENAL

QTVGTGEPWCDVVLAILADGTVLPTLVFYRGQMDQPA

NMPDSILLEAKESGYSDDEIMELWSTRVWQKHTACQR

SKGMLVMDCHRTHLSEEVLAMLSASSTLPAVVPAGCS

SKIQPLDVCIKRTVKNFLHKKWKEQAREMADTACDSD

VLLQLVLVWLGEVLGVIGDCPELVQRSELVASVLPGP

DGNINSPTRNADMQEELIASLEEQLKLSGEHSESSTP

RPRSSPEETIEPESLHQLFEGESETESFYGFEEADLD

LMEI

Histone
KAT6B
242
MADTDLFMECEEEELEPWQKISDVIEDSVVEDYNSVD

acetyltransferase
Disorder

KTTTVSVSQQPVSAPVPIAAHASVAGHLSTSTTVSSS

KAT6B

GAQNSDSTKKTLVTLIANNNAGNPLVQQGGQPLILTQ

(KAT6B)

NPAPGLGTMVTQPVLRPVQVMQNANHVTSSPVASQPI

FITTQGFPVRNVRPVQNAMNQVGIVLNVQQGQTVRPI

TLVPAPGTQFVKPTVGVPQVFSQMTPVRPGSTMPVRP

TTNTFTTVIPATLTIRSTVPQSQSQQTKSTPSTSTTP

TATQPTSLGQLAVQSPGQSNQTTNPKLAPSFPSPPAV

SIASFVTVKRPGVTGENSNEVAKLVNTLNTIPSLGQS

PGPVVVSNNSSAHGSQRTSGPESSMKVTSSIPVEDLQ

DGGRKICPRCNAQFRVTEALRGHMCYCCPEMVEYQKK

GKSLDSEPSVPSAAKPPSPEKTAPVASTPSSTPIPAL

SPPTKVPEPNENVGDAVQTKLIMLVDDFYYGRDGGKV

AQLTNFPKVATSFRCPHCTKRLKNNIREMNHMKHHVE

LDQQNGEVDGHTICQHCYRQFSTPFQLQCHLENVHSP

YESTTKCKICEWAFESEPLFLQHMKDTHKPGEMPYVC

QVCQYRSSLYSEVDVHERMIHEDTRHLLCPYCLKVEK

NGNAFQQHYMRHQKRNVYHCNKCRLQFLFAKDKIEHK

LQHHKTFRKPKQLEGLKPGTKVTIRASRGQPRTVPVS

SNDTPPSALQEAAPLTSSMDPLPVFLYPPVQRSIQKR

AVRKMSVMGRQTCLECSFEIPDFPNHFPTYVHCSLCR

YSTCCSRAYANHMINNHVPRKSPKYLALFKNSVSGIK

LACTSCTFVTSVGDAMAKHLVENPSHRSSSILPRGLT

WIAHSRHGQTRDRVHDRNVKNMYPPPSFPTNKAATVK

SAGATPAEPEELLTPLAPALPSPASTATPPPTPTHPQ

ALALPPLATEGAECLNVDDQDEGSPVTQEPELASGGG

GSGGVGKKEQLSVKKLRVVLFALCCNTEQAAEHERNP

QRRIRRWLRRFQASQGENLEGKYLSFEAEEKLAEWVL

TQREQQLPVNEETLFQKATKIGRSLEGGEKISYEWAV

RFMLRHHLTPHARRAVAHTLPKDVAENAGLFIDEVQR

QIHNQDLPLSMIVAIDEISLELDTEVLSSDDRKENAL

QTVGTGEPWCDVVLAILADGTVLPTLVFYRGQMDQPA

NMPDSILLEAKESGYSDDEIMELWSTRVWQKHTACQR

SKGMLVMDCHRTHLSEEVLAMLSASSTLPAVVPAGCS

SKIQPLDVCIKRTVKNFLHKKWKEQAREMADTACDSD

VLLQLVLVWLGEVLGVIGDCPELVQRSELVASVLPGP

DGNINSPTRNADMQEELIASLEEQLKLSGEHSESSTP

RPRSSPEETIEPESLHQLFEGESETESFYGFEEADLD

LMEI

AT-hook DNA-
Xia-Gibbs
243
MRVKPQGLVVTSSAVCSSPDYLREPKYYPGGPPTPRP

binding motif-
Syndrome

LLPTRPPASPPDKAFSTHAFSENPRPPPRRDPSTRRP

containing

PVLAKGDDPLPPRAARPVSQARCPTPVGDGSSSRRCW

protein 1

DNGRVNLRPVVQLIDIMKDLTRLSQDLQHSGVHLDCG

(AHDC1)

GLRLSRPPAPPPGDLQYSFFSSPSLANSIRSPEERAT

PHAKSERPSHPLYEPEPEPRDSPQPGQGHSPGATAAA

TGLPPEPEPDSTDYSELADADILSELASLTCPEAQLL

EAQALEPPSPEPEPQLLDPQPRELDPQALEPLGEALE

LPPLQPLADPLGLPGLALQALDTLPDSLESQLLDPQA

LDPLPKLLDVPGRRLEPQQPLGHCPLAEPLRLDLCSP

HGPPGPEGHPKYALRRTDRPKILCRRRKAGRGRKADA

GPEGRLLPLPMPTGLVAALAEPPPPPPPPPPALPGPG

PVSVPELKPESSQTPVVSTRKGKCRGVRRMVVKMAKI

PVSLGRRNKTTYKVSSLSSSLSVEGKELGLRVSAEPT

PLLKMKNNGRNVVVVFPPGEMPIILKRKRGRPPKNLL

LGPGKPKEPAVVAAEAATVAAATMAMPEVKKRRRRKQ

KLASPQPSYAADANDSKAEYSDVLAKLAFLNRQSQCA

GRCSPPRCWTPSEPESVHQAPDTQSISHELHRVQGER

RRGGKAGGFGGRGGGHAAKSARCSFSDFFEGIGKKKK

VVAVAAAGVGGPGLTELGHPRKRGRGEVDAVTGKPKR

KRRSRKNGTLFPEQVPSGPGFGEAGAEWAGDKGGGWA

PHHGHPGGQAGRNCGFQGTEARAFASTGLESGASGRG

SYYSTGAPSGQTELSQERQNLFTGYFRSLLDSDDSSD

LLDFALSASRPESRKASGTYAGPPTSALPAQRGLATE

PSRGAKASPVAVGSSGAGADPSFQPVLSARQTFPPGR

AASYGLTPAASDCRAAETFPKLVPPPSAMARSPTTHP

PANTYLPQYGGYGAGQSVFAPTKPFTGQDCANSKDCS

FAYGSGNSLPASPSSAHSAGYAPPPTGGPCLPPSKAS

FFSSSEGAPFSGSAPTPLRCDSRASTVSPGGYMVPKG

TTASATSAASAASSSSSSFQPSPENCRQFAGASQWPF

RQGYGGLDWASEAFSQLYNPSEDCHVSEPNVILDISN

YTPQKVKQQTAVSETFSESSSDSTQFNQPVGGGGERR

ANSEASSSEGQSSLSSLEKLMMDWNEASSAPGYNWNQ

SVLFQSSSKPGRGRRKKVDLFEASHLGFPTSASAAAS

GYPSKRSTGPRQPRGGRGGGACSAKKERGGAAAKAKE

IPKPQPVNPLFQDSPDLGLDYYSGDSSMSPLPSQSRA

FGVGERDPCDFIGPYSMNPSTPSDGTFGQGFHCDSPS

LGAPELDGKHFPPLAHPPTVEDAGLQKAYSPTCSPTL

GFKEELRPPPTKLAACEPLKHGLQGASLGHAAAAQAH

LSCRDLPLGQPHYDSPSCKGTAYWYPPGSAARSPPYE

GKVGTGLLADELGRTEAACLSAPHLASPPATPKADKE

PLEMARPPGPPRGPAAAAAGYGCPLLSDLTLSPVPRD

SLLPLQDTAYRYPGFMPQAHPGLGGGPKSGELGPMAE

PHPEDTFTVTSL

Histone
Menke-
244
MAENVVEPGPPSAKRPKLSSPALSASASDGTDFGSLF

acetyltransferase
Hennekam

DLEHDLPDELINSTELGLINGGDINQLQTSLGMVQDA

p300
Syndrome 2

ASKHKQLSELLRSGSSPNLNMGVGGPGQVMASQAQQS

(EP300)

SPGLGLINSMVKSPMTQAGLTSPNMGMGTSGPNQGPT

QSTGMMNSPVNQPAMGMNTGMNAGMNPGMLAAGNGQG

IMPNQVMNGSIGAGRGRQNMQYPNPGMGSAGNLLTEP

LQQGSPQMGGQTGLRGPQPLKMGMMNNPNPYGSPYTQ

NPGQQIGASGLGLQIQTKTVLSNNLSPFAMDKKAVPG

GGMPNMGQQPAPQVQQPGLVTPVAQGMGSGAHTADPE

KRKLIQQQLVLLLHAHKCQRREQANGEVRQCNLPHCR

TMKNVLNHMTHCQSGKSCQVAHCASSRQIISHWKNCT

RHDCPVCLPLKNAGDKRNQQPILTGAPVGLGNPSSLG

VGQQSAPNLSTVSQIDPSSIERAYAALGLPYQVNQMP

TQPQVQAKNQQNQQPGQSPQGMRPMSNMSASPMGVNG

GVGVQTPSLLSDSMLHSAINSQNPMMSENASVPSLGP

MPTAAQPSTTGIRKQWHEDITQDLRNHLVHKLVQAIF

PTPDPAALKDRRMENLVAYARKVEGDMYESANNRAEY

YHLLAEKIYKIQKELEEKRRTRLQKQNMLPNAAGMVP

VSMNPGPNMGQPQPGMTSNGPLPDPSMIRGSVPNQMM

PRITPQSGLNQFGQMSMAQPPIVPRQTPPLQHHGQLA

QPGALNPPMGYGPRMQQPSNQGQFLPQTQFPSQGMNV

TNIPLAPSSGQAPVSQAQMSSSSCPVNSPIMPPGSQG

SHIHCPQLPQPALHQNSPSPVPSRTPTPHHTPPSIGA

QQPPATTIPAPVPTPPAMPPGPQSQALHPPPRQTPTP

PTTQLPQQVQPSLPAAPSADQPQQQPRSQQSTAASVP

TPTAPLLPPQPATPLSQPAVSIEGQVSNPPSTSSTEV

NSQAIAEKQPSQEVKMEAKMEVDQPEPADTQPEDISE

SKVEDCKMESTETEERSTELKTEIKEEEDQPSTSATQ

SSPAPGQSKKKIFKPEELRQALMPTLEALYRQDPESL

PFRQPVDPQLLGIPDYFDIVKSPMDLSTIKRKLDTGQ

YQEPWQYVDDIWLMENNAWLYNRKTSRVYKYCSKLSE

VFEQEIDPVMQSLGYCCGRKLEFSPQTLCCYGKQLCT

IPRDATYYSYQNRYHFCEKCFNEIQGESVSLGDDPSQ

PQTTINKEQFSKRKNDTLDPELFVECTECGRKMHQIC

VLHHEIIWPAGFVCDGCLKKSARTRKENKFSAKRLPS

TRLGTFLENRVNDELRRQNHPESGEVTVRVVHASDKT

VEVKPGMKARFVDSGEMAESFPYRTKALFAFEEIDGV

DLCFFGMHVQEYGSDCPPPNQRRVYISYLDSVHFFRP

KCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEG

DDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAVSERIV

HDYKDIFKQATEDRLTSAKELPYFEGDEWPNVLEESI

KELEQEEEERKREENTSNESTDVTKGDSKNAKKKNNK

KTSKNKSSLSRGNKKKPGMPNVSNDLSQKLYATMEKH

KEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRD

AFLTLARDKHLEFSSLRRAQWSTMCMLVELHTQSQDR

FVYTCNECKHHVETRWHCTVCEDYDLCITCYNTKNHD

HKMEKLGLGLDDESNNQQAAATQSPGDSRRLSIQRCI

QSLVHACQCRNANCSLPSCQKMKRVVQHTKGCKRKTN

GGCPICKQLIALCCYHAKHCQENKCPVPFCLNIKQKL

RQQQLQHRLQQAQMLRRRMASMQRTGVVGQQQGLPSP

TPATPTTPTGQQPTTPQTPQPTSQPQPTPPNSMPPYL

PRTQAAGPVSQGKAAGQVTPPTPPQTAQPPLPGPPPA

AVEMAMQIQRAAETQRQMAHVQIFQRPIQHQMPPMTP

MAPMGMNPPPMTRGPSGHLEPGMGPTGMQQQPPWSQG

GLPQPQQLQSGMPRPAMMSVAQHGQPLNMAPQPGLGQ

VGISPLKPGTVSQQALQNLLRTLRSPSSPLQQQQVLS

ILHANPQLLAAFIKQRAAKYANSNPQPIPGQPGMPQG

QPGLQPPTMPGQQGVHSNPAMQNMNPMQAGVQRAGLP

QQQPQQQLQPPMGGMSPQAQQMNMNHNTMPSQFRDIL

RRQQMMQQQQQQGAGPGIGPGMANHNQFQQPQGVGYP

PQQQQRMQHHMQQMQQGNMGQIGQLPQALGAEAGASL

QAYQQRLLQQQMGSPVQPNPMSPQQHMLPNQAQSPHL

QGQQIPNSLSNQVRSPQPVPSPRPQSQPPHSSPSPRM

QPQPSPHHVSPQTSSPHPGLVAAQANPMEQGHFASPD

QNSMLSQLASNPGMANLHGASATDLGLSTDNSDLNSN

LSQSTLDIH

IQ motif and
IQSEC2-
245
MEAGSGPPGGPGSESPNRAVEYLLELNNIIESQQQLL

SEC7 domain-
Related

ETQRRRIEELEGQLDQLTQENRDLREESQLHRGELHR

containing
Disorder

DPHGARDSPGRESQYQNLRETQFHHRELRESQFHQAA

protein 2

RDVGYPNREGAYQNREAVYRDKERDASYPLQDTTGYT

(IQSEC2)

ARERDVAQCHLHHENPALGRERGGREAGPAHPGREKE

AGYSAAVGVGPRPPRERGQLSRGASRSSSPGAGGGHS

TSTSTSPATTLQRKSDGENSRTVSVEGDAPGSDLSTA

VDSPGSQPPYRLSQLPPSSSHMGGPPAGVGLPWAQRA

RLQPASVALRKQEEEEIKRSKALSDSYELSTDLQDKK

VEMLERKYGGSELSRRAARTIQTAFRQYRMNKNFERL

RSSASESRMSRRIILSNMRMQFSFEEYEKAQNPAYFE

GKPASLDEGAMAGARSHRLERGLPYGGSCGGGIDGGG

SSVTTSGEFSNDITELEDSFSKQVKSLAESIDEALNC

HPSGPMSEEPGSAQLEKRESKEQQEDSSATSESDLPL

YLDDTVPQQSPERLPSTEPPPQGRPEFWAPAPLPPVP

PPVPSGTREDGSREEGTRRGPGCLECRDERLRAAHLP

LLTIEPPSDSSVDLSDRSDRGSVHRQLVYEADGCSPH

GTLKHKGPPGRAPIPHRHYPAPEGPAPAPPGPLPPAP

NSGTGPSGVAGGRRLGKCEAAGENSDGGDNESLESSS

NSNETINCSSGSSSRDSLREPPATGLCKQTYQRETRH

SWDSPAFNNDVVQRRHYRIGLNLENKKPEKGIQYLIE

RGFLSDTPVGVAHFILERKGLSRQMIGEFLGNRQKQF

NRDVLDCVVDEMDESSMDLDDALRKFQSHIRVQGEAQ

KVERLIEAFSQRYCVCNPALVRQFRNPDTIFILAFAI

ILLNTDMYSPSVKAERKMKLDDFIKNLRGVDNGEDIP

RDLLVGIYQRIQGRELRTNDDHVSQVQAVERMIVGKK

PVLSLPHRRLVCCCQLYEVPDPNRPQRLGLHQREVEL

FNDLLVVTKIFQKKKILVTYSFRQSFPLVEMHMQLFQ

NSYYQFGIKLLSAVPGGERKVLIIFNAPSLQDRLRET

SDLRESIAEVQEMEKYRVESELEKQKGMMRPNASQPG

GAKDSVNGTMARSSLEDTYGAGDGLKRGALSSSLRDL

SDAGKRGRRNSVGSLDSTIEGSVISSPRPHQRMPPPP

PPPPPEEYKSQRPVSNSSSFLGSLFGSKRGKGPFQMP

PPPTGQASASSSSASSTHHHHHHHHHGHSHGGLGVLP

DGQSKLQALHAQYCQGPGPAPPPYLPPQQPSLPPPPQ

QPPPLPQLGSIPPPPASAPPVGPHRHFHAHGPVPGPQ

HYTLGRPGRAPRRGAGGHPQFAPHGRHPLHQPTSPLP

LYSPAPQHPPAHKQGPKHFIFSHHPQMMPAAGAAGGP

GSRPPGGSYSHPHHPQSPLSPHSPIPPHPSYPPLPPP

SPHTPHSPLPPTSPHGPLHASGPPGTANPPSANPKAK

PSRISTVV

Transcription
TCF20-Related
246
MQSFREQSSYHGNQQSYPQEVHGSSRLEEFSPRQAQM

factor 20
Disorder

FQNFGGTGGSSGSSGSGSGGGRRGAAAAAAAMASETS

(TCF20)

GHQGYQGFRKEAGDFYYMAGNKDPVTTGTPQPPQRRP

SGPVQSYGPPQGSSFGNQYGSEGHVGQFQAQHSGLGG

VSHYQQDYTGPFSPGSAQYQQQASSQQQQQQVQQLRQ

QLYQSHQPLPQATGQPASSSSHLQPMQRPSTLPSSAA

GYQLRVGQFGQHYQSSASSSSSSSFPSPQRESQSGQS

YDGSYNVNAGSQYEGHNVGSNAQAYGTQSNYSYQPQS

MKNFEQAKIPQGTQQGQQQQQPQQQQHPSQHVMQYTN

AATKLPLQSQVGQYNQPEVPVRSPMQFHQNFSPISNP

SPAASVVQSPSCSSTPSPLMQTGENLQCGQGSVPMGS

RNRILQLMPQLSPTPSMMPSPNSHAAGFKGFGLEGVP

EKRLTDPGLSSLSALSTQVANLPNTVQHMLLSDALTP

QKKTSKRPSSSKKADSCTNSEGSSQPEEQLKSPMAES

LDGGCSSSSEDQGERVRQLSGQSTSSDTTYKGGASEK

AGSSPAQGAQNEPPRLNASPAAREEATSPGAKDMPLS

SDGNPKVNEKTVGVIVSREAMTGRVEKPGGQDKGSQE

DDPAATQRPPSNGGAKETSHASLPQPEPPGGGGSKGN

KNGDNNSNHNGEGNGQSGHSAAGPGFTSRTEPSKSPG

SLRYSYKDSFGSAVPRNVSGFPQYPTGQEKGDETGHG

ERKGRNEKFPSLLQEVLQGYHHHPDRRYSRSTQEHQG

MAGSLEGTTRPNVLVSQTNELASRGLLNKSIGSLLEN

PHWGPWERKSSSTAPEMKQINLTDYPIPRKFEIEPQS

SAHEPGGSLSERRSVICDISPLRQIVRDPGAHSLGHM

SADTRIGRNDRLNPTLSQSVILPGGLVSMETKLKSQS

GQIKEEDFEQSKSQASENNKKSGDHCHPPSIKHESYR

GNASPGAATHDSLSDYGPQDSRPTPMRRVPGRVGGRE

GMRGRSPSQYHDFAEKLKMSPGRSRGPGGDPHHMNPH

MTFSERANRSSLHTPFSPNSETLASAYHANTRAHAYG

DPNAGLNSQLHYKRQMYQQQPEEYKDWSSGSAQGVIA

AAQHRQEGPRKSPRQQQFLDRVRSPLKNDKDGMMYGP

PVGTYHDPSAQEAGRCLMSSDGLPNKGMELKHGSQKL

QESCWDLSRQTSPAKSSGPPGMSSQKRYGPPHETDGH

GLAEATQSSKPGSVMLRLPGQEDHSSQNPLIMRRRVR

SFISPIPSKRQSQDVKNSSTEDKGRLLHSSKEGADKA

FNSYAHLSHSQDIKSIPKRDSSKDLPSPDSRNCPAVT

LTSPAKTKILPPRKGRGLKLEAIVQKITSPNIRRSAS

SNSAEAGGDTVTLDDILSLKSGPPEGGSVAVQDADIE

KRKGEVASDLVSPANQELHVEKPLPRSSEEWRGSVDD

KVKTETHAETVTAGKEPPGAMTSTTSQKPGSNQGRPD

GSLGGTAPLIFPDSKNVPPVGILAPEANPKAEEKEND

TVTISPKQEGFPPKGYFPSGKKKGRPIGSVNKQKKQQ

QPPPPPPQPPQIPEGSADGEPKPKKQRQRRERRKPGA

QPRKRKTKQAVPIVEPQEPEIKLKYATQPLDKTDAKN

KSFYPYIHVVNKCELGAVCTIINAEEEEQTKLVRGRK

GQRSLTPPPSSTESKALPASSEMLQGPVVTESSVMGH

LVCCLCGKWASYRNMGDLFGPFYPQDYAATLPKNPPP

KRATEMQSKVKVRHKSASNGSKTDTEEEEEQQQQQKE

QRSLAAHPREKRRHRSEDCGGGPRSLSRGLPCKKAAT

EGSSEKTVLDSKPSVPTTSEGGPELELQIPELPLDSN

EFWVHEGCILWANGIYLVCGRLYGLQEALEIAREMKC

SHCQEAGATLGCYNKGCSFRYHYPCAIDADCLLHEEN

FSVRCPKHKPPLPCPLPPLQNKTAKGSLSTEQSERG

Putative
Bainbridge-
247
MKDKRKKKDRTWAEAARLALEKHPNSPMTAKQILEVI

Polycomb group
Ropers

QKEGLKETSGTSPLACLNAMLHTNTRIGDGTFFKIPG

protein ASXL3
Syndrome

KSGLYALKKEESSCPADGTLDLVCESELDGTDMAEAN

(ASXL3)

AHGEENGVCSKQVTDEASSTRDSSLTNTAVQSKLVSS

FQQHTKKALKQALRQQQKRRNGVSMMVNKTVPRVVLT

PLKVSDEQSDSPSGSESKNGEADSSDKEMKHGQKSPT

GKQTSQHLKRLKKSGLGHLKWTKAEDIDIETPGSILV

NTNLRALINKHTFASLPQHFQQYLLLLLPEVDRQMGS

DGILRLSTSALNNEFFAYAAQGWKQRLAEGEFTPEMQ

LRIRQEIEKEKKTEPWKEKFFERFYGEKLGMSREESV

KLTTGPNNAGAQSSSSCGTSGLPVSAQTALAEQQPKS

MKSPASPEPGFCATLCPMVEIPPKDIMAELESEDILI

PEESVIQEEIAEEVETSICECQDENHKTIPEFSEEAE

SLTNSHEEPQIAPPEDNLESCVMMNDVLETLPHIEVK

IEGKSESPQEEMTVVIDQLEVCDSLIPSTSSMTHVSD

TEHKESETAVETSTPKIKTGSSSLEGQFPNEGIAIDM

ELQSDPEEQLSENACISETSESSESPEGACTSLPSPG

GETQSTSEESCTPASLETTFCSEVSSTENTDKYNQRN

STDENFHASLMSEISPISTSPEISEASLMSNLPLTSE

ASPVSNLPLTSETSPMSDLPLTSETSSVSSMLLTSET

TFVSSLPLPSETSPISNSSINERMAHQQRKSPSVSEE

PLSPQKDESSATAKPLGENLTSQQKNLSNTPEPIIMS

SSSIAPEAFPSEDLHNKTLSQQTCKSHVDTEKPYPAS

IPELASTEMIKVKNHSVLQRTEKKVLPSPLELSVESE

GTDNKGNELPSAKLQDKQYISSVDKAPFSEGSRNKTH

KQGSTQSRLETSHTSKSSEPSKSPDGIRNESRDSEIS

KRKTAEQHSFGICKEKRARIEDDQSTRNISSSSPPEK

EQPPREEPRVPPLKIQLSKIGPPFIIKSQPVSKPESR

ASTSTSVSGGRNTGARTLADIKARAQQARAQREAAAA

AAVAAAASIVSGAMGSPGEGGKTRTLAHIKEQTKAKL

FAKHQARAHLFQTSKETRLPPPLSSKEGPPNLEVSST

PETKMEGSTGVIIVNPNCRSPSNKSAHLRETTTVLQQ

SLNPSKLPETATDLSVHSSDENIPVSHLSEKIVSSTS

SENSSVPMLFNKNSVPVSVCSTAISGAIKEHPFVSSV

DKSSVLMSVDSANTTISACNISMLKTIQGTDTPCIAI

IPKCIESTPISATTEGSSISSSMDDKQLLISSSSASN

LVSTQYTSVPTPSIGNNLPNLSTSSVLIPPMGINNRE

PSEKIAIPGSEEQATVSMGTTVRAALSCSDSVAVTDS

LVAHPTVAMFTGNMLTINSYDSPPKLSAESLDKNSGP

RNRADNSGKPQQPPGGFAPAAINRSIPCKVIVDHSTT

LTSSLSLTVSVESSEASLDLQGRPVRTEASVQPVACP

QVSVISRPEPVANEGIDHSSTFIAASAAKQDSKTLPA

TCTSLRELPLVPDKLNEPTAPSHNFAEQARGPAPEKS

EADTTCSNQYNPSNRICWNDDGMRSTGQPLVTHSGSS

KQKEYLEQSCPKAIKTEHANYLNVSELHPRNLVINVA

LPVKSELHEADKGFRMDTEDFPGPELPPPAAEGASSV

QQTQNMKASTSSPMEEAISLATDALKRVPGAGSSGCR

LSSVEANNPLVTQLLQGNLPLEKVLPQPRLGAKLEIN

RLPLPLQTTSVGKTAPERNVEIPPSSPNPDGKGYLAG

TLAPLQMRKRENHPKKRVARTVGEHTQVKCEPGKLLV

EPDVKGVPCVISSGISQLGHSQPFKQEWLNKHSMQNR

IVHSPEVKQQKRLLPSCSFQQNLFHVDKNGGFHTDAG

TSHRQQFYQMPVAARGPIPTAALLQASSKTPVGCNAF

AFNRHLEQKGLGEVSLSSAPHQLRLANMLSPNMPMKE

GDEVGGTAHTMPNKALVHPPPPPPPPPPPPLALPPPP

PPPPPLPPPLPNAEVPSDQKQPPVTMETTKRLSWPQS

TGICSNIKSEPLSFEEGLSSSCELGMKQVSYDQNEMK

EQLKAFALKSADESSYLLSEPQKPFTQLAAQKMQVQQ

QQQLCGNYPTIHFGSTSFKRAASAIEKSIGILGSGSN

PATGLSGQNAQMPVQNFADSSNADELELKCSCRLKAM

IVCKGCGAFCHDDCIGPSKLCVACLVVR

Histone
KATA6
248
MVKLANPLYTEWILEAIKKVKKQKQRPSEERICNAVS

acetyltransferase
Syndrome

SSHGLDRKTVLEQLELSVKDGTILKVSNKGLNSYKDP

KAT6A

DNPGRIALPKPRNHGKLDNKQNVDWNKLIKRAVEGLA

(KAT6A)

ESGGSTLKSIERFLKGQKDVSALFGGSAASGFHQQLR

LAIKRAIGHGRLLKDGPLYRLNTKATNVDGKESCESL

SCLPPVSLLPHEKDKPVAEPIPICSFCLGTKEQNREK

KPEELISCADCGNSGHPSCLKFSPELTVRVKALRWQC

IECKTCSSCRDQGKNADNMLFCDSCDRGFHMECCDPP

LTRMPKGMWICQICRPRKKGRKLLQKKAAQIKRRYTN

PIGRPKNRLKKQNTVSKGPFSKVRTGPGRGRKRKITL

SSQSASSSSEEGYLERIDGLDFCRDSNVSLKENKKTK

GLIDGLTKFFTPSPDGRKARGEVVDYSEQYRIRKRGN

RKSSTSDWPTDNQDGWDGKQENEERLEGSQEIMTEKD

MELFRDIQEQALQKVGVTGPPDPQVRCPSVIEFGKYE

IHTWYSSPYPQEYSRLPKLYLCEFCLKYMKSRTILQQ

HMKKCGWFHPPANEIYRKNNISVFEVDGNVSTIYCQN

LCLLAKLFLDHKTLYYDVEPFLFYVLTQNDVKGCHLV

GYFSKEKHCQQKYNVSCIMILPQYQRKGYGRFLIDES

YLLSKREGQAGSPEKPLSDLGRLSYMAYWKSVILECL

YHQNDKQISIKKLSKLTGICPQDITSTLHHLRMLDER

SDQFVIIRREKLIQDHMAKLQLNLRPVDVDPECLRWT

PVIVSNSVVSEEEEEEAEEGENEEPQCQERELEISVG

KSVSHENKEQDSYSVESEKKPEVMAPVSSTRLSKQVL

PHDSLPANSQPSRRGRWGRKNRKTQERFGDKDSKLLL

EETSSAPQEQYGECGEKSEATQEQYTESEEQLVASEE

QPSQDGKPDLPKRRLSEGVEPWRGQLKKSPEALKCRL

TEGSERLPRRYSEGDRAVLRGFSESSEEEEEPESPRS

SSPPILTKPTLKRKKPFLHRRRRVRKRKHHNSSVVTE

TISETTEVLDEPFEDSDSERPMPRLEPTFEIDEEEEE

EDENELFPREYFRRLSSQDVLRCQSSSKRKSKDEEED

EESDDADDTPILKPVSLLRKRDVKNSPLEPDTSTPLK

KKKGWPKGKSRKPIHWKKRPGRKPGFKLSREIMPVST

QACVIEPIVSIPKAGRKPKIQESEETVEPKEDMPLPE

ERKEEEEMQAEAEEAEEGEEEDAASSEVPAASPADSS

NSPETETKEPEVEEEEEKPRVSEEQRQSEEEQQELEE

PEPEEEEDAAAETAQNDDHDADDEDDGHLESTKKKEL

EEQPTREDVKEEPGVQESELDANMQKSREKIKDKEET

ELDSEEEQPSHDTSVVSEQMAGSEDDHEEDSHTKEEL

IELKEEEEIPHSELDLETVQAVQSLTQEESSEHEGAY

QDCEETLAACQTLQSYTQADEDPQMSMVEDCHASEHN

SPISSVQSHPSQSVRSVSSPNVPALESGYTQISPEQG

SLSAPSMQNMETSPMMDVPSVSDHSQQVVDSGESDLG

SIESTTENYENPSSYDSTMGGSICGNSSSQSSCSYGG

LSSSSSLTQSSCVVTQQMASMGSSCSMMQQSSVQPAA

NCSIKSPQSCVVERPPSNQQQQPPPPPPQQPQPPPPQ

PQPAPQPPPPQQQPQQQPQPQPQQPPPPPPPQQQPPL

SQCSMNNSFTPAPMIMEIPESGSTGNISIYERIPGDE

GAGSYSQPSATFSLAKLQQLTNTIMDPHAMPYSHSPA

VTSYATSVSLSNTGLAQLAPSHPLAGTPQAQATMTPP

PNLASTTMNLTSPLLQCNMSATNIGIPHTQRLQGQMP

VKGHISIRSKSAPLPSAAAHQQQLYGRSPSAVAMQAG

PRALAVQRGMNMGVNLMPTPAYNVNSMNMNTLNAMNS

YRMTQPMMNSSYHSNPAYMNQTAQYPMQMQMGMMGSQ

AYTQQPMQPNPHGNMMYTGPSHHSYMNAAGVPKQSLN

GPYMRR

Small nuclear
—
424
MSKAHPPELKKFMDKKLSLKLNGGRHVQGILRGEDPF

ribonucleoprotein

MNLVIDECVEMATSGQQNNIGMVVIRGNSIIMLEALE

G

RV

(SNRPG)

U6 snRNA-
—
425
MLFYSFFKSLVGKDVVVELKNDLSICGTLHSVDQYLN

associated Sm-

IKLTDISVTDPEKYPHMLSVKNCFIRGSVVRYVQLPA

like protein

DEVDTQLLQDAARKEALQQKQ

LSm2

(LSM2)

Nuclear protein
—
426
MEAPAERALPRLQALARPPPPISYEEELYDCLDYYYL

2

RDFPACGAGRSKGRTRREQALRTNWPAPGGHERKVAQ

(NUPR2)

KLLNGQRKRRQRQLHPKMRTRLT

5.3.3 Nuclear Localization Signals

In some embodiments, the fusion protein comprises a nuclear localization signal (NLS) at the N terminus of the fusion protein. Exemplary NLSs are provided in Table 3. In some embodiments, the NLS comprises an amino acid sequence at least 95%, 96%, 97%, 98%, 99%, or 100% identical to one of SEQ ID NO: 249-367.

TABLE 3

The amino acid sequence of exemplary NLSs

SEQ

Amino Acid Sequence
ID NO

AHFKISGEKRPSTDPGKKAKNPKKKKKKDP
249

AHRAKKMSKTHA
250

ASPEYVNLPINGNG
251

CTKRPRW
252

DKAKRVSRNKSEKKRR
253

EELRLKEELLKGIYA
254

EEQLRRRKNSRLNNTG
255

EVLKVIRTGKRKKKAWKRMVTKVC
256

HHHHHHHHHHHHQPH
257

HKKKHPDASVNFSEFSK
258

HKRTKKNLS
259

IINGRKLKLKKSRRRSSQTSNNSFTSRRS
260

KAEQERRK
261

KEKRKRREELFIEQKKRK
262

KKGKDEWFSRGKKP
263

KKGPSVQKRKKTNLS
264

KKKTVINDLLHYKKEK
265

KKNGGKGKNKPSAKIKK
266

KKPKWDDFKKKKK
267

KKRKKDNLS
268

KKRRKRRRK
269

KKRRRRARK
270

KKSKRGR
272

KKSRKRGS
272

KKSTALSRELGKIMRRR
273

KKSYQDPEIIAHSRPRK
274

KKTGKNRKLKSKRVKTR
275

KKVSIAGQSGKLWRWKR
276

KKYENVVIKRSPRKRGRPRK
278

KNKKRK
279

KPKKKR
280

KRAMKDDSHGNSTSPKRRK
281

KRANSNLVAAYEKAKKK
282

KRASEDTTSGSPPKKSSAGPKR
283

KRFKRRWMVRKMKTKK
284

KRGLNSSFETSPKKVK
285

KRGNSSIGPNDLSKRKQRKK
286

KRIHSVSLSQSQIDPSKKVKRAK
287

KRKGKLKNKGSKRKK
288

KRRRRRRREKRKR
289

KRSNDRTYSPEEEKQRRA
290

KRTVATNGDASGAHRAKKMSK
291

KRVYNKGEDEQEHLPKGKKR
292

KSGKAPRRRAVSMDNSNK
293

KVNFLDMSLDDIIIYKELE
294

KVQHRIAKKTTRRRR
295

LSPSLSPL
296

MDSLLMNRRKFLYQFKNVRWAKGRRETYLC
297

MPQNEYIELHRKRYGYRLDYHEKKRKKESREAHERSKKAK
298

KMIGLKAKLYHK

MVQLRPRASR
299

NNKLLAKRRKGGASPKDDPMDDIK
300

NYKRPMDGTYGPPAKRHEGE
301

PDTKRAKLDSSETTMVKKK
302

PEKRTKI
303

PGGRGKKK
304

PGKMDKGEHRQERRDRPY
305

PKKGDKYDKTD
306

PKKKSRK
307

PKKNKPE
308

PKKRAKV
309

PKPKKLKVE
310

PKRGRGR
311

PKRRLVDDA
312

PKRRRTY
313

PLFKRR
314

PLRKAKR
315

PPAKRKCIF
316

PPARRRRL
317

PPKKKRKV
318

PPNKRMKVKH
319

PPRIYPQLPSAPT
320

PQRSPFPKSSVKR
321

PRPRKVPR
322

PRRRVQRKR
323

PRRVRLK
324

PSRKRPR
325

PSSKKRKV
326

PTKKRVK
327

QRPGPYDRP
328

RGKGGKGLGKGGAKRHRK
329

RKAGKGGGGHKTTKKRSAKDEKVP
330

RKIKLKRAK
331

RKIKRKRAK
332

RKKEAPGPREELRSRGR
333

RKKRKGK
334

RKKRRQRRR
335

RKKSIPLSIKNLKRKHKRKKNKITR
336

RKLVKPKNTKMKTKLRTNPY
337

RKRLILSDKGQLDWKK
338

RKRLKSK
339

RKRRVRDNM
340

RKRSPKDKKEKDLDGAGKRRKT
341

RKRTPRVDGQTGENDMNKRRRK
342

RLPVRRRRRR
343

RLRFRKPKSK
344

RQQRKR
345

RRDLNSSFETSPKKVK
346

RRDRAKLR
347

RRGDGRRR
348

RRGRKRKAEKQ
349

RRKKRR
350

RRKRSKSEDMDSVESKRRR
351

RRKRSR
352

RRPKGKTLQKRKPK
353

RRRGFERFGPDNMGRKRK
354

RRRGKNKVAAQNCRK
355

RRRKRRNLS
356

RRRQKQKGGASRRR
357

RRRREGPRARRRR
358

RRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSVGM
359

SHNAIRFGRMPRSEKAKLKAE

RRVPQRKEVSRCRKCRK
360

RVGGRRQAVECIEDLLNEPGQPLDLSCKRPRP
361

RVVKLRIAP
362

RVVRRR
363

SKRKTKISRKTR
364

SYVKTVPNRTRTYIKL
365

TGKNEAKKRKIA
366

TLSPASSPSSVSCPVIPASTDESPGSALNI
367

5.3.4 Orientation and Linkers

In some embodiments, the effector domain is N-terminal of the targeting domain in the fusion protein. In some embodiments, the targeting domain is N-terminal of the effector domain in the fusion protein. In some embodiments, the effector domain is operably connected (directly or indirectly) to the C terminus of the targeting domain. In some embodiments, the effector domain is operably connected (directly or indirectly) to the N terminus of the targeting domain. In some embodiments, the effector domain is directly operably connected to the C terminus of the targeting domain. In some embodiments, the effector domain is directly operably connected to the N terminus of the targeting domain.

In some embodiments, the effector domain is indirectly operably connected to the C terminus of the targeting domain. In some embodiments, the effector domain is indirectly operably connected to the N terminus of the targeting domain. One or more amino acid sequences comprising e.g., a linker, or encoding one or more polypeptides may be positioned between the effector moiety and the targeting moiety. In some embodiments, the effector domain is indirectly operably connected to the C terminus of the targeting domain through a peptide linker. In some embodiments, the effector domain is indirectly operably connected to the N terminus of the targeting domain through a peptide linker.

Each component of the fusion protein described herein can be directly linked to the other to indirectly linked to the other via a peptide linker. [0080] Any suitable peptide linker known in the art can be used that enables the effector domain and the targeting domain to bind their respective antigens. In some embodiments, the linker is one or any combination of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a peptide linker that comprises glycine or serine, or both glycine and serine amino acid residues. In some embodiments, the peptide linker comprises from about 1-20, 1-15, 1-10, 1-5, 5-20, 5-15, 5-10, or 15-20 amino acids. In some embodiments, the peptide linker comprises from or from about 2-25, 5-25, 10-25, 15-25, 20-25, 2-20, 5-20, 10-20, 15-20, 2-15, 5-15, 10-15, 2-10, or 5-10 amino acids. In some embodiments, the linker is a peptide linker that consists of glycine or serine, or both glycine and serine amino acid residues. In some embodiments, the peptide linker consists of from or from about 2-25, 5-25, 10-25, 15-25, 20-25, 2-20, 5-20, 10-20, 15-20, 2-15, 5-15, 10-15, 2-10, or 5-10 amino acids. In some embodiments, the peptide linker comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acid residues. In some embodiments, the linker is at least 11 amino acids in length. In some embodiments, the linker is at least 15 amino acids in length. In some embodiments, the linker is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acid residues in length.

In some embodiments, the linker is a glycine/serine linker, e.g., a peptide linker substantially consisting of the amino acids glycine and serine. In some embodiments, the linker is a glycine/serine/proline linker, e.g., a peptide linker substantially consisting of the amino acids glycine, serine, and proline.

In some embodiments, the amino acid sequence of the linker comprises the amino acid sequence of any one of SEQ ID NOS: 249-367 or 427-436, or the amino acid sequence of any one of SEQ ID NOS: 249-367 or 427-436 comprising 1, 2, or 3 amino acid modifications (e.g., a substitution, deletion, or addition). In some embodiments, the amino acid sequence of the linker consists of the amino acid sequence of any one of SEQ ID NOS: 249-367 or 427-436, or the amino acid sequence of any one of SEQ ID NOS: 249-367 or 427-436 comprising 1, 2, or 3 amino acid modifications (e.g., a substitution, deletion, or addition).

In some embodiments, the amino acid sequence of the linker comprises the amino acid sequence of any one of SEQ ID NOS: 427-436, or the amino acid sequence of any one of SEQ ID NOS: 427-436 comprising 1, 2, or 3 amino acid modifications (e.g., a substitution, deletion, or addition). In some embodiments, the amino acid sequence of the linker consists of the amino acid sequence of any one of SEQ ID NOS: 427-436, or the amino acid sequence of any one of SEQ ID NOS: 427-436 comprising 1, 2, or 3 amino acid modifications (e.g., a substitution, deletion, or addition).

The amino acid sequence of exemplary linkers for use in any one or more of the fusion proteins described herein is provided in Table 4 below.

TABLE 4

Amino Acid Sequence of Exemplary Linkers

SEQ

Amino Acid Sequence
ID NO

GGGGSGGGGSGGGGSGGGGSGGGGS
427

GGGGSGGGGSGGGGSGGGGS
428

GGGGSGGGGSGGGGS
429

GGGGSGGGGS
430

GGGGS
431

SGGGGSGGGGSGGGGS
432

SGGGGSGGGGSGGGG
433

SGGGGSGGGG
434

SGGGG
435

GGSGG
436

AHFKISGEKRPSTDPGKKAKNPKKKKKKDP
249

AHRAKKMSKTHA
250

ASPEYVNLPINGNG
251

CTKRPRW
252

DKAKRVSRNKSEKKRR
253

EELRLKEELLKGIYA
254

EEQLRRRKNSRLNNTG
255

EVLKVIRTGKRKKKAWKRMVTKVC
256

HHHHHHHHHHHHQPH
257

HKKKHPDASVNFSEFSK
258

HKRTKKNLS
259

IINGRKLKLKKSRRRSSQTSNNSFTSRRS
260

KAEQERRK
261

KEKRKRREELFIEQKKRK
262

KKGKDEWFSRGKKP
263

KKGPSVQKRKKTNLS
264

KKKTVINDLLHYKKEK
265

KKNGGKGKNKPSAKIKK
266

KKPKWDDFKKKKK
267

KKRKKDNLS
268

KKRRKRRRK
269

KKRRRRARK
270

KKSKRGR
272

KKSRKRGS
272

KKSTALSRELGKIMRRR
273

KKSYQDPEIIAHSRPRK
274

KKTGKNRKLKSKRVKTR
275

KKVSIAGQSGKLWRWKR
276

KKYENVVIKRSPRKRGRPRK
278

KNKKRK
279

KPKKKR
280

KRAMKDDSHGNSTSPKRRK
281

KRANSNLVAAYEKAKKK
282

KRASEDTTSGSPPKKSSAGPKR
283

KRFKRRWMVRKMKTKK
284

KRGLNSSFETSPKKVK
285

KRGNSSIGPNDLSKRKQRKK
286

KRIHSVSLSQSQIDPSKKVKRAK
287

KRKGKLKNKGSKRKK
288

KRRRRRRREKRKR
289

KRSNDRTYSPEEEKQRRA
290

KRTVATNGDASGAHRAKKMSK
291

KRVYNKGEDEQEHLPKGKKR
292

KSGKAPRRRAVSMDNSNK
293

KVNFLDMSLDDIIIYKELE
294

KVQHRIAKKTTRRRR
295

LSPSLSPL
296

MDSLLMNRRKFLYQFKNVRWAKGRRETYLC
297

MPQNEYIELHRKRYGYRLDYHEKKRKKESREAHERSKKAK
298

KMIGLKAKLYHK

MVQLRPRASR
299

NNKLLAKRRKGGASPKDDPMDDIK
300

NYKRPMDGTYGPPAKRHEGE
301

PDTKRAKLDSSETTMVKKK
302

PEKRTKI
303

PGGRGKKK
304

PGKMDKGEHRQERRDRPY
305

PKKGDKYDKTD
306

PKKKSRK
307

PKKNKPE
308

PKKRAKV
309

PKPKKLKVE
310

PKRGRGR
311

PKRRLVDDA
312

PKRRRTY
313

PLFKRR
314

PLRKAKR
315

PPAKRKCIF
316

PPARRRRL
317

PPKKKRKV
318

PPNKRMKVKH
319

PPRIYPQLPSAPT
320

PQRSPFPKSSVKR
321

PRPRKVPR
322

PRRRVQRKR
323

PRRVRLK
324

PSRKRPR
325

PSSKKRKV
326

PTKKRVK
327

QRPGPYDRP
328

RGKGGKGLGKGGAKRHRK
329

RKAGKGGGGHKTTKKRSAKDEKVP
330

RKIKLKRAK
331

RKIKRKRAK
332

RKKEAPGPREELRSRGR
333

RKKRKGK
334

RKKRRQRRR
335

RKKSIPLSIKNLKRKHKRKKNKITR
336

RKLVKPKNTKMKTKLRTNPY
337

RKRLILSDKGQLDWKK
338

RKRLKSK
339

RKRRVRDNM
340

RKRSPKDKKEKDLDGAGKRRKT
341

RKRTPRVDGQTGENDMNKRRRK
342

RLPVRRRRRR
343

RLRFRKPKSK
344

RQQRKR
345

RRDLNSSFETSPKKVK
346

RRDRAKLR
347

RRGDGRRR
348

RRGRKRKAEKQ
349

RRKKRR
350

RRKRSKSEDMDSVESKRRR
351

RRKRSR
352

RRPKGKTLQKRKPK
353

RRRGFERFGPDNMGRKRK
354

RRRGKNKVAAQNCRK
355

RRRKRRNLS
356

RRRQKQKGGASRRR
357

RRRREGPRARRRR
358

RRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSVGM
359

SHNAIREGRMPRSEKAKLKAE

RRVPQRKEVSRCRKCRK
360

RVGGRRQAVECIEDLLNEPGQPLDLSCKRPRP
361

RVVKLRIAP
362

RVVRRR
363

SKRKTKISRKTR
364

SYVKTVPNRTRTYIKL
365

TGKNEAKKRKIA
366

TLSPASSPSSVSCPVIPASTDESPGSALNI
367

5.3.4.1 Conditional Constructs

Also described herein are constructs that comprise a targeting domain (e.g., a VHH, (VHH)₂) bound to an effector domain (e.g., an effector domain that comprises a catalytic domain of an deubiquitinase, or an effector domain that comprises a deubiquitinase). In some embodiments, the association of the targeting domain and the effector domain is mediated by binding of a first agent (e.g., a small molecule, protein, or peptide) attached to the targeting domain and a second agent (e.g., a small, molecule, protein, or peptide) attached to the effector domain. For example, in one embodiment, the targeting domain may be attached to a first agent that specifically binds to a second agent that is attached to the effector domain. In some embodiments, specific binding of the first agent to the second agent is mediated by addition of a third agent (e.g., a small molecule).

For example, a conditional construct includes an KBP/FRB-based dimerization switch, e.g., as described in US20170081411 (the entire contents of which are incorporated by reference herein), can be utilized herein. FKBP12 (FKBP or FK506 binding protein) is an abundant cytoplasmic protein that serves as the initial intracellular target for the natural product immunosuppressive drug, rapamycin. Rapamycin binds to FKBP and to the large PI3K homolog FRAP (RAFT, mTOR), thereby acting to dimerize these molecules. In some embodiments, an FKBP/FRAP based switch, also referred to herein as an FKBP/FRB based switch, can utilize a heterodimerization molecule, e.g., rapamycin or a rapamycin analog. FRB is a 93 amino acid portion of FRAP, that is sufficient for binding the FKBP-rapamycin complex (Chen, J., Zheng, X. F., Brown, E. J. & Schreiber, S. L. (1995) Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA 92: 4947-51), the entire contents of which is incorporated by reference herein. For example, the targeting domain can be attached to FKBP and the effector domain attached to FRB. Thereby, the association of the targeting domain and the effector domain is mediated by rapamycin and only takes place in the presence of rapamycin.

Exemplary conditional activation systems that can be used here include, but are not limited to those described in US20170081411; Lajoie M J, et al. Designed protein logic to target cells with precise combinations of surface antigens. Science. 2020 Sep. 25; 369(6511):1637-1643. doi: 10.1126/science.aba6527. Epub 2020 Aug. 20. PMID: 32820060; Farrants H, et al. Chemogenetic Control of Nanobodies. Nat Methods. 2020 March; 17(3):279-282. doi: 10.1038/s41592-020-0746-7. Epub 2020 Feb. 17. PMID: 32066961; and US20170081411, the entire contents of each of which is incorporated by reference herein for all purposes.

5.3.5 Exemplary Fusion Proteins

Exemplary fusion proteins of the present disclosure include, but are not limited to, those described below. In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a cysteine protease deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a metalloprotease deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the deubiquitinase is a ubiquitin-specific protease (USP), a ubiquitin C-terminal hydrolase (UCH), a Machado-Josephin domain protease (MJD), an ovarian tumour protease (OTU), a MINDY protease, or a ZUFSP protease; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the deubiquitinase is selected from the group consisting of USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, USP46, BAP1, UCHL1, UCHL3, UCHL5, ATXN3 ATXN3L, OTUB1, OTUB2 MINDY1, MINDY2, MINDY3, MINDY4, or ZUP1; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the deubiquitinase is described in Table 1; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein selected is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the catalytic domain is described in Table 1; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 1-112; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 113-220 or 423; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 1-112; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 221-248.

In one embodiment, the fusion protein comprises an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof, wherein the catalytic domain comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 113-220 or 423; and a targeting domain comprising a targeting moiety that specifically binds a nuclear protein, wherein the nuclear protein comprises an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 221-248.

5.3.5.1 Additional Exemplary Embodiments

Additional exemplary embodiments of fusion proteins described herein are provided below, which should not be construed as limiting.

Embodiment 1. A fusion protein comprising: (a) an effector moiety comprising a functional fragment of a human deubiquitinase that is capable of mediating deubiquitination, wherein the human deubiquitinase comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 1-112, and a targeting moiety comprising a VHH, (VHH)₂. or scFv that specifically binds to a nuclear protein.

Embodiment 2. A fusion protein comprising an effector moiety comprising a functional fragment of a human deubiquitinase that is capable of mediating deubiquitination that comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOS: 113-220 or 423, and a targeting moiety comprising a VHH, (VHH)₂, or scFv that specifically binds to a nuclear protein.

Embodiment 3. A fusion protein comprising an effector moiety comprising a functional fragment of a human deubiquitinase that is capable of mediating deubiquitination that comprises an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 423, and a targeting moiety comprising a VHH, (VHH)₂, or scFv that specifically binds to a nuclear protein.

Embodiment 4. The fusion protein of any one of Embodiments 1-3, wherein said targeting moiety is a VHH or (VHH)₂.

Embodiment 5. The fusion protein of any one of Embodiments 1-4, wherein the nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, KAT6A, SNRPG, LSM2, or NUPR2.

Embodiment 6. The fusion protein of any one of Embodiments 1-5, wherein said nuclear protein is CHD2, RERE, CDKL5, MECP2, KMT2D, SETD5, ZEB2, CAMTA1, FMR1, PRPF8, RAI1, CREBBP, NF1, KMT2A, CHD4, NSD1, MED13L, SMC1A, SMARCA2, ARID1B, POGZ, KAT6B, AHDC1, EP300, IQSEC2, TCF20, ASXL3, or KAT6A.

Embodiment 7. The fusion protein of any one of Embodiments 1-6, wherein said nuclear protein is SNRPG, LSM2, or NUPR2.

5.3.6 Methods of Making Fusion Proteins

Fusion proteins described herein can be made by any conventional technique known in the art, for example, recombinant techniques or chemical synthesis (e.g., solid phase peptide synthesis). In some embodiments, the fusion protein is made through recombinant expression in a cell (e.g., a eukaryotic cell, e.g., a mammalian cell). Briefly, the fusion protein can be made by synthesizing the DNA encoding the fusion protein and cloning the DNA into any suitable expression vector. Numerous cloning vectors are known to those of skill in the art, and the selection of an appropriate cloning vector is a matter of choice. The gene can be placed under the control of a promoter, ribosome binding site (for bacterial expression) and, optionally, an operator and/or one or more enhancer elements, so that the DNA sequence encoding the fusion protein is transcribed into RNA in the host cell transformed by a vector containing this expression construction. The coding sequence may or may not contain a signal peptide or leader sequence. Heterologous leader sequences can be added to the coding sequence that causes the secretion of the expressed polypeptide from the host organism. Other regulatory sequences may also be desirable which allow for regulation of expression of the protein sequences relative to the growth of the host cell. Such regulatory sequences are known to those of skill in the art, and examples include those which cause the expression of a gene to be turned on or off in response to a chemical or physical stimulus, including the presence of a regulatory compound. Other types of regulatory elements may also be present in the vector, for example, enhancer sequences. The control sequences and other regulatory sequences may be ligated to the coding sequence prior to insertion into a vector, such as the cloning vectors described above. Alternatively, the coding sequence can be cloned directly into an expression vector which already contains the control sequences and an appropriate restriction site.

The expression vector may then be used to transform an appropriate host cell. A number of mammalian cell lines are known in the art and include immortalized cell lines available from the American Type Culture Collection (ATCC), such as, but not limited to, Chinese hamster ovary (CHO) cells, CHO-suspension cells (CHO-S), HeLa cells, HEK293, baby hamster kidney (BHK) cells, monkey kidney cells (COS), VERO, HepG2, MadinDarby bovine kidney (MDBK) cells, NOS, U2OS, A549, HT1080, CAD, P19, NIH3T3, L929, N2a, MCF-7, Y79, SO-Rb50, DUKX-X11, and J558L.

Depending on the expression system and host selected, the fusion protein is produced by growing host cells transformed by an expression vector described above under conditions whereby the fusion protein is expressed. The fusion protein is then isolated from the host cells and purified. If the expression system secretes the fusion protein into growth media, the fusion protein can be purified directly from the media. If the fusion protein is not secreted, it is isolated from cell lysates. The selection of the appropriate growth conditions and recovery methods are within the skill of the art. Once purified, the amino acid sequences of the fusion proteins can be determined, i.e., by repetitive cycles of Edman degradation, followed by amino acid analysis by HPLC. Other methods of amino acid sequencing are also known in the art. Once purified, the functionality of the fusion protein can be assessed, e.g., as described herein, e.g., utilizing a bifunctional ELISA.

As described above, functionality of the fusion protein can be tested by any method known in the art. Each functionality can be measured in a separate assay. For example, binding of the targeting domain to the target protein can be measure using an enzyme linked immunosorbent assay (ELISA). Catalytic activity of the effector domain can be measured using any standard deubiquitinase activity assay known in the art. For example, BioVision Deubiquitinase Activity Assay Kit (Fluorometric) Catalog #K485-100 according to the manufacturer's instructions. The deubiquitinase activity of a fusion protein described herein can be measured for example by using a fluorescent deubiquitinase substrate to detect deubiquitinase activity upon cleavage of the fluorescent substrate. The deubiquitinase activity can also be measured according to the materials and methods set forth in the Examples provided herein.

5.4 Nucleic Acids, Host Cells, Vectors, and Viral Particles

In one aspect, provided herein are nucleic acid molecules encoding a fusion protein described herein. In some embodiments, the nucleic acid molecule is a DNA molecule. In some embodiments, the nucleic acid molecule is an RNA molecule. In some embodiments, the nucleic acid molecule contains at least one modified nucleic acid (e.g., that increases stability of the nucleic acid molecule), e.g., phosphorothioate, N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), 8-oxo-7,8-dihydroguanosine (8-oxoG), pseudouridine (Ψ), 5-methylcytidine (m5C), and N4-acetylcytidine (ac4C).

In one aspect, provided herein is a host cell (or population of host cells) comprising a nucleic acid encoding a fusion protein described herein. In some embodiments, the nucleic acid is incorporated into the genome of the host cell. In some embodiments, the nucleic acid is not incorporated into the genome of the host cell. In some embodiments, the nucleic acid is present in the cell episomally. In some embodiments, the host cell is a human cell. In some embodiments, the host cell is a mammalian cell. In some embodiments, the host cell is a mouse, rat, hamster, guinea pig, cat, dog, or human cell. In some embodiments, the host cell is modified in vitro, ex vivo, or in vivo.

The nucleic acid can be introduced into the host cell by any suitable method known in the art (e.g., as described herein). For example, a viral delivery system (e.g., a retrovirus, an adenovirus, an adeno associated virus, a herpes virus, a lentivirus, a pox virus, a vaccinia virus, a vesicular stomatitis virus, a polio virus, a Newcastle's Disease virus, an Epstein-Barr virus, an influenza virus, a reoviruses, a myxoma virus, a maraba virus, a rhabdovirus, or a coxsackie virus delivery system) can be utilized to deliver a nucleic acid (e.g., DNA or RNA molecule) encoding the fusion protein for expression with the host cell. In some embodiments, the nucleic acid encoding the fusion protein is present episomally within the host cell. In some embodiments, the nucleic acid encoding the fusion protein is incorporated into the genome of the host cell. In some embodiments, the virus replication competent. In some embodiments, the virus is replication deficient.

In some embodiments, a nucleic acid (DNA or RNA) is delivered to the host cell using a non-viral vector (e.g., a plasmid) encoding the fusion protein. In some embodiments, the nucleic acid encoding the fusion protein is present episomally within the host cell. In some embodiments, the nucleic acid encoding the fusion protein is incorporated into the genome of the host cell. Exemplary non-viral transfection methods known in the art include, but are not limited to, direct delivery of DNA such as by ex vivo transfection, by injection (e.g., microinjection), electroporation, liposome mediated transfection, receptor-mediated transfection, microprojectile bombardment, by agitation with silicon carbide fibers Through the application of techniques such as these cells may be stably or transiently transfected with a nucleic acid encoding a fusion protein described herein to express the encoded fusion protein.

In one aspect, provided herein are vectors comprising a nucleic acid encoding a fusion protein described herein (e.g., a nucleic acid described herein). In some embodiments, the vector is a viral vector. Exemplary viral vectors include, but are not limited to, retroviral vectors, adenoviral vectors, adeno associated viral vectors, herpes viral vectors, lentiviral vectors, pox viral vectors, vaccinia viral vectors, vesicular stomatitis viral vectors, polio viral vectors, Newcastle's Disease viral vectors, Epstein-Barr viral vectors, influenza viral vectors, reovirus vectors, myxoma viral vectors, maraba viral vectors, rhabdoviral vectors, and coxsackie viral vectors. In some embodiments, the vector is a non-viral vector. In some embodiments, the non-viral vector is a plasmid.

In one aspect, provided herein is a viral particle (or population of viral particles) that comprise a nucleic acid encoding a fusion protein described herein (e.g., a nucleic acid described herein). In some embodiments, the viral particle is an RNA virus. In some embodiments, the viral particle is a DNA virus. In some embodiments, the viral particle comprises a double stranded genome. In some embodiments, the viral particle comprises a single stranded genome. Exemplary viral particles include, but are not limited to, a retrovirus, an adenovirus, an adeno associated virus, a herpes virus, a lentivirus, a pox virus, a vaccinia virus, a vesicular stomatitis virus, a polio virus, a Newcastle's Disease virus, an Epstein-Barr virus, an influenza virus, a reoviruses, a myxoma virus, a maraba virus, a rhabdovirus, or a coxsackie.

5.5 Pharmaceutical Compositions

In one aspect, provided herein are pharmaceutical compositions comprising 1) a fusion protein described herein, a nucleic acid encoding a fusion protein described herein, a vector comprising a nucleic acid encoding a fusion protein described herein, or a viral particle comprising a nucleic acid encoding a fusion protein described herein; and 2) at least one pharmaceutically acceptable carrier, excipient, stabilizer buffer, diluent, surfactant, preservative and/or adjuvant, etc. (see, e.g., Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA). A person of ordinary skill in the art can select suitable excipient for inclusion in the pharmaceutical composition. For example, the formulation of the pharmaceutical composition may differ based on the route of administration (e.g., intravenous, subcutaneous, etc.), and/or the active molecule contained within the pharmaceutical composition (e.g., a viral particle, a non-viral vector, a nucleic acid not contained within a vector).

Acceptable carriers, excipients, or stabilizers are preferably nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, or other organic acids; antioxidants including ascorbic acid or methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; or m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™ PLURONICS™ or polyethylene glycol (PEG).

In one embodiment, the present disclosure provides a pharmaceutical composition comprising a fusion protein described herein for use as a medicament. In another embodiment, the disclosure provides a pharmaceutical composition for use in a method for the treatment of cancer. In some embodiments, pharmaceutical compositions comprise a fusion protein disclosed herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier.

A pharmaceutical composition may be formulated for any route of administration to a subject. Specific examples of routes of administration include parenteral administration (e.g., intravenous, subcutaneous, intramuscular). In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions. The injectables can contain one or more excipients. Exemplary excipients include, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, or other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate or cyclodextrins.

In some embodiments, the pharmaceutical composition is formulated for intravenous administration. Suitable carriers for intravenous administration include physiological saline or phosphate buffered saline (PBS), or solutions containing thickening or solubilizing agents, such as glucose, polyethylene glycol, or polypropylene glycol or mixtures thereof.

The compositions to be used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes.

Pharmaceutically acceptable carriers used in the parenteral preparations described herein include for example, aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents or other pharmaceutically acceptable substances. Examples of aqueous vehicles, which can be incorporated in one or more of the formulations described herein, include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose or lactated Ringer's injection. Nonaqueous parenteral vehicles, which can be incorporated in one or more of the formulations described herein, include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil or peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations can be added to the parenteral preparations described herein and packaged in multiple-dose containers, which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride or benzethonium chloride. Isotonic agents, which can be incorporated in one or more of the formulations described herein, include sodium chloride or dextrose. Buffers, which can be incorporated in one or more of the formulations described herein, include phosphate or citrate. Antioxidants, which can be incorporated in one or more of the formulations described herein, include sodium bisulfate. Local anesthetics, which can be incorporated in one or more of the formulations described herein, include procaine hydrochloride. Suspending and dispersing agents, which can be incorporated in one or more of the formulations described herein, include sodium carboxymethylcelluose, hydroxypropyl methylcellulose or polyvinylpyrrolidone. Emulsifying agents, which can be incorporated in one or more of the formulations described herein, include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions, which can be incorporated in one or more of the formulations described herein, is EDTA. Pharmaceutical carriers, which can be incorporated in one or more of the formulations described herein, also include ethyl alcohol, polyethylene glycol or propylene glycol for water miscible vehicles; orsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

The precise dose to be employed in a pharmaceutical composition will also depend on the route of administration, and the seriousness of the condition caused by it, and should be decided according to the judgment of the practitioner and each subject's circumstances. For example, effective doses may also vary depending upon means of administration, target site, physiological state of the subject (including age, body weight, and health), other medications administered, or whether therapy is prophylactic or therapeutic. Therapeutic dosages are preferably titrated to optimize safety and efficacy.

5.6 Methods of Therapeutic Use

In one aspect, provided herein are methods of treating a disease in a subject by administering to the subject having the disease a fusion protein described herein, a nucleic acid encoding a fusion protein described herein, a vector comprising a nucleic acid encoding a fusion protein described herein, or a viral particle comprising a nucleic acid encoding a fusion protein described herein.

The fusion protein can be delivered to host cells via any method known in the art. For example, a viral delivery system (e.g., a retrovirus, an adenovirus, an adeno associated virus, a herpes virus, a lentivirus, a pox virus, a vaccinia virus, a vesicular stomatitis virus, a polio virus, a Newcastle's Disease virus, an Epstein-Barr virus, an influenza virus, a reoviruses, a myxoma virus, a maraba virus, a rhabdovirus, an enadenotucirev or a coxsackie) can be utilized to deliver a nucleic acid (e.g., DNA or RNA molecule) encoding the fusion protein for expression within a population of cells of a subject. In some embodiments, the nucleic acid encoding the fusion protein is present episomally within the population of cells of the subject. In some embodiments, the nucleic acid encoding the fusion protein is incorporated into the genome of the population of cells of the subject. In some embodiments, the virus is replication competent. In some embodiments, the virus is replication deficient.

In some embodiments, the fusion protein is administered to the subject. In some embodiments, a nucleic acid (DNA or RNA) is administered to the subject. In some embodiments, the nucleic acid (DNA or RNA) is complexed within a carrier (e.g., a nanoparticle, a liposome, a microsphere). In some embodiments, a nucleic acid (DNA or RNA) within a non-viral vector (e.g., a plasmid) encoding the fusion protein is administered to the subject.

5.6.1 Administration

In some embodiment, the fusion protein is administered parenterally. In some embodiments, the fusion protein is administered via intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural or intrasternal injection or infusion. In some embodiments, the fusion protein is intravenously administered. In some embodiments, the fusion protein is subcutaneously administered. In some embodiments, the fusion protein is administered via a non-parenteral route, or orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

In some embodiments, the methods disclosed herein are used in place of standard of care therapies. In certain embodiments, a standard of care therapy is used in combination with any method disclosed herein. In some embodiments, the methods disclosed herein are used after standard of care therapy has failed. In some embodiments, the fusion protein is co-administered, administered prior to, or administered after, an additional therapeutic agent. In some embodiments, the disease is a genetic disease.

5.6.2 Exemplary Genetic Diseases

In some embodiments, the disease is a genetic disease. In some embodiments, the genetic disease is associated with decreased expression of a functional target nuclear protein. In some embodiments, the genetic disease is associated with decreased stability of a functional target nuclear protein. In some embodiments, the genetic disease is associated with increased ubiquitination of a target nuclear protein. In some embodiments, the genetic disease is associated with increased ubiquitination and degradation of a target nuclear protein. In some embodiments, the genetic disease is a haploinsufficiency disease.

In some embodiments, the disease is selected from the group consisting of early CHD2 encephalopathy, CDKL5 deficiency disorder, SETD5 syndrome, CAMTA1 syndrome, infantile epileptic encephalopathy (e.g., type 2), childhood onset epileptic encephalopathy, 1p36 deletion syndrome, Rett syndrome, Kabuki syndrome 1, mental retardation autosomal dominant 23, Mowat-Wilson syndrome, Wiedmann-Steiner Syndrome, Sifrim-Hitz-Weiss Syndrome, Sotos Syndrome, MED13L Syndrome, SMC1A Syndrome, Nicolaides-Baraitser Syndrome, ARID1B-Related Disorder, White-Sutton Syndrome, KAT6B Disorder, Xia-Gibbs Syndrome, Menke-Hennekam Syndrome 2, IQSEC2-Related Disorder, TCF20-Related Disorder, Bainbridge-Ropers Syndrome, and KATA6 Syndrome.

In some embodiments, the target nuclear protein is CHD2 and the disease is childhood onset epileptic encephalopathy. In some embodiments, the target nuclear protein is CHD2 and the disease is CHD2 encephalopathy. In some embodiments, the target nuclear protein is RERE and the disease is 1p36 deletion syndrome. In some embodiments, the target nuclear protein is CDKL5 and the disease is early infantile epileptic encephalopathy (e.g., type 2). In some embodiments, the target nuclear protein is CDKL5 and the disease is CDKL5 deficiency disorder. In some embodiments, the target nuclear protein is MECP2 and the disease is Rett syndrome. In some embodiments, the target nuclear protein is KMT2D and the disease is Kabuki syndrome 1. In some embodiments, the target nuclear protein is SETD5 and the disease is mental retardation autosomal dominant 23. In some embodiments, the target nuclear protein is ZEB2 and the disease is Mowat-Wilson syndrome. In some embodiments, the target nuclear protein is KMT2A, and the disease is Wiedmann-Steiner Syndrome. In some embodiments, the target nuclear protein is CHD4, and the disease is Sifrim-Hitz-Weiss Syndrome. In some embodiments, the target nuclear protein is NSD1, and the disease is Sotos Syndrome. In some embodiments, the target nuclear protein is SMC1A, and the disease is SMC1A Syndrome. In some embodiments, the target nuclear protein is SMARCA2, and the disease is Nicolaides-Baraitser Syndrome. In some embodiments, the target nuclear protein is ARID1B, and the disease is ARID1B-Related Disorder. In some embodiments, the target nuclear protein is POGZ, and the disease is White-Sutton Syndrome. In some embodiments, the target nuclear protein is KAT6B, and the disease is KAT6B Disorder. In some embodiments, the target nuclear protein is AHDC1, and the genetic disease is Xia-Gibbs Syndrome. In some embodiments, the target nuclear protein is EP300, and the disease is Menke-Hennekam Syndrome 2. In some embodiments, the target nuclear protein is IQSEC2, and the disease is IQSEC2-Related Disorder. In some embodiments, the target nuclear protein is TCF20, and the disease is TCF20-Related Disorder. In some embodiments, the target nuclear protein is ASXL3, and the disease is Bainbridge-Ropers Syndrome. In some embodiments, the target nuclear protein is KAT6A, and the disease is KATA6 Syndrome. In some embodiments, the target nuclear protein is MED13L, and the disease is MED13L Syndrome. In some embodiments, the target nuclear protein is CAMTA1, and the disease is CAMTA1 Syndrome. In some embodiments, the target nuclear protein is FMR1, and the disease is Fragile X syndrome. In some embodiments, the target nuclear protein is PRPF8, and the disease is Retinitis pigmentosa 13. In some embodiments, the target nuclear protein is RAI1, and the disease is Smith-Magenis Syndrome. In some embodiments, the target nuclear protein is CREBBP, and the disease is Rubinstein-Taybi syndrome. In some embodiments, the target nuclear protein is NF1, and the disease is Neurofibromatosis (e.g., type 1).

5.7 Kits

In one aspect, provided herein are kits comprising a fusion protein described herein, a nucleic acid encoding a fusion protein described herein, a vector comprising a nucleic acid encoding a fusion protein described herein, or a viral particle comprising a nucleic acid encoding a fusion protein described herein, for therapeutic uses. Kits typically include a label indicating the intended use of the contents of the kit and instructions for use. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit. Accordingly, this disclosure provides a kit for treating a subject afflicted with a disease (e.g., a genetic disease), the kit comprising: (a) a dosage of a fusion protein, a nucleic acid encoding a fusion protein described herein, a vector comprising a nucleic acid encoding a fusion protein described herein, or a viral particle comprising a nucleic acid encoding a fusion described herein; and (b) instructions for using the fusion protein in any of the therapy methods disclosed herein.

6. EXAMPLES

The present invention is further illustrated by the following examples which should not be construed as further limiting.

6.1 Example 1. Generation of Targeted Engineered Deubiquitinases

This example provides general experimental methods of using fluorescent tagged target proteins together with fluorophore tagged engineered deubiquitinases (enDUBs) to demonstrate up-regulation of expression in the context of an enDUB. For illustrative purposes the constructs disclosed below will be synthesized in a suitable vector for mammalian expression. Generally, the target protein will be expressed with a C-terminal YFP followed by a P2A cleavage signal and an mCherry protein as a second reporter (Target protein-YFP-P2A-mCherry). This construct will be co-transfected in the presence of a trifunctional fusion protein comprising of a CFP protein followed by a P2A signal and a nanobody specifically binding to YPF followed by the engineered DUB (CFP-P2A-Anti-YFPnanobody-enDUB). In applications for drug treatment the targeting nanobodies (or other specific binders) will be directed to the wild type (or disease-causing mutant) protein in the cell to be upregulated while the enDUB is fused to a binding protein directed to the target protein. Target protein binding moieties could be any antibody or antibody fragments, nanobodies, or any other non-antibody scaffold such as fibronectins, anticalins, ankyrin repeats or natural binding proteins interacting specifically with the target protein to be upregulated. The amino acid sequence of the components of the test fusion proteins is provided in Table 5 below.

TABLE 5

Amino Acid Sequence of Components of test fusion proteins

Description
SEQ ID NO
Amino Acid Sequence

Target Proteins

STAT3
368
MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYA

ASKESHATLVFHNLLGEIDQQYSRELQESNVLYQHNLRRIKQFLQS

RYLEKPMEIARIVARCLWEESRLLQTAATAAQQGGQANHPTAAVVT

EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDENYKTLKSQGD

MQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEY

VQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQ

TRQQIKKLEELQQKVSYKGDPIVQHRPMLEERIVELERNLMKSAFV

VERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCI

DKDSGDVAALRGSRKENILGTNTKVMNMEESNNGSLSAEFKHLTLR

EQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLP

VVVISNICQMPNAWASILWYNMLTNNPKNVNFFTKPPIGTWDQVAE

VLSWQFSSTTKRGLSIEQLTTLAEKLLGPGVNYSGCQITWAKFCKE

NMAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAIL

STKPPGTELLRESESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQQ

LNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPE

SQEHPEADPGSAAPYLKTKFICVTPTTCSNTIDLPMSPRTLDSLMQ

FGNNGEGAEPSAGGQFESLTEDMELTSECATSPM

PRDM14
369
MALPRPSEAVPQDKVCYPPESSPQNLAAYYTPEPSYGHYRNSLATV

EEDFQPFRQLEAAASAAPAMPPEPERMAPPLLSPGLGLQREPLYDL

PWYSKLPPWYPIPHVPREVPPELSSSHEYAGASSEDLGHQIIGGDN

ESGPCCGPDTLIPPPPADASLLPEGLRTSQLLPCSPSKQSEDGPKP

SNQEGKSPARFQFTEEDLHFVLYGVTPSLEHPASLHHAISGLLVPP

DSSGSDSLPQTLDKDSLQLPEGLCLMQTVFGEVPHFGVFCSSFIAK

GVRFGPFQGKVVNASEVKTYGDNSVMWEIFEDGHLSHFIDGKGGTG

NWMSYVNCARFPKEQNLVAVQCQGHIFYESCKEIHQNQELLVWYGD

CYEKFLDIPVSLQVTEPGKQPSGPSEESAEGYRCERCGKVFTYKYY

RDKHLKYTPCVDKGDRKFPCSLCKRSFEKRDRLRIHILHVHEKHRP

HKCSTCGKCFSQSSSLNKHMRVHSGDRPYQCVYCTKRFTASSILRT

HIRQHSGEKPFKCKYCGKSFASHAAHDSHVRRSHKEDDGCSCSICG

KIFSDQETFYSHMKFHEDY

WDR5
370
MATEEKKPETEAARAQPTPSSSATQSKPTPVKPNYALKFTLAGHTK

AVSSVKESPNGEWLASSSADKLIKIWGAYDGKFEKTISGHKLGISD

VAWSSDSNLLVSASDDKTLKIWDVSSGKCLKTLKGHSNYVFCCNEN

PQSNLIVSGSFDESVRIWDVKTGKCLKTLPAHSDPVSAVHENRDGS

LIVSSSYDGLCRIWDTASGQCLKTLIDDDNPPVSFVKESPNGKYIL

AATLDNTLKLWDYSKGKCLKTYTGHKNEKYCIFANFSVTGGKWIVS

GSEDNLVYIWNLQTKEIVQKLQGHTDVVISTACHPTENIIASAALE

NDKTIKLWKSDC

NR112
371
MEVRPKESWNHADEVHCEDTESVPGKPSVNADEEVGGPQICRVCGD

KATGYHFNVMTCEGCKGFFRRAMKRNARLRCPERKGACEITRKTRR

QCQACRLRKCLESGMKKEMIMSDEAVEERRALIKRKKSERTGTQPL

GVQGLTEEQRMMIRELMDAQMKTEDTTESHFKNERLPGVLSSGCEL

PESLQAPSREEAAKWSQVRKDLCSLKVSLQLRGEDGSVWNYKPPAD

SGGKEIFSLLPHMADMSTYMFKGIISFAKVISYERDLPIEDQISLL

KGAAFELCQLRFNTVFNAETGTWECGRLSYCLEDTAGGFQQLLLEP

MLKFHYMLKKLQLHEEEYVLMQAISLESPDRPGVLQHRVVDQLQEQ

FAITLKSYIECNRPQPAHRFLFLKIMAMLTELRSINAQHTQRLLRI

QDIHPFATPLMQELFGITGS

FluorescentProteins

YFP
372
VSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKF

ICTTGKLPVPWPTLVTTFGYGLQCFARYPDHMKQHDFFKSAMPEGY

VQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILG

HKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQ

NTPIGDGPVLLPDNHYLSYQSALSKDPNEKRDHMVLLEFVTAAGIT

LGMDELYK

mCherry
373
MVSKGEEDNMAIIKEFMRFKVHMEGSVNGHEFEIEGEGEGRPYEGT

QTAKLKVTKGGPLPFAWDILSPQFMYGSKAYVKHPADIPDYLKLSE

PEGFKWERVMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNFPSDG

PVMQKKTMGWEASSERMYPEDGALKGEIKQRLKLKDGGHYDAEVKT

TYKAKKPVQLPGAYNVNIKLDITSHNEDYTIVEQYERAEGRHSTGG

MDELYK

CFP
374
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYK

A2 Peptides

P2A
375
GSGATNFSLLKQAGDVEENPGP

T2A
376
GSGEGRGSLLTCGDVEENPGP

E2A
377
GSGQCTNYALLKLAGDVESNPGP

Target Binders

YFP targeting
378
QVQLVESGGALVQPGGSLRLSCAASGFPVNRYSMRWYRQAPGKERE

nanobody

WVAGMSSAGDRSSYEDSVKGRFTISRDDARNTVYLQMNSLKPEDTA

VYYCNVNVGFEYWGQGTQVTVSS

STAT3 binder
379
GSVSSVPTKLEVVAATPTSLLISWDAPAVTVDFYHITYGETGGNSP

(monobody)

VQEFTVPGSKSTATISGLKPGVDYTITVYAYVSYPEYYFPSPISIN

YRT

PRDM14binder
380
GSVSSVPTKLEVVAATPTSLLISWDAPAVTVDLYFITYGETGGNSP

(monobody)

VQKFTVPGSKSTATISGLKPGVDYTITVYAQYYYRGWYVGSPISIN

YRT

WDR5 binder
381
GSVSSVPTKLEVVAATPTSLLISWDAPAVTVVHYVITYGETGGNSP

(monobody)

VQKFKVPGSKSTATISGLKPGVDYTITVYAYQGGGRWHPYGYYSPI

SINYRT

NR112 binder
382
ASTSGSTHYYKQTADLEVVAATPTSLLISWPPPYYVEGVTVFRITY

(adnectin)

GETGGNSPVQEFTVPYWTETATISGLKPGVDYTITVYAEMYPGSPW

AGQVMDIQPISINYRTEGSGS

EnDUBS

Cezanne
383
PPSFSEGSGGSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRG

ISHASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYN

EDFRSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTG

DGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWRW

QQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANCGG

VESSEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAP

IPFGGIYLPLEVPASQCHRSPLVLAYDQAHESALVSMEQKENTKEQ

AVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEV

KLHLLHSYMNVKWIPLSSDAQAPLAQ

OTUD1
384
DEKLALYLAEVEKQDKYLRQRNKYRFHIIPDGNCLYRAVSKTVYGD

QSLHRELREQTVHYIADHLDHESPLIEGDVGEFIIAAAQDGAWAGY

PELLAMGQMLNVNIHLTTGGRLESPTVSTMIHYLGPEDSLRPSIWL

SWLSNGHYDAVEDHSYPNPEYDNWCKQTQVQRKRDEELAKSMAISL

SKMYIEQNACS

TRABID
385
LEVDFKKLKQIKNRMKKTDWLFLNACVGVVEGDLAAIEAYKSSGGD

IARQLTADEVRLLNRPSAFDVGYTLVHLAIRFQRQDMLAILLTEVS

QQAAKCIPAMVCPELTEQIRREIAASLHQRKGDFACYFLTDLVTFT

LPADIEDLPPTVQEKLFDEVLDRDVQKELEEESPIINWSLELATRL

DSRLYALWNRTAGDCLLDSVLQATWGIYDKDSVLRKALHDSLHDCS

HWFYTRWKDWESWYSQSFGLHESLREEQWQEDWAFILSLASQPGAS

LEQTHIFVLAHILRRPIIVYGVKYYKSFRGETLGYTRFQGVYLPLL

WEQSFCWKSPIALGYTRGHFSALVAMENDGYGNRGAGANLNTDDDV

TITFLPLVDSERKLLHVHELSAQELGNEEQQEKLLREWLDCCVTEG

GVLVAMQKSSRRRNHPLVTQMVEKWLDRYRQIRPCTSLS

USP21
386
SDDKMAHHTLLLGSGHVGLRNLGNTCELNAVLQCLSSTRPLRDFCL

RRDFRQEVPGGGRAQELTEAFADVIGALWHPDSCEAVNPTRFRAVE

QKYVPSFSGYSQQDAQEFLKLLMERLHLEINRRGRRAPPILANGPV

PSPPRRGGALLEEPELSDDDRANLMWKRYLEREDSKIVDLFVGQLK

SCLKCQACGYRSTTFEVECDLSLPIPKKGFAGGKVSLRDCFNLFTK

EEELESENAPVCDRCRQKTRSTKKLTVQRFPRILVLHLNRESASRG

SIKKSSVGVDFPLQRLSLGDFASDKAGSPVYQLYALCNHSGSVHYG

HYTALCRCQTGWHVYNDSRVSPVSENQVASSEGYVLFYQLMQEPPR

CI

OTUD4
387
ATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQSRHVEVRMA

CIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMY

RKDFIIYREPNVSPSQVTENNFPEKVLLCESNGNHYDIVYPIKYKE

SSAMCQSLLYELLYEKVEKTDVSKIVMELDTLEVADE

Human USP3
388
MECPHLSSSVCIAPDSAKFPNGSPSSWCCSVCRSNKSPWVCLTCSS

(full length)

VHCGRYVNGHAKKHYEDAQVPLTNHKKSEKQDKVQHTVCMDCSSYS

nuclear located

TYCYRCDDFVVNDTKLGLVQKVREHLQNLENSAFTADRHKKRKLLE

NSTLNSKLLKVNGSTTAICATGLRNLGNTCEMNAILQSLSNIEQFC

CYFKELPAVELRNGKTAGRRTYHTRSQGDNNVSLVEEFRKTLCALW

QGSQTAFSPESLFYVVWKIMPNERGYQQQDAHEFMRYLLDHLHLEL

QGGFNGVSRSAILQENSTLSASNKCCINGASTVVTAIFGGILQNEV

NCLICGTESRKFDPFLDLSLDIPSQFRSKRSKNQENGPVCSLRDCL

RSFTDLEELDETELYMCHKCKKKQKSTKKFWIQKLPKVLCLHLKRE

HWTAYLRNKVDTYVEFPLRGLDMKCYLLEPENSGPESCLYDLAAVV

VHHGSGVGSGHYTAYATHEGRWFHENDSTVTLTDEETVVKAKAYIL

FYVEHQAKAGSDKL

The amino acid sequence of the test fusion proteins is provided in Table 6 below.

TABLE 6

Amino acid sequence of exemplary test fusion proteins

Description
SEQ ID NO
Amino Acid Sequence

STAT3 Target-
389
MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYA

YFP-P2A-

ASKESHATLVFHNLLGEIDQQYSRELQESNVLYQHNLRRIKQFLQS

mCherrry

RYLEKPMEIARIVARCLWEESRLLQTAATAAQQGGQANHPTAAVVT

EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDENYKTLKSQGD

MQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEY

VQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQ

TRQQIKKLEELQQKVSYKGDPIVQHRPMLEERIVELFRNLMKSAFV

VERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCI

DKDSGDVAALRGSRKENILGTNTKVMNMEESNNGSLSAEFKHLTLR

EQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLP

VVVISNICQMPNAWASILWYNMLTNNPKNVNFFTKPPIGTWDQVAE

VLSWQFSSTTKRGLSIEQLTTLAEKLLGPGVNYSGCQITWAKFCKE

NMAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAIL

STKPPGTELLRESESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQQ

LNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPE

SQEHPEADPGSAAPYLKTKFICVTPTTCSNTIDLPMSPRTLDSLMQ

FGNNGEGAEPSAGGQFESLTEDMELTSECATSPMVSKGEELFTGVV

PILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWP

TLVTTFGYGLQCFARYPDHMKQHDFFKSAMPEGYVQERTIFFKDDG

NYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILGHKLEYNYNSHNV

YIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLP

DNHYLSYQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYKGSGA

TNFSLLKQAGDVEENPGPMVSKGEEDNMAIIKEFMRFKVHMEGSVN

GHEFEIEGEGEGRPYEGTQTAKLKVTKGGPLPFAWDILSPQFMYGS

KAYVKHPADIPDYLKLSFPEGFKWERVMNFEDGGVVTVTQDSSLQD

GEFIYKVKLRGTNFPSDGPVMQKKTMGWEASSERMYPEDGALKGEI

KQRLKLKDGGHYDAEVKTTYKAKKPVQLPGAYNVNIKLDITSHNED

YTIVEQYERAEGRHSTGGMDELYK

PRDM14 Target-
390
MALPRPSEAVPQDKVCYPPESSPQNLAAYYTPFPSYGHYRNSLATV

YFP-P2A-

EEDFQPFRQLEAAASAAPAMPPFPFRMAPPLLSPGLGLQREPLYDL

mCherrry

PWYSKLPPWYPIPHVPREVPPFLSSSHEYAGASSEDLGHQIIGGDN

ESGPCCGPDTLIPPPPADASLLPEGLRTSQLLPCSPSKQSEDGPKP

SNQEGKSPARFQFTEEDLHFVLYGVTPSLEHPASLHHAISGLLVPP

DSSGSDSLPQTLDKDSLQLPEGLCLMQTVFGEVPHFGVFCSSFIAK

GVRFGPFQGKVVNASEVKTYGDNSVMWEIFEDGHLSHFIDGKGGTG

NWMSYVNCARFPKEQNLVAVQCQGHIFYESCKEIHQNQELLVWYGD

CYEKFLDIPVSLQVTEPGKQPSGPSEESAEGYRCERCGKVFTYKYY

RDKHLKYTPCVDKGDRKFPCSLCKRSFEKRDRLRIHILHVHEKHRP

HKCSTCGKCFSQSSSLNKHMRVHSGDRPYQCVYCTKRFTASSILRT

HIRQHSGEKPFKCKYCGKSFASHAAHDSHVRRSHKEDDGCSCSICG

KIFSDQETFYSHMKFHEDYVSKGEELFTGVVPILVELDGDVNGHKE

SVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTFGYGLQCFAR

YPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTL

VNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNE

KIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSYQSALSKDP

NEKRDHMVLLEFVTAAGITLGMDELYKGSGATNFSLLKQAGDVEEN

PGPMVSKGEEDNMAIIKEFMRFKVHMEGSVNGHEFEIEGEGEGRPY

EGTQTAKLKVTKGGPLPFAWDILSPQFMYGSKAYVKHPADIPDYLK

LSFPEGFKWERVMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNEP

SDGPVMQKKTMGWEASSERMYPEDGALKGEIKQRLKLKDGGHYDAE

VKTTYKAKKPVQLPGAYNVNIKLDITSHNEDYTIVEQYERAEGRHS

TGGMDELYK

WDR5 Target-
391
MATEEKKPETEAARAQPTPSSSATQSKPTPVKPNYALKFTLAGHTK

YFP-P2A-

AVSSVKESPNGEWLASSSADKLIKIWGAYDGKFEKTISGHKLGISD

mCherrry

VAWSSDSNLLVSASDDKTLKIWDVSSGKCLKTLKGHSNYVFCCNEN

PQSNLIVSGSFDESVRIWDVKTGKCLKTLPAHSDPVSAVHENRDGS

LIVSSSYDGLCRIWDTASGQCLKTLIDDDNPPVSFVKESPNGKYIL

AATLDNTLKLWDYSKGKCLKTYTGHKNEKYCIFANFSVTGGKWIVS

GSEDNLVYIWNLQTKEIVQKLQGHTDVVISTACHPTENIIASAALE

NDKTIKLWKSDCVSKGEELFTGVVPILVELDGDVNGHKESVSGEGE

GDATYGKLTLKFICTTGKLPVPWPTLVTTFGYGLQCFARYPDHMKQ

HDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELK

GIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIE

DGSVQLADHYQQNTPIGDGPVLLPDNHYLSYQSALSKDPNEKRDHM

VLLEFVTAAGITLGMDELYKGSGATNFSLLKQAGDVEENPGPMVSK

GEEDNMAIIKEFMRFKVHMEGSVNGHEFEIEGEGEGRPYEGTQTAK

LKVTKGGPLPFAWDILSPQFMYGSKAYVKHPADIPDYLKLSFPEGE

KWERVMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNFPSDGPVMQ

KKTMGWEASSERMYPEDGALKGEIKQRLKLKDGGHYDAEVKTTYKA

KKPVQLPGAYNVNIKLDITSHNEDYTIVEQYERAEGRHSTGGMDEL

YK

NR112 Target-
392
MEVRPKESWNHADFVHCEDTESVPGKPSVNADEEVGGPQICRVCGD

YFP-P2A-

KATGYHFNVMTCEGCKGFFRRAMKRNARLRCPFRKGACEITRKTRR

mCherrry

QCQACRLRKCLESGMKKEMIMSDEAVEERRALIKRKKSERTGTQPL

GVQGLTEEQRMMIRELMDAQMKTEDTTFSHFKNERLPGVLSSGCEL

PESLQAPSREEAAKWSQVRKDLCSLKVSLQLRGEDGSVWNYKPPAD

SGGKEIFSLLPHMADMSTYMFKGIISFAKVISYFRDLPIEDQISLL

KGAAFELCQLRFNTVFNAETGTWECGRLSYCLEDTAGGFQQLLLEP

MLKFHYMLKKLQLHEEEYVLMQAISLESPDRPGVLQHRVVDQLQEQ

FAITLKSYIECNRPQPAHRFLFLKIMAMLTELRSINAQHTQRLLRI

QDIHPFATPLMQELFGITGSVSKGEELFTGVVPILVELDGDVNGHK

FSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTFGYGLQCFA

RYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDT

LVNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVN

FKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSYQSALSKD

PNEKRDHMVLLEFVTAAGITLGMDELYKGSGATNFSLLKQAGDVEE

NPGPMVSKGEEDNMAIIKEFMRFKVHMEGSVNGHEFEIEGEGEGRP

YEGTQTAKLKVTKGGPLPFAWDILSPQFMYGSKAYVKHPADIPDYL

KLSFPEGFKWERVMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNF

PSDGPVMQKKTMGWEASSERMYPEDGALKGEIKQRLKLKDGGHYDA

EVKTTYKAKKPVQLPGAYNVNIKLDITSHNEDYTIVEQYERAEGRH

STGGMDELYK

CFP-P2A-
393
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Cezanne enDUB

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPPPSESEGSGGSRTPE

KGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSSIVSLARSH

VSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSFIERDLIEQS

MLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCLLHAASLGMWG

FHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQQNKESGLVYTE

DEWQKEWNELIKLASSEPRMHLGTNGANCGGVESSEEPVYESLEEF

HVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIPEGGIYLPLEVPAS

QCHRSPLVLAYDQAHFSALVSMEQKENTKEQAVIPLTDSEYKLLPL

HFAVDPGKGWEWGKDDSDNVRLASVILSLEVKLHLLHSYMNVKWIP

LSSDAQAPLAQ

CFP-P2A-
394
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

OTUD1 enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDEKLALYLAEVEKQD

KYLRQRNKYRFHIIPDGNCLYRAVSKTVYGDQSLHRELREQTVHYI

ADHLDHFSPLIEGDVGEFIIAAAQDGAWAGYPELLAMGQMLNVNIH

LTTGGRLESPTVSTMIHYLGPEDSLRPSIWLSWLSNGHYDAVEDHS

YPNPEYDNWCKQTQVQRKRDEELAKSMAISLSKMYIEQNACS

CFP-P2A-
395
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

TRABID

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPLEVDEKKLKQIKNRM

KKTDWLFLNACVGVVEGDLAAIEAYKSSGGDIARQLTADEVRLLNR

PSAFDVGYTLVHLAIRFQRQDMLAILLTEVSQQAAKCIPAMVCPEL

TEQIRREIAASLHQRKGDFACYFLTDLVTFTLPADIEDLPPTVQEK

LFDEVLDRDVQKELEEESPIINWSLELATRLDSRLYALWNRTAGDC

LLDSVLQATWGIYDKDSVLRKALHDSLHDCSHWFYTRWKDWESWYS

QSFGLHESLREEQWQEDWAFILSLASQPGASLEQTHIFVLAHILRR

PIIVYGVKYYKSFRGETLGYTRFQGVYLPLLWEQSFCWKSPIALGY

TRGHFSALVAMENDGYGNRGAGANLNTDDDVTITFLPLVDSERKLL

HVHELSAQELGNEEQQEKLLREWLDCCVTEGGVLVAMQKSSRRRNH

PLVTQMVEKWLDRYRQIRPCTSLS

CFP-P2A-
396
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

USP21 enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPSDDKMAHHTLLLGSG

HVGLRNLGNTCFLNAVLQCLSSTRPLRDFCLRRDERQEVPGGGRAQ

ELTEAFADVIGALWHPDSCEAVNPTRFRAVFQKYVPSFSGYSQQDA

QEFLKLLMERLHLEINRRGRRAPPILANGPVPSPPRRGGALLEEPE

LSDDDRANLMWKRYLEREDSKIVDLFVGQLKSCLKCQACGYRSTTF

EVFCDLSLPIPKKGFAGGKVSLRDCENLFTKEEELESENAPVCDRC

RQKTRSTKKLTVQRFPRILVLHLNRFSASRGSIKKSSVGVDEPLQR

LSLGDFASDKAGSPVYQLYALCNHSGSVHYGHYTALCRCQTGWHVY

NDSRVSPVSENQVASSEGYVLFYQLMQEPPRCL

CFP-P2A-
397
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

OTUD4 enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPATPMDAYLRKLGLYR

KLVAKDGSCLFRAVAEQVLHSQSRHVEVRMACIHYLRENREKFEAF

IEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNVSPS

QVTENNFPEKVLLCESNGNHYDIVYPIKYKESSAMCQSLLYELLYE

KVFKTDVSKIVMELDTLEVADE

CFP-P2A-a-
398
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

Cezanne enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSPPSFSEGSGGSRTPEKGFSDREPTRPPRPILQRQDDIV

QEKRLSRGISHASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQ

LPDLTVYNEDERSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQR

LLPLATTGDGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKE

ALKRRWRWQQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLG

TNGANCGGVESSEEPVYESLEEFHVEVLAHVLRRPIVVVADTMLRD

SGGEAFAPIPEGGIYLPLEVPASQCHRSPLVLAYDQAHFSALVSME

QKENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLA

SVILSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

CFP-P2A-a-
399
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

OTUD1 enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSDEKLALYLAEVEKQDKYLRQRNKYRFHIIPDGNCLYRA

VSKTVYGDQSLHRELREQTVHYIADHLDHFSPLIEGDVGEFIIAAA

QDGAWAGYPELLAMGQMLNVNIHLTTGGRLESPTVSTMIHYLGPED

SLRPSIWLSWLSNGHYDAVEDHSYPNPEYDNWCKQTQVQRKRDEEL

AKSMAISLSKMYIEQNACS

CFP-P2A-a-
400
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

TRABID

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSLEVDFKKLKQIKNRMKKTDWLFLNACVGVVEGDLAAIE

AYKSSGGDIARQLTADEVRLLNRPSAFDVGYTLVHLAIRFQRQDML

AILLTEVSQQAAKCIPAMVCPELTEQIRREIAASLHQRKGDFACYF

LTDLVTFTLPADIEDLPPTVQEKLEDEVLDRDVQKELEEESPIINW

SLELATRLDSRLYALWNRTAGDCLLDSVLQATWGIYDKDSVLRKAL

HDSLHDCSHWFYTRWKDWESWYSQSFGLHESLREEQWQEDWAFILS

LASQPGASLEQTHIFVLAHILRRPIIVYGVKYYKSFRGETLGYTRE

QGVYLPLLWEQSFCWKSPIALGYTRGHFSALVAMENDGYGNRGAGA

NLNTDDDVTITFLPLVDSERKLLHVHELSAQELGNEEQQEKLLREW

LDCCVTEGGVLVAMQKSSRRRNHPLVTQMVEKWLDRYRQIRPCTSL

CFP-P2A-a-
401
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

USP21 enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGEPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSSDDKMAHHTLLLGSGHVGLRNLGNTCFLNAVLQCLSST

RPLRDFCLRRDFRQEVPGGGRAQELTEAFADVIGALWHPDSCEAVN

PTRFRAVFQKYVPSFSGYSQQDAQEFLKLLMERLHLEINRRGRRAP

PILANGPVPSPPRRGGALLEEPELSDDDRANLMWKRYLEREDSKIV

DLFVGQLKSCLKCQACGYRSTTFEVECDLSLPIPKKGFAGGKVSLR

DCFNLFTKEEELESENAPVCDRCRQKTRSTKKLTVQRFPRILVLHL

NRFSASRGSIKKSSVGVDFPLQRLSLGDFASDKAGSPVYQLYALCN

HSGSVHYGHYTALCRCQTGWHVYNDSRVSPVSENQVASSEGYVLFY

QLMQEPPRCL

CFP-P2A-a-
402
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

OTUD4 enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQS

RHVEVRMACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVE

ISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCESNGNHYDI

VYPIKYKESSAMCQSLLYELLYEKVEKTDVSKIVMELDTLEVADE

CFP-P2A-anti-
403
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Stat3 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-Cezanne

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDFYHITYGETGGNSPVQEFTVPGSKSTATI

SGLKPGVDYTITVYAYVSYPEYYFPSPISINYRTPPSFSEGSGGSR

TPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSSIVSLA

RSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSFIERDLI

EQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCLLHAASLG

MWGFHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQQNKESGLV

YTEDEWQKEWNELIKLASSEPRMHLGTNGANCGGVESSEEPVYESL

EEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIPEGGIYLPLEV

PASQCHRSPLVLAYDQAHFSALVSMEQKENTKEQAVIPLTDSEYKL

LPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEVKLHLLHSYMNVK

WIPLSSDAQAPLAQ

CFP-P2A-anti-
404
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Stat3 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-OTUD1

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDFYHITYGETGGNSPVQEFTVPGSKSTATI

SGLKPGVDYTITVYAYVSYPEYYFPSPISINYRTDEKLALYLAEVE

KQDKYLRQRNKYRFHIIPDGNCLYRAVSKTVYGDQSLHRELREQTV

HYIADHLDHFSPLIEGDVGEFIIAAAQDGAWAGYPELLAMGQMLNV

NIHLTTGGRLESPTVSTMIHYLGPEDSLRPSIWLSWLSNGHYDAVE

DHSYPNPEYDNWCKQTQVQRKRDEELAKSMAISLSKMYIEQNACS

CFP-P2A-anti-
405
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Stat3 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

TRABID

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDFYHITYGETGGNSPVQEFTVPGSKSTATI

SGLKPGVDYTITVYAYVSYPEYYFPSPISINYRTLEVDEKKLKQIK

NRMKKTDWLFLNACVGVVEGDLAAIEAYKSSGGDIARQLTADEVRL

LNRPSAFDVGYTLVHLAIRFQRQDMLAILLTEVSQQAAKCIPAMVC

PELTEQIRREIAASLHQRKGDFACYFLTDLVTFTLPADIEDLPPTV

QEKLFDEVLDRDVQKELEEESPIINWSLELATRLDSRLYALWNRTA

GDCLLDSVLQATWGIYDKDSVLRKALHDSLHDCSHWFYTRWKDWES

WYSQSFGLHESLREEQWQEDWAFILSLASQPGASLEQTHIFVLAHI

LRRPIIVYGVKYYKSFRGETLGYTRFQGVYLPLLWEQSFCWKSPIA

LGYTRGHFSALVAMENDGYGNRGAGANLNTDDDVTITELPLVDSER

KLLHVHELSAQELGNEEQQEKLLREWLDCCVTEGGVLVAMQKSSRR

RNHPLVTQMVEKWLDRYRQIRPCTSLS

CFP-P2A-anti-
406
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Stat3 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-USP21

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDFYHITYGETGGNSPVQEFTVPGSKSTATI

SGLKPGVDYTITVYAYVSYPEYYFPSPISINYRTSDDKMAHHTLLL

GSGHVGLRNLGNTCFLNAVLQCLSSTRPLRDFCLRRDERQEVPGGG

RAQELTEAFADVIGALWHPDSCEAVNPTRFRAVFQKYVPSFSGYSQ

QDAQEFLKLLMERLHLEINRRGRRAPPILANGPVPSPPRRGGALLE

EPELSDDDRANLMWKRYLEREDSKIVDLFVGQLKSCLKCQACGYRS

TTFEVFCDLSLPIPKKGFAGGKVSLRDCFNLFTKEEELESENAPVC

DRCRQKTRSTKKLTVQRFPRILVLHLNRFSASRGSIKKSSVGVDFP

LQRLSLGDFASDKAGSPVYQLYALCNHSGSVHYGHYTALCRCQTGW

HVYNDSRVSPVSENQVASSEGYVLFYQLMQEPPRCL

CFP-P2A-anti-
407
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Stat3 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-OTUD4

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDFYHITYGETGGNSPVQEFTVPGSKSTATI

SGLKPGVDYTITVYAYVSYPEYYFPSPISINYRTATPMDAYLRKLG

LYRKLVAKDGSCLFRAVAEQVLHSQSRHVEVRMACIHYLRENREKE

EAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNV

SPSQVTENNFPEKVLLCESNGNHYDIVYPIKYKESSAMCQSLLYEL

LYEKVEKTDVSKIVMELDTLEVADE

CFP-P2A-anti-
408
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

PRDM14

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

Cezanne enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDLYFITYGETGGNSPVQKFTVPGSKSTATI

SGLKPGVDYTITVYAQYYYRGWYVGSPISINYRTPPSFSEGSGGSR

TPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSSIVSLA

RSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSFIERDLI

EQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCLLHAASLG

MWGFHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQQNKESGLV

YTEDEWQKEWNELIKLASSEPRMHLGTNGANCGGVESSEEPVYESL

EEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIPEGGIYLPLEV

PASQCHRSPLVLAYDQAHESALVSMEQKENTKEQAVIPLTDSEYKL

LPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEVKLHLLHSYMNVK

WIPLSSDAQAPLAQ

CFP-P2A-anti-
409
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

PRDM14

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

OTUD1 enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDLYFITYGETGGNSPVQKFTVPGSKSTATI

SGLKPGVDYTITVYAQYYYRGWYVGSPISINYRTDEKLALYLAEVE

KQDKYLRQRNKYRFHIIPDGNCLYRAVSKTVYGDQSLHRELREQTV

HYIADHLDHFSPLIEGDVGEFIIAAAQDGAWAGYPELLAMGQMLNV

NIHLTTGGRLESPTVSTMIHYLGPEDSLRPSIWLSWLSNGHYDAVE

DHSYPNPEYDNWCKQTQVQRKRDEELAKSMAISLSKMYIEQNACS

CFP-P2A-anti-
410
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

PRDM14

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

TRABID enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDLYFITYGETGGNSPVQKFTVPGSKSTATI

SGLKPGVDYTITVYAQYYYRGWYVGSPISINYRTLEVDEKKLKQIK

NRMKKTDWLFLNACVGVVEGDLAAIEAYKSSGGDIARQLTADEVRL

LNRPSAFDVGYTLVHLAIRFQRQDMLAILLTEVSQQAAKCIPAMVC

PELTEQIRREIAASLHQRKGDFACYFLTDLVTFTLPADIEDLPPTV

QEKLFDEVLDRDVQKELEEESPIINWSLELATRLDSRLYALWNRTA

GDCLLDSVLQATWGIYDKDSVLRKALHDSLHDCSHWFYTRWKDWES

WYSQSFGLHESLREEQWQEDWAFILSLASQPGASLEQTHIFVLAHI

LRRPIIVYGVKYYKSFRGETLGYTRFQGVYLPLLWEQSFCWKSPIA

LGYTRGHESALVAMENDGYGNRGAGANLNTDDDVTITELPLVDSER

KLLHVHELSAQELGNEEQQEKLLREWLDCCVTEGGVLVAMQKSSRR

RNHPLVTQMVEKWLDRYRQIRPCTSLS

CFP-P2A-anti-
411
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

PRDM14

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

targeting binder-

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

USP21 enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDLYFITYGETGGNSPVQKFTVPGSKSTATI

SGLKPGVDYTITVYAQYYYRGWYVGSPISINYRTSDDKMAHHTLLL

GSGHVGLRNLGNTCELNAVLQCLSSTRPLRDFCLRRDERQEVPGGG

RAQELTEAFADVIGALWHPDSCEAVNPTRFRAVFQKYVPSFSGYSQ

QDAQEFLKLLMERLHLEINRRGRRAPPILANGPVPSPPRRGGALLE

EPELSDDDRANLMWKRYLEREDSKIVDLFVGQLKSCLKCQACGYRS

TTFEVFCDLSLPIPKKGFAGGKVSLRDCENLFTKEEELESENAPVC

DRCRQKTRSTKKLTVQRFPRILVLHLNRESASRGSIKKSSVGVDFP

LQRLSLGDFASDKAGSPVYQLYALCNHSGSVHYGHYTALCRCQTGW

HVYNDSRVSPVSENQVASSEGYVLFYQLMQEPPRCL

CFP-P2A-anti-
412
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

PRDM14

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting binder-

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

OTUD4 enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVDLYFITYGETGGNSPVQKFTVPGSKSTATI

SGLKPGVDYTITVYAQYYYRGWYVGSPISINYRTATPMDAYLRKLG

LYRKLVAKDGSCLFRAVAEQVLHSQSRHVEVRMACIHYLRENREKF

EAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNV

SPSQVTENNFPEKVLLCESNGNHYDIVYPIKYKESSAMCQSLLYEL

LYEKVEKTDVSKIVMELDTLEVADE

CFP-P2A-anti-
413
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

NR112 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-Cezanne

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPASTSGSTHYYKQTAD

LEVVAATPTSLLISWPPPYYVEGVTVFRITYGETGGNSPVQEFTVP

YWTETATISGLKPGVDYTITVYAEMYPGSPWAGQVMDIQPISINYR

TEGSGSPPSFSEGSGGSRTPEKGESDREPTRPPRPILQRQDDIVQE

KRLSRGISHASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQLP

DLTVYNEDERSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLL

PLATTGDGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKEAL

KRRWRWQQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTN

GANCGGVESSEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRDSG

GEAFAPIPFGGIYLPLEVPASQCHRSPLVLAYDQAHFSALVSMEQK

ENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASV

ILSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

CFP-P2A-anti-
414
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

NR112 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-OTUD1

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPASTSGSTHYYKQTAD

LEVVAATPTSLLISWPPPYYVEGVTVFRITYGETGGNSPVQEFTVP

YWTETATISGLKPGVDYTITVYAEMYPGSPWAGQVMDIQPISINYR

TEGSGSDEKLALYLAEVEKQDKYLRQRNKYRFHIIPDGNCLYRAVS

KTVYGDQSLHRELREQTVHYIADHLDHFSPLIEGDVGEFIIAAAQD

GAWAGYPELLAMGQMLNVNIHLTTGGRLESPTVSTMIHYLGPEDSL

RPSIWLSWLSNGHYDAVEDHSYPNPEYDNWCKQTQVQRKRDEELAK

SMAISLSKMYIEQNACS

CFP-P2A-anti-
415
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

NR112 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

TRABID

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPASTSGSTHYYKQTAD

LEVVAATPTSLLISWPPPYYVEGVTVFRITYGETGGNSPVQEFTVP

YWTETATISGLKPGVDYTITVYAEMYPGSPWAGQVMDIQPISINYR

TEGSGSLEVDFKKLKQIKNRMKKTDWLFLNACVGVVEGDLAAIEAY

KSSGGDIARQLTADEVRLLNRPSAFDVGYTLVHLAIRFQRQDMLAI

LLTEVSQQAAKCIPAMVCPELTEQIRREIAASLHQRKGDFACYFLT

DLVTFTLPADIEDLPPTVQEKLFDEVLDRDVQKELEEESPIINWSL

ELATRLDSRLYALWNRTAGDCLLDSVLQATWGIYDKDSVLRKALHD

SLHDCSHWFYTRWKDWESWYSQSFGLHESLREEQWQEDWAFILSLA

SQPGASLEQTHIFVLAHILRRPIIVYGVKYYKSERGETLGYTREQG

VYLPLLWEQSFCWKSPIALGYTRGHFSALVAMENDGYGNRGAGANL

NTDDDVTITFLPLVDSERKLLHVHELSAQELGNEEQQEKLLREWLD

CCVTEGGVLVAMQKSSRRRNHPLVTQMVEKWLDRYRQIRPCTSLS

CFP-P2A-anti-
416
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

NR112 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-USP21

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPASTSGSTHYYKQTAD

LEVVAATPTSLLISWPPPYYVEGVTVFRITYGETGGNSPVQEFTVP

YWTETATISGLKPGVDYTITVYAEMYPGSPWAGQVMDIQPISINYR

TEGSGSSDDKMAHHTLLLGSGHVGLRNLGNTCELNAVLQCLSSTRP

LRDFCLRRDERQEVPGGGRAQELTEAFADVIGALWHPDSCEAVNPT

RFRAVFQKYVPSFSGYSQQDAQEFLKLLMERLHLEINRRGRRAPPI

LANGPVPSPPRRGGALLEEPELSDDDRANLMWKRYLEREDSKIVDL

FVGQLKSCLKCQACGYRSTTFEVFCDLSLPIPKKGFAGGKVSLRDC

FNLFTKEEELESENAPVCDRCRQKTRSTKKLTVQRFPRILVLHLNR

FSASRGSIKKSSVGVDFPLQRLSLGDFASDKAGSPVYQLYALCNHS

GSVHYGHYTALCRCQTGWHVYNDSRVSPVSENQVASSEGYVLFYQL

MQEPPRCL

CFP-P2A-anti-
417
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

NR112 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-OTUD4

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPASTSGSTHYYKQTAD

LEVVAATPTSLLISWPPPYYVEGVTVFRITYGETGGNSPVQEFTVP

YWTETATISGLKPGVDYTITVYAEMYPGSPWAGQVMDIQPISINYR

TEGSGSATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQSRH

VEVRMACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEIS

ALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCESNGNHYDIVY

PIKYKESSAMCQSLLYELLYEKVEKTDVSKIVMELDTLEVADE

CFP-P2A-anti-
418
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

WDR5 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

binder-Cezanne

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVVHYVITYGETGGNSPVQKFKVPGSKSTATI

SGLKPGVDYTITVYAYQGGGRWHPYGYYSPISINYRTPPSFSEGSG

GSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSSIV

SLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSFIER

DLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCLLHAA

SLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQQNKES

GLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANCGGVESSEEPVY

ESLEEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIPEGGIYLP

LEVPASQCHRSPLVLAYDQAHESALVSMEQKENTKEQAVIPLTDSE

YKLLPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEVKLHLLHSYM

NVKWIPLSSDAQAPLAQ

CFP-P2A-anti-
419
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

WDR5 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-OTUD1

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVVHYVITYGETGGNSPVQKFKVPGSKSTATI

SGLKPGVDYTITVYAYQGGGRWHPYGYYSPISINYRTDEKLALYLA

EVEKQDKYLRQRNKYRFHIIPDGNCLYRAVSKTVYGDQSLHRELRE

QTVHYIADHLDHFSPLIEGDVGEFIIAAAQDGAWAGYPELLAMGQM

LNVNIHLTTGGRLESPTVSTMIHYLGPEDSLRPSIWLSWLSNGHYD

AVFDHSYPNPEYDNWCKQTQVQRKRDEELAKSMAISLSKMYIEQNA

CS

CFP-P2A-anti-
420
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

WDR5 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

TRABID

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVVHYVITYGETGGNSPVQKFKVPGSKSTATI

SGLKPGVDYTITVYAYQGGGRWHPYGYYSPISINYRTLEVDFKKLK

QIKNRMKKTDWLFLNACVGVVEGDLAAIEAYKSSGGDIARQLTADE

VRLLNRPSAFDVGYTLVHLAIRFQRQDMLAILLTEVSQQAAKCIPA

MVCPELTEQIRREIAASLHQRKGDFACYFLTDLVTFTLPADIEDLP

PTVQEKLFDEVLDRDVQKELEEESPIINWSLELATRLDSRLYALWN

RTAGDCLLDSVLQATWGIYDKDSVLRKALHDSLHDCSHWFYTRWKD

WESWYSQSFGLHESLREEQWQEDWAFILSLASQPGASLEQTHIFVL

AHILRRPIIVYGVKYYKSFRGETLGYTRFQGVYLPLLWEQSFCWKS

PIALGYTRGHFSALVAMENDGYGNRGAGANLNTDDDVTITELPLVD

SERKLLHVHELSAQELGNEEQQEKLLREWLDCCVTEGGVLVAMQKS

SRRRNHPLVTQMVEKWLDRYRQIRPCTSLS

CFP-P2A-anti-
421
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

WDR5 targeting

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDEFKSAMPEG

binder-USP21

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVVHYVITYGETGGNSPVQKFKVPGSKSTATI

SGLKPGVDYTITVYAYQGGGRWHPYGYYSPISINYRTSDDKMAHHT

LLLGSGHVGLRNLGNTCFLNAVLQCLSSTRPLRDFCLRRDERQEVP

GGGRAQELTEAFADVIGALWHPDSCEAVNPTRFRAVFQKYVPSFSG

YSQQDAQEFLKLLMERLHLEINRRGRRAPPILANGPVPSPPRRGGA

LLEEPELSDDDRANLMWKRYLEREDSKIVDLFVGQLKSCLKCQACG

YRSTTFEVFCDLSLPIPKKGFAGGKVSLRDCENLFTKEEELESENA

PVCDRCRQKTRSTKKLTVQRFPRILVLHLNRFSASRGSIKKSSVGV

DFPLQRLSLGDFASDKAGSPVYQLYALCNHSGSVHYGHYTALCRCQ

TGWHVYNDSRVSPVSENQVASSEGYVLFYQLMQEPPRCL

CFP-P2A-anti-
422
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

WDR5 targeting

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

binder-OTUD4

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPGSVSSVPTKLEVVAA

TPTSLLISWDAPAVTVVHYVITYGETGGNSPVQKFKVPGSKSTATI

SGLKPGVDYTITVYAYQGGGRWHPYGYYSPISINYRTATPMDAYLR

KLGLYRKLVAKDGSCLFRAVAEQVLHSQSRHVEVRMACIHYLRENR

EKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYRE

PNVSPSQVTENNFPEKVLLCFSNGNHYDIVYPIKYKESSAMCQSLL

YELLYEKVEKTDVSKIVMELDTLEVADE

6.2 Example 2. Testing of Targeted Engineered Deubiquitinases

To demonstrate upregulation of a target protein in the context of a specific targeting enDUB the following experiments will be performed. Schematic constructs used:

- Control experiment using non-targeting enDUB fusion
  - Target-YFP-P2A-mCherrry
  - CFP-P2A-enDUB (nontargeting control enDUB)
- Test constructs for up-regulation:
  - Target-YFP-P2A-mCherry
  - CFP-P2A-a-YFPnanobody-enDUB
- Or specific targeting enDUB fusion composed of
  - CFP-P2A-anti-targeting binder-enDUB

Co-transfection of both plasmids carrying the YFP tagged target protein together with the enDUB fused to a target binding protein into HEK cells will be performed. A control construct carrying the enDUB in the absence of the targeting binder will also be co-transfected together with the labeled target protein. After 24-48 hours the transfected cells will be analyzed by FACS or upregulation over the control. The mCherry signal on the target protein will be used to normalize for transfection efficiency while the CFP signal will be used to normalize for the transfection efficiency of the enDUB constructs. The YFP fused to the target protein is the read-out for target gene expression and will be plotted vs the signal in the control transfection. Relative increase in the YFP fluorescence over control will demonstrate upregulation in the presence of the enDUB.

6.3 Example 3. Screening Assay for Testing Fusion Proteins

The following example describes an assay to analyze the ability of a targeted engineered deubiquitinase (enDub) (e.g., an enDub described herein) to increase expression of a target protein. Generally, the assay involves tagging the target protein with a fluorescent tag (e.g., NanoLuciferase (NLuc)) and an alfa-tag (a-Tag); and tagging a fusion protein of the enDub and an anti-alfa Tag nanobody with a different fluorescent tag (e.g., Firefly Luciferase (FLuc)) through a cleavable linker. The use of two different fluorescent tags enables normalization of the signal to compensate for variation in transfection/expression, as the second fluorescent tag is rapidly cleaved from the enDub-anti-alfa tag fusion protein inside the cell through cleavage of the cleavable linker. FIG. 2 provides a general schematic of the cellular aspects of the assay. The protocol, including materials and methods is described below.

CHO-K1 cells were digested with 0.25% (w/v) Trypsin-EDTA, at 37° C., for 5 min. Complete medium was added for the CHO-K1 cell cultures to stop the digestion. The CHO-K1 cells were centrifuges at 800 rpm for 5 minutes. After centrifugation, the supernatant was discarded and the CHO-K1 cells were resuspend in 2 mL culture medium and counted. 10{circumflex over ( )}6 CHO-K1 cells were electroporated under 440V with 0.5 ug of a plasmid encoding the target protein tagged with NLuc and alfa-tag, and 1 ug of a plasmid encoding a) enDub-anti-alfa tag nanobody-FLuc fusion protein (experimental), b) the enDub (control), or the anti-alfa tag nanobody (control). 5E+4 cells/well were placed in in 24 well plates and cultured for 24 h, at 37° C., 5% CO₂. The cells were digested with 0.25% (w/v) Trypsin-EDTA, at 37° C. for 5 min. Complete medium was added to the culture to stop the digestion and the cells were counted for use in NanoGlo® Dual Luciferase® Assay (Promega), which enables detection of FLuc and NLuc® in a single sample. The NanoGlo® Dual Luciferase® Assay was carried out according to manufacturer's instructions (Promega, Nano-Glo® Dual-Luciferase® Reporter Assay Technical Manual #TM426). Briefly, 1E+4 cells/well were placed in 96 well black plates and cultured for 24 h, at 37° C., 5% CO₂. The plates were removed from the incubator and allowed to equilibrate to room temperature. The samples were modified as needed to have a starting volume of 80 μl per well. All sample wells were injected with 80 μl of ONE-Glo™ EX Reagent and incubated for 3 minutes. The firefly luminescence was read in all sample wells using a 1-second integration time. All sample wells were injected with 80 μl of NanoDLR™ Stop & Glo® Reagent; and incubated for 5 minutes. The NanoLuc® luminescence of all sample wells was read using a 1-second integration time. The dispensing lines were cleaned according to manufacturer's instructions (Nano-Glo® Dual-Luciferase® Reporter Assay Technical Manual #TM426.) and the data analyzed.

The amino acid sequence of the components of the fusion proteins used in the assay are detailed in Table 7 below.

TABLE 7

Amino acid sequence of components of test fusion proteins

Description
SEQ ID NO
Amino Acid Sequence

Fluorescent
NanoLuc
437
VFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQ

Protein

NLGVSVTPIQRIVLSGENGLKIDIHVIIPYEGL

SGDQMGQIEKIFKVVYPVDDHHFKVILHYGTLV

IDGVTPNMIDYFGRPYEGIAVEDGKKITVTGTL

WNGNKIIDERLINPDGSLLFRVTINGVTGWRLC

ERILA

Firefly
438
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRY

Luciferase

ALVPGTIAFTDAHIEVDITYAEYFEMSVRLAEA

MKRYGLNTNHRIVVCSENSLQFFMPVLGALFIG

VAVAPANDIYNERELLNSMGISQPTVVFVSKKG

LQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMY

TFVTSHLPPGENEYDFVPESEDRDKTIALIMNS

SGSTGLPKGVALPHRTACVRESHARDPIFGNQI

IPDTAILSVVPFHHGFGMFTTLGYLICGERVVL

MYRFEEELFLRSLQDYKIQSALLVPTLESFFAK

STLIDKYDLSNLHEIASGGAPLSKEVGEAVAKR

FHLPGIRQGYGLTETTSAILITPEGDDKPGAVG

KVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPM

IMSGYVNNPEATNALIDKDGWLHSGDIAYWDED

EHFFIVDRLKSLIKYKGYQVAPAELESILLQHP

NIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTG

KLDARKIREILIKAKKGGKIAVTRLK

Alfa Tag
439
PSRLEEELRRRLTEP

P2A
440
GSGATNFSLLKQAGDVEENPGP

Cezanne

441
PPSFSEGSGGSRTPEKGFSDREPTRPPRPILQR

(Exemplary

QDDIVQEKRLSRGISHASSSIVSLARSHVSSNG

Catalytic Domain)

GGGGSNEHPLEMPICAFQLPDLTVYNEDERSFI

ERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLL

PLATTGDGNCLLHAASLGMWGFHDRDLMLRKAL

YALMEKGVEKEALKRRWRWQQTQQNKESGLVYT

EDEWQKEWNELIKLASSEPRMHLGTNGANCGGV

ESSEEPVYESLEEFHVFVLAHVLRRPIVVVADT

MLRDSGGEAFAPIPEGGIYLPLEVPASQCHRSP

LVLAYDQAHFSALVSMEQKENTKEQAVIPLTDS

EYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVI

LSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

The amino acid sequence of exemplary target fusion proteins comprising a target protein, NLuc, and the alfa tag are detailed in Table 8 below.

TABLE 8

Amino Acid Sequence of exemplary Target Protein-NLuc-Alfa Tag Fusion Proteins

Test Protein
SEQ ID NO
Amino Acid Sequence

SETD5-nanoluc-
442
MSIAIPLGVTTSDTSYSDMAAGSDPESVEASPAVNEKSVYSTHNY

alfa-tag-fusion

GTTQRHGCRGLPYATIIPRSDLNGLPSPVEERCGDSPNSEGETVP

TWCPCGLSQDGFLLNCDKCRGMSRGKVIRLHRRKQDNISGGDSSA

TESWDEELSPSTVLYTATQHTPTSITLTVRRTKPKKRKKSPEKGR

AAPKTKKIKNSPSEAQNLDENTTEGWENRIRLWTDQYEEAFTNQY

SADVQNALEQHLHSSKEFVGKPTILDTINKTELACNNTVIGSQMQ

LQLGRVTRVQKHRKILRAARDLALDTLIIEYRGKVMLRQQFEVNG

HFFKKPYPFVLFYSKENGVEMCVDARTEGNDARFIRRSCTPNAEV

RHMIADGMIHLCIYAVSAITKDAEVTIAFDYEYSNCNYKVDCACH

KGNRNCPIQKRNPNATELPLLPPPPSLPTIGAETRRRKARRKELE

MEQQNEASEENNDQQSQEVPEKVTVSSDHEEVDNPEEKPEEEKEE

VIDDQENLAHSRRTREDRKVEAIMHAFENLEKRKKRRDQPLEQSN

SDVEITTTTSETPVGEETKTEAPESEVSNSVSNVTIPSTPQSVGV

NTRRSSQAGDIAAEKLVPKPPPAKPSRPRPKSRISRYRTSSAQRL

KRQKQANAQQAELSQAALEEGGSNSLVTPTEAGSLDSSGENRPLT

GSDPTVVSITGSHVNRAASKYPKTKKYLVTEWLNDKAEKQECPVE

CPLRITTDPTVLATTLNMLPGLIHSPLICTTPKHYIRFGSPFIPE

RRRRPLLPDGTESSCKKRWIKQALEEGMTQTSSVPQETRTQHLYQ

SNENSSSSSICKDNADLLSPLKKWKSRYLMEQNVTKLLRPLSPVT

PPPPNSGSKSPQLATPGSSHPGEEECRNGYSLMFSPVTSLTTASR

CNTPLQFELCHRKDLDLAKVGYLDSNTNSCADRPSLLNSGHSDLA

PHPSLGPTSETGFPSRSGDGHQTLVRNSDQAFRTEENLMYAYSPL

NAMPRADGLYRGSPLVGDRKPLHLDGGYCSPAEGFSSRYEHGLMK

DLSRGSLSPGGERACEGVPSAPQNPPQRKKVSLLEYRKRKQEAKE

NSAGGGGDSAQSKSKSAGAGQGSSNSVSDTGAHGVQGSSARTPSS

PHKKESPSHSSMSHLEAVSPSDSRGTSSSHCRPQENISSRWMVPT

SVERLREGGSIPKVLRSSVRVAQKGEPSPTWESNITEKDSDPADG

EGPETLSSALSKGATVYSPSRYSYQLLQCDSPRTESQSLLQQSSS

PFRGHPTQSPGYSYRTTALRPGNPPSHGSSESSLSSTSYSSPAHP

VSTDSLAPFTGTPGYFSSQPHSGNSTGSNLPRRSCPSSAASPTLQ

GPSDSPTSDSVSQSSTGTLSSTSFPQNSRSSLPSDLRTISLPSAG

QSAVYQASRVSAVSNSQHYPHRGSGGVHQYRLQPLQGSGVKTQTG

LSKVPVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNLGVSVT

PIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQIEKIFKVVYPVD

DHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVEDGKKITVTG

TLWNGNKIIDERLINPDGSLLFRVTINGVTGWRLCERILAGGGGS

PSRLEEELRRRLTEP

RAI1-nanoluc-
443
MQSFRERCGFHGKQQNYQQTSQETSRLENYRQPSQAGLSCDRQRL

alfa-

LAKDYYNPQPYPSYEGGAGTPSGTAAAVAADKYHRGSKALPTQQG

tag-fusion

LQGRPAFPGYGVQDSSPYPGRYAGEESLQAWGAPQPPPPQPQPLP

AGVAKYDENLMKKTAVPPSRQYAEQGAQVPFRTHSLHVQQPPPPQ

QPLAYPKLQRQKLQNDIASPLPFPQGTHEPQHSQSFPTSSTYSSS

VQGGGQGAHSYKSCTAPTAQPHDRPLTASSSLAPGQRVQNLHAYQ

SGRLSYDQQQQQQQQQQQQQQALQSRHHAQETLHYQNLAKYQHYG

QQGQGYCQPDAAVRTPEQYYQTFSPSSSHSPARSVGRSPSYSSTP

SPLMPNLENFPYSQQPLSTGAFPAGITDHSHEMPLLNPSPTDATS

SVDTQAGNCKPLQKDKLPENLLSDLSLQSLTALTSQVENISNTVQ

QLLLSKAAVPQKKGVKNLVSRTPEQHKSQHCSPEGSGYSAEPAGT

PLSEPPSSTPQSTHAEPQEADYLSGSEDPLERSFLYCNQARGSPA

RVNSNSKAKPESVSTCSVTSPDDMSTKSDDSFQSLHGSLPLDSFS

KFVAGERDCPRLLLSALAQEDLASEILGLQEAIGEKADKAWAEAP

SLVKDSSKPPFSLENHSACLDSVAKSAWPRPGEPEALPDSLQLDK

GGNAKDESPGLFEDPSVAFATPDPKKTTGPLSFGTKPTLGVPAPD

PTTAAFDCFPDTTAASSADSANPFAWPEENLGDACPRWGLHPGEL

TKGLEQGGKASDGISKGDTHEASACLGFQEEDPPGEKVASLPGDE

KQEEVGGVKEEAGGLLQCPEVAKADRWLEDSRHCCSTADFGDLPL

LPPTSRKEDLEAEEEYSSLCELLGSPEQRPGMQDPLSPKAPLICT

KEEVEEVLDSKAGWGSPCHLSGESVILLGPTVGTESKVQSWFESS

LSHMKPGEEGPDGERAPGDSTTSDASLAQKPNKPAVPEAPIAKKE

PVPRGKSLRSRRVHRGLPEAEDSPCRAPVLPKDLLLPESCTGPPQ

GQMEGAGAPGRGASEGLPRMCTRSLTALSEPRTPGPPGLTTTPAP

PDKLGGKQRAAFKSGKRVGKPSPKAASSPSNPAALPVASDSSPMG

SKTKETDSPSTPGKDQRSMILRSRTKTQEIFHSKRRRPSEGRLPN

CRATKKLLDNSHLPATFKVSSSPQKEGRVSQRARVPKPGAGSKLS

DRPLHALKRKSAFMAPVPTKKRNLVLRSRSSSSSNASGNGGDGKE

ERPEGSPTLFKRMSSPKKAKPTKGNGEPATKLPPPETPDACLKLA

SRAAFQGAMKTKVLPPRKGRGLKLEAIVQKITSPSLKKFACKAPG

ASPGNPLSPSLSDKDRGLKGAGGSPVGVEEGLVNVGTGQKLPTSG

ADPLCRNPTNRSLKGKLMNSKKLSSTDCFKTEAFTSPEALQPGGT

ALAPKKRSRKGRAGAHGLSKGPLEKRPYLGPALLLTPRDRASGTQ

GASEDNSGGGGKKPKMEELGLASQPPEGRPCQPQTRAQKQPGHTN

YSSYSKRKRLTRGRAKNTTSSPCKGRAKRRRQQQVLPLDPAEPEI

RLKYISSCKRLRSDSRTPAFSPFVRVEKRDAFTTICTVVNSPGDA

PKPHRKPSSSASSSSSSSSESLDAAGASLATLPGGSILQPRPSLP

LSSTMHLGPVVSKALSTSCLVCCLCQNPANFKDLGDLCGPYYPEH

CLPKKKPKLKEKVRPEGTCEEASLPLERTLKGPECAAAATAGKPP

RPDGPADPAKQGPLRTSARGLSRRLQSCYCCDGREDGGEEAAPAD

KGRKHECSKEAPAEPGGEAQEHWVHEACAVWTGGVYLVAGKLFGL

QEAMKVAVDMMCSSCQEAGATIGCCHKGCLHTYHYPCASDAGCIF

IEENFSLKCPKHKRLPKVPVFTLEDFVGDWRQTAGYNLDQVLEQG

GVSSLFQNLGVSVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQM

GQIEKIFKVVYPVDDHHFKVILHYGTLVIDGVTPNMIDYEGRPYE

GIAVFDGKKITVTGTLWNGNKIIDERLINPDGSLLERVTINGVTG

WRLCERILAGGGGSPSRLEEELRRRLTEP

MECP2-nanoluc-
444
MVAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKEEKEGKHEP

alfa-tag-fusion

VQPSAHHSAEPAEAGKAETSEGSGSAPAVPEASASPKQRRSIIRD

RGPMYDDPTLPEGWTRKLKQRKSGRSAGKYDVYLINPQGKAFRSK

VELIAYFEKVGDTSLDPNDFDFTVTGRGSPSRREQKPPKKPKSPK

APGTGRGRGRPKGSGTTRPKAATSEGVQVKRVLEKSPGKLLVKMP

FQTSPGGKAEGGGATTSTQVMVIKRPGRKRKAEADPQAIPKKRGR

KPGSVVAAAAAEAKKKAVKESSIRSVQETVLPIKKRKTRETVSIE

VKEVVKPLLVSTLGEKSGKGLKTCKSPGRKSKESSPKGRSSSASS

PPKKEHHHHHHHSESPKAPVPLLPPLPPPPPEPESSEDPTSPPEP

QDLSSSVCKEEKMPRGGSLESDGCPKEPAKTQPAVATAATAAEKY

KHRGEGERKDIVSSSMPRPNREEPVDSRTPVTERVSKVPVFTLED

FVGDWRQTAGYNLDQVLEQGGVSSLFQNLGVSVTPIQRIVLSGEN

GLKIDIHVIIPYEGLSGDQMGQIEKIFKVVYPVDDHHFKVILHYG

TLVIDGVTPNMIDYFGRPYEGIAVEDGKKITVTGTLWNGNKIIDE

RLINPDGSLLFRVTINGVTGWRLCERILAGGGGSPSRLEEELRRR

LTEP

CHD2-nanoluc-
445
MMRNKDKSQEEDSSLHSNASSHSASEEASGSDSGSQSESEQGSDP

alfa-tag-fusion

GSGHGSESNSSSESSESQSESESESAGSKSQPVLPEAKEKPASKK

ERIADVKKMWEEYPDVYGVRRSNRSRQEPSRENIKEEASSGSESG

SPKRRGQRQLKKQEKWKQEPSEDEQEQGTSAESEPEQKKVKARRP

VPRRTVPKPRVKKQPKTQRGKRKKQDSSDEDDDDDEAPKRQTRRR

AAKNVSYKEDDDFETDSDDLIEMTGEGVDEQQDNSETIEKVLDSR

LGKKGATGASTTVYAIEANGDPSGDEDTEKDEGEIQYLIKWKGWS

YIHSTWESEESLQQQKVKGLKKLENFKKKEDEIKQWLGKVSPEDV

EYFNCQQELASELNKQYQIVERVIAVKTSKSTLGQTDFPAHSRKP

APSNEPEYLCKWMGLPYSECSWEDEALIGKKFQNCIDSFHSRNNS

KTIPTRECKALKQRPRFVALKKQPAYLGGENLELRDYQLEGLNWL

AHSWCKNNSVILADEMGLGKTIQTISFLSYLFHQHQLYGPFLIVV

PLSTLTSWQREFEIWAPEINVVVYIGDLMSRNTIREYEWIHSQTK

RLKFNALITTYEILLKDKTVLGSINWAFLGVDEAHRLKNDDSLLY

KTLIDFKSNHRLLITGTPLQNSLKELWSLLHFIMPEKFEFWEDFE

EDHGKGRENGYQSLHKVLEPFLLRRVKKDVEKSLPAKVEQILRVE

MSALQKQYYKWILTRNYKALAKGTRGSTSGELNIVMELKKCCNHC

YLIKPPEENERENGQEILLSLIRSSGKLILLDKLLTRLRERGNRV

LIFSQMVRMLDILAEYLTIKHYPFQRLDGSIKGEIRKQALDHENA

DGSEDFCFLLSTRAGGLGINLASADTVVIFDSDWNPQNDLQAQAR

AHRIGQKKQVNIYRLVTKGTVEEEIIERAKKKMVLDHLVIQRMDT

TGRTILENNSGRSNSNPENKEELTAILKFGAEDLFKELEGEESEP

QEMDIDEILRLAETRENEVSTSATDELLSQFKVANFATMEDEEEL

EERPHKDWDEIIPEEQRKKVEEEERQKELEEIYMLPRIRSSTKKA

QTNDSDSDTESKRQAQRSSASESETEDSDDDKKPKRRGRPRSVRK

DLVEGETDAEIRRFIKAYKKEGLPLERLECIARDAELVDKSVADL

KRLGELIHNSCVSAMQEYEEQLKENASEGKGPGKRRGPTIKISGV

QVNVKSIIQHEEEFEMLHKSIPVDPEEKKKYCLTCRVKAAHEDVE

WGVEDDSRLLLGIYEHGYGNWELIKTDPELKLTDKILPVETDKKP

QGKQLQTRADYLLKLLRKGLEKKGAVTGGEEAKLKKRKPRVKKEN

KVPRLKEEHGIELSSPRHSDNPSEEGEVKDDGLEKSPMKKKQKKK

ENKENKEKQMSSRKDKEGDKERKKSKDKKEKPKSGDAKSSSKSKR

SQGPVHITAGSEPVPIGEDEDDDLDQETESICKERMRPVKKALKQ

LDKPDKGLNVQEQLEHTRNCLLKIGDRIAECLKAYSDQEHIKLWR

RNLWIFVSKFTEFDARKLHKLYKMAHKKRSQEEEEQKKKDDVTGG

KKPFRPEASGSSRDSLISQSHTSHNLHPQKPHLPASHGPQMHGHP

RDNYNHPNKRHFSNADRGDWQRERKENYGGGNNNPPWGSDRHHQY

EQHWYKDHHYGDRRHMDAHRSGSYRPNNMSRKRPYDQYSSDRDHR

GHRDYYDRHHHDSKRRRSDEFRPQNYHQQDERRMSDHRPAMGYHG

QGPSDHYRSFHTDKLGEYKQPLPPLHPAVSDPRSPPSQKSPHDSK

SPLDHRSPLERSLEQKNNPDYNWNVRKTKVPVFTLEDFVGDWRQT

AGYNLDQVLEQGGVSSLFQNLGVSVTPIQRIVLSGENGLKIDIHV

IIPYEGLSGDQMGQIEKIFKVVYPVDDHHFKVILHYGTLVIDGVT

PNMIDYFGRPYEGIAVEDGKKITVTGTLWNGNKIIDERLINPDGS

LLFRVTINGVTGWRLCERILAGGGGSPSRLEEELRRRLTEP

SNRGP-nanoluc-
446
MSKAHPPELKKFMDKKLSLKLNGGRHVQGILRGFDPEMNLVIDEC

alfa-tag-fusion

VEMATSGQQNNIGMVDNIPNKAVSPKFLKKVNQKGQLTFSKLLSI

KTSKEWKVPVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNLG

VSVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQIEKIFKVV

YPVDDHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVEDGKKI

TVTGTLWNGNKIIDERLINPDGSLLFRVTINGVTGWRLCERILAG

GGGSPSRLEEELRRRLTEP

LSM2-nanoluc-
447
MLFYSFFKSLVGKDVVVELKNDLSICGTLHSVDQYLNIKLTDISV

alfa-tag-fusion

TDPEKYPHMLSVKNCFIRGSVVRYVQLPADEVDTQLLQDAARKEA

LQQKQKVPVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNLGV

SVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQIEKIFKVVY

PVDDHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVEDGKKIT

VTGTLWNGNKIIDERLINPDGSLLFRVTINGVTGWRLCERILAGG

GGSPSRLEEELRRRLTEP

NUPR2-nanoluc-
448
MEAPAERALPRLQALARPPPPISYEEELYDCLDYYYLRDEPACGA

alfa-tag-fusion

GRSKGRTRREQALRTNWPAPGGHERKVAQKLLNGQRKRRQRQLHP

KMRTRLTKVPVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNL

GVSVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQIEKIFKV

VYPVDDHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVEDGKK

ITVTGTLWNGNKIIDERLINPDGSLLFRVTINGVTGWRLCERILA

GGGGSPSRLEEELRRRLTEP

The amino acid sequence of exemplary fusion proteins comprising a control or a targeted engineered deubiquitinase are detailed in Table 9 below.

TABLE 9

Amino Acid Sequence of exemplary enDub Control and Screening Fusion Proteins

Description
SEQ ID NO
Amino Acid Sequence

FireflyLuciferase-
449
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDA

P2A-nano

HIEVDITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFM

(Control)

PVLGALFIGVAVAPANDIYNERELLNSMGISQPTVVFVSKKGLQK

ILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGENEYD

FVPESFDRDKTIALIMNSSGSTGLPKGVALPHRTACVRESHARDP

IFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEE

ELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASG

GAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPG

AVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNP

EATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVA

PAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILI

KAKKGGKIAVTRLKGSGATNFSLLKQAGDVEENPGPRSGTGSSGE

VQLQESGGGLVQPGGSLRLSCTASGVTISALNAMAMGWYRQAPGE

RRVMVAAVSERGNAMYRESVQGRFTVTRDFTNKMVSLQMDNLKPE

DTAVYYCHVLEDRVDSFHDYWGQGTQVTVSS

FireflyLuciferase-
450
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDA

P2A-Cezanne

HIEVDITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFM

(Control)

PVLGALFIGVAVAPANDIYNERELLNSMGISQPTVVFVSKKGLQK

ILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGENEYD

FVPESEDRDKTIALIMNSSGSTGLPKGVALPHRTACVRESHARDP

IFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEE

ELFLRSLQDYKIQSALLVPTLESFFAKSTLIDKYDLSNLHEIASG

GAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPG

AVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNP

EATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVA

PAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILI

KAKKGGKIAVTRLKGSGATNFSLLKQAGDVEENPGPRSGTGSPPS

FSEGSGGSRTPEKGESDREPTRPPRPILQRQDDIVQEKRLSRGIS

HASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNE

DERSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTG

DGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWR

WQQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANC

GGVESSEEPVYESLEEFHVEVLAHVLRRPIVVVADTMLRDSGGEA

FAPIPFGGIYLPLEVPASQCHRSPLVLAYDQAHESALVSMEQKEN

TKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVI

LSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

FireflyLuciferase-
451
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDA

P2A-

HIEVDITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFM

a_alfatag_nano-

PVLGALFIGVAVAPANDIYNERELLNSMGISQPTVVFVSKKGLQK

Cezanne

ILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGENEYD

FVPESEDRDKTIALIMNSSGSTGLPKGVALPHRTACVRESHARDP

IFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEE

ELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASG

GAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPG

AVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNP

EATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVA

PAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILI

KAKKGGKIAVTRLKGSGATNFSLLKQAGDVEENPGPRSGTGSSGE

VQLQESGGGLVQPGGSLRLSCTASGVTISALNAMAMGWYRQAPGE

RRVMVAAVSERGNAMYRESVQGRFTVTRDFTNKMVSLQMDNLKPE

DTAVYYCHVLEDRVDSFHDYWGQGTQVTVSSGAPGSGPPSFSEGS

GGSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSS

IVSLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSE

IERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCL

LHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQ

QNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANCGGVES

SEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIP

FGGIYLPLEVPASQCHRSPLVLAYDQAHFSALVSMEQKENTKEQA

VIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEV

KLHLLHSYMNVKWIPLSSDAQAPLAQ

The assay was conducted with utilizing the tagged proteins and targeted enDubs described above in Tables 7 and 8. The results of the SNRPG targeting are shown in FIG. 3, showing a 2.37-fold increase in SNRPG protein expression. The results of the LSM2 targeting are shown in FIG. 4, showing a 1.87-fold increase in LSM2 protein expression. The results of the NUPR2 targeting are shown in FIG. 5, showing a 1.13-fold increase in NURP2 protein expression. The control used for the SNRPG, LSM2, and NUPR2 experiments is the engineered deubiquitinase without the nanobody targeting the alfa-tag. Normalization of transduction efficiency was performed using the firefly luciferase signal as the reference and the ratio between NLuc signal divided by firefly luciferase signal plotted on the y axes.

The invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entireties and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

NUCLEAR PROTEIN TARGETING DEUBIQUITINASES AND METHODS OF USE

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