MITOCHONDRIAL PROTEIN TARGETING ENGINEERED DEUBIQUITINASES AND METHODS OF USE THEREOF

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 mitochondrial 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 mitochondrial protein or a decrease in the stability of a mitochondrial 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 mitochondrial protein expression or stability.

3. SUMMARY

Provided herein are, inter alia, engineered deubiquitinases (enDubs) that comprise a targeting moiety that specifically binds a mitochondrial target protein and a catalytic domain of a deubiquitinase. The targeting moiety directs that deubiquitinase catalytic domain to the specific target mitochondrial 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 mitochondrial 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 mitochondrial 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 mitochondrial 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, or a (VHH)₂. In some embodiments, the antibody, or functional fragment or functional variant thereof, comprises a VHH or a (VHH)₂.

In some embodiments, the mitochondrial protein is dynamin-like 120 kDa protein (OPA1), protoporphyrinogen oxidase (PPOX), frataxin (FXN), DNA polymerase subunit gamma-1 (POLG), cytochrome c oxidase subunit 6A2, mitochondrial (COX6A2), ubiquinol-cytochrome-c reductase complex assembly factor 2 (UQCC2), or complex III assembly factor LYRM7 (LYRM7).

In some embodiments, the mitochondrial protein is dynamin-like 120 kDa protein (OPA1), protoporphyrinogen oxidase (PPOX), frataxin (FXN), or DNA polymerase subunit gamma-1 (POLG).

In some embodiments, the mitochondrial protein is cytochrome c oxidase subunit 6A2, mitochondrial (COX6A2), ubiquinol-cytochrome-c reductase complex assembly factor 2 (UQCC2), or complex III assembly factor LYRM7 (LYRM7).

In some embodiments, the mitochondrial 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: 221-224 or 271-273.

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 operably connected 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: 279-406, or the amino acid sequence of any one of SEQ ID NOS: 279-406 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: 279-288, or the amino acid sequence of any one of SEQ ID NOS: 279-288 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 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 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 of the nuclear 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.

In some embodiments, the disease is selected from the group consisting of optic atrophy 1, Porphyria variegata, Friedreich's Ataxia, Alpers Syndrome mitochondrial complex IV deficiency nuclear type 18 (MC4DN18), mitochondrial complex III deficiency nuclear 7 (MC3DN7), mitochondrial complex III deficiency nuclear 8 (MC3DN8).

In some embodiments, the target mitochondrial protein is OPA1, and the disease is Optic atrophy 1; the target mitochondrial protein is PPOX, and the disease is Porphyria variegata; the target mitochondrial protein is FXN, and the disease is Friedreich's Ataxia; the target mitochondrial protein is POLG, and the disease is Alpers Syndrome; the target mitochondrial protein is COX6A2, and the disease is mitochondrial complex IV deficiency nuclear type 18 (MC4DN18); the target mitochondrial protein is UQCC2, and the disease is mitochondrial complex III deficiency nuclear 7 (MC3DN7); or the target mitochondrial protein is LYRM7, and the disease is mitochondrial complex III deficiency nuclear 8 (MC3DN8).

In some embodiments, the disease is a haploinsufficiency disease.

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 mitochondrial 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 mitochondrial 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 mitochondrial protein is selected from the group consisting of dynamin-like 120 kDa protein (OPA1), protoporphyrinogen oxidase (PPOX), frataxin (FXN), and DNA polymerase subunit gamma-1 (POLG).

In some embodiments, the mitochondrial 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: 221-224.

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 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.

In some embodiments, the disease is optic atrophy 1, Porphyria variegata, Friedreich's Ataxia, and Alpers Syndrome.

In some embodiments, the disease is a haploinsufficiency disease.

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

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 mitochondrial 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 mitochondrial target protein and a VHH that specifically binds a mitochondrial 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 mitochondrial 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 mitochondrial target protein and a VHH that specifically binds a mitochondrial 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 mitochondrial proteins on target protein expression.

FIG. 3 is a bar graph depicting the fold change in COX6A2 protein expression relative to control (deubiquitinase without the nanobody targeting the alfa-tag).

FIG. 4 is a bar graph depicting the fold change in UQCC2 protein expression relative to control (deubiquitinase without the nanobody targeting the alfa-tag).

FIG. 5 is a bar graph depicting the fold change in LYRM7 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 mitochondrial protein or the stability of the mitochondrial 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 mitochondrial protein. In some embodiments, decreased expression of a functional version of the target mitochondrial protein or decreased stability of a functional version of the target mitochondrial 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 mitochondrial protein or the stability of the target mitochondrial protein. Upon expression of the fusion protein by host cells, the catalytic domain of the deubiquitinase will be specifically targeted to the target mitochondrial protein and deubiquitinated, resulting in increased expression of the target mitochondrial 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 Systéme 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: 270 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: 270.

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

ID

ID
Domains (Amino

Description
NO
Amino Acid Sequence
NO
Acid Sequence)

UBP27_HUMAN
1
MCKDYVYDKDIEQIAKEEQGEA
113
SSFTIGLRGLINLGNTCEMN

Ubiquitin

LKLQASTSTEVSHQQCSVPGLG

CIVQALTHTPILRDFFLSDR

carboxyl-

EKFPTWETTKPELELLGHNPRR

HRCEMPSPELCLVCEMSSLF

terminal

RRITSSFTIGLRGLINLGNTCF

RELYSGNPSPHVPYKLLHLV

hydrolase

MNCIVQALTHTPILRDFFLSDR

WIHARHLAGYRQQDAHEFLI

27

HRCEMPSPELCLVCEMSSLFRE

AALDVLHRHCKGDDVGKAAN

LYSGNPSPHVPYKLLHLVWIHA

NPNHCNCIIDQIFTGGLQSD

RHLAGYRQQDAHEFLIAALDVL

VTCQACHGVSTTIDPCWDIS

HRHCKGDDVGKAANNPNHCNCI

LDLPGSCTSFWPMSPGRESS

IDQIFTGGLQSDVTCQACHGVS

VNGESHIPGITTLTDCLRRF

TTIDPCWDISLDLPGSCTSFWP

TRPEHLGSSAKIKCGSCQSY

MSPGRESSVNGESHIPGITTLT

QESTKQLTMNKLPVVACFHF

DCLRRFTRPEHLGSSAKIKCGS

KRFEHSAKQRRKITTYISFP

CQSYQESTKQLTMNKLPVVACF

LELDMTPFMASSKESRMNGQ

HFKRFEHSAKQRRKITTYISFP

LQLPTNSGNNENKYSLFAVV

LELDMTPFMASSKESRMNGQLQ

NHQGTLESGHYTSFIRHHKD

LPTNSGNNENKYSLFAVVNHQG

QWFKCDDAVITKASIKDVLD

TLESGHYTSFIRHHKDQWFKCD

SEGYLLFYHKQVLEHESEKV

DAVITKASIKDVLDSEGYLLFY

KEMNTQAY

HKQVLEHESEKVKEMNTQAY

UBP48_HUMAN
2
MAPRLQLEKAAWRWAETVRPEE
114
NSFHNIDDPNCERRKKNSFV

Ubiquitin

VSQEHIETAYRIWLEPCIRGVC

GLTNLGATCYVNTFLQVWFL

carboxyl-

RRNCKGNPNCLVGIGEHIWLGE

NLELRQALYLCPSTCSDYML

terminal

IDENSFHNIDDPNCERRKKNSF

GDGIQEEKDYEPQTICEHLQ

hydrolase

VGLTNLGATCYVNTFLQVWFLN

YLFALLQNSNRRYIDPSGFV

48

LELRQALYLCPSTCSDYMLGDG

KALGLDTGQQQDAQEFSKLF

IQEEKDYEPQTICEHLQYLFAL

MSLLEDTLSKQKNPDVRNIV

LQNSNRRYIDPSGFVKALGLDT

QQQFCGEYAYVTVCNQCGRE

GQQQDAQEFSKLFMSLLEDTLS

SKLLSKFYELELNIQGHKQL

KQKNPDVRNIVQQQFCGEYAYV

TDCISEFLKEEKLEGDNRYF

TVCNQCGRESKLLSKFYELELN

CENCQSKQNATRKIRLLSLP

IQGHKQLTDCISEFLKEEKLEG

CTLNLQLMRFVFDRQTGHKK

DNRYFCENCQSKQNATRKIRLL

KLNTYIGFSEILDMEPYVEH

SLPCTLNLQLMRFVFDRQTGHK

KGGSYVYELSAVLIHRGVSA

KKLNTYIGFSEILDMEPYVEHK

YSGHYIAHVKDPQSGEWYKF

GGSYVYELSAVLIHRGVSAYSG

NDEDIEKMEGKKLQLGIEED

HYIAHVKDPQSGEWYKFNDEDI

LAEPSKSQTRKPKCGKGTHC

EKMEGKKLQLGIEEDLAEPSKS

SRNAYMLVYRLQT

QTRKPKCGKGTHCSRNAYMLVY

RLQTQEKPNTTVQVPAFLQELV

DRDNSKFEEWCIEMAEMRKQSV

DKGKAKHEEVKELYQRLPAGAE

PYEFVSLEWLQKWLDESTPTKP

IDNHACLCSHDKLHPDKISIMK

RISEYAADIFYSRYGGGPRLTV

KALCKECVVERCRILRLKNQLN

EDYKTVNNLLKAAVKGSDGFWV

GKSSLRSWRQLALEQLDEQDGD

AEQSNGKMNGSTLNKDESKEER

KEEEELNFNEDILCPHGELCIS

ENERRLVSKEAWSKLQQYFPKA

PEFPSYKECCSQCKILEREGEE

NEALHKMIANEQKTSLPNLFQD

KNRPCLSNWPEDTDVLYIVSQF

FVEEWRKFVRKPTRCSPVSSVG

NSALLCPHGGLMFTFASMTKED

SKLIALIWPSEWQMIQKLFVVD

HVIKITRIEVGDVNPSETQYIS

EPKLCPECREGLLCQQQRDLRE

YTQATIYVHKVVDNKKVMKDSA

PELNVSSSETEEDKEEAKPDGE

KDPDFNQSNGGTKRQKISHQNY

IAYQKQVIRRSMRHRKVRGEKA

LLVSANQTLKELKIQIMHAFSV

APFDQNLSIDGKILSDDCATLG

TLGVIPESVILLKADEPIADYA

AMDDVMQVCMPEEGFKGTGLLG

H

UBP3_HUMAN
3
MECPHLSSSVCIAPDSAKFPNG
115
TAICATGLRNLGNTCFMNAI

Ubiquitin

SPSSWCCSVCRSNKSPWVCLTC

LQSLSNIEQFCCYFKELPAV

carboxyl-

SSVHCGRYVNGHAKKHYEDAQV

ELRNGKTAGRRTYHTRSQGD

terminal

PLTNHKKSEKQDKVQHTVCMDC

NNVSLVEEFRKTLCALWQGS

hydrolase

SSYSTYCYRCDDFVVNDTKLGL

QTAFSPESLFYVVWKIMPNF

3

VQKVREHLQNLENSAFTADRHK

RGYQQQDAHEFMRYLLDHLH

KRKLLENSTLNSKLLKVNGSTT

LELQGGFNGVSRSAILQENS

AICATGLRNLGNTCFMNAILQS

TLSASNKCCINGASTVVTAI

LSNIEQFCCYFKELPAVELRNG

FGGILQNEVNCLICGTESRK

KTAGRRTYHTRSQGDNNVSLVE

FDPFLDLSLDIPSQFRSKRS

EFRKTLCALWQGSQTAFSPESL

KNQENGPVCSLRDCLRSFTD

FYVVWKIMPNFRGYQQQDAHEF

LEELDETELYMCHKCKKKQK

MRYLLDHLHLELQGGFNGVSRS

STKKFWIQKLPKVLCLHLKR

AILQENSTLSASNKCCINGAST

FHWTAYLRNKVDTYVEFPLR

VVTAIFGGILQNEVNCLICGTE

GLDMKCYLLEPENSGPESCL

SRKFDPFLDLSLDIPSQFRSKR

YDLAAVVVHHGSGVGSGHYT

SKNQENGPVCSLRDCLRSFTDL

AYATHEGRWFHFNDSTVTLT

EELDETELYMCHKCKKKQKSTK

DEETVVKAKAYILFYVEHQ

KFWIQKLPKVLCLHLKRFHWTA

YLRNKVDTYVEFPLRGLDMKCY

LLEPENSGPESCLYDLAAVVVH

HGSGVGSGHYTAYATHEGRWFH

FNDSTVTLTDEETVVKAKAYIL

FYVEHQAKAGSDKL

U17LB_HUMAN
4
QLAPREKLPLSSRRPAAVGAGL
116
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

QNMGNTCYVNASLQCLTYTPPL

CLTYTPPLANYMLSREHSQT

carboxyl-

ANYMLSREHSQTCHRHKGCMLC

CHRHKGCMLCTMQAHITRAL

terminal

TMQAHITRALHNPGHVIQPSQA

HNPGHVIQPSQALAAGFHRG

hydrolase

LAAGFHRGKQEDAHEFLMFTVD

KQEDAHEFLMFTVDAMKKAC

17-like

AMKKACLPGHKQVDHHSKDTTL

LPGHKQVDHHSKDTTLIHQI

protein 11

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

VLYFCPGFKSGVKHLFNIIS

carboxyl-

NEEKASEYRASEIDQVVPAAQS

RKKEALKDEANQKDKGNCKE

terminal

SPINCEKRENLLPFVGLNNLGN

DSLASYELICSLQSLIISVE

hydrolase

TCYLNSILQVLYFCPGFKSGVK

QLQASFLLNPEKYTDELATQ

1

HLFNIISRKKEALKDEANQKDK

PRRLLNTLRELNPMYEGYLQ

GNCKEDSLASYELICSLQSLII

HDAQEVLQCILGNIQETCQL

SVEQLQASFLLNPEKYTDELAT

LKKEEVKNVAELPTKVEEIP

QPRRLLNTLRELNPMYEGYLQH

HPKEEMNGINSIEMDSMRHS

DAQEVLQCILGNIQETCQLLKK

EDFKEKLPKGNGKRKSDTEF

EEVKNVAELPTKVEEIPHPKEE

GNMKKKVKLSKEHQSLEENQ

MNGINSIEMDSMRHSEDFKEKL

RQTRSKRKATSDTLESPPKI

PKGNGKRKSDTEFGNMKKKVKL

IPKYISENESPRPSQKKSRV

SKEHQSLEENQRQTRSKRKATS

KINWLKSATKQPSILSKFCS

DTLESPPKIIPKYISENESPRP

LGKITTNQGVKGQSKENECD

SQKKSRVKINWLKSATKQPSIL

PEEDLGKCESDNTTNGCGLE

SKFCSLGKITTNQGVKGQSKEN

SPGNTVTPVNVNEVKPINKG

ECDPEEDLGKCESDNTTNGCGL

EEQIGFELVEKLFQGQLVLR

ESPGNTVTPVNVNEVKPINKGE

TRCLECESLTERREDFQDIS

EQIGFELVEKLFQGQLVLRTRC

VPVQEDELSKVEESSEISPE

LECESLTERREDFQDISVPVQE

PKTEMKTLRWAISQFASVER

DELSKVEESSEISPEPKTEMKT

IVGEDKYFCENCHHYTEAER

LRWAISQFASVERIVGEDKYFC

SLLFDKMPEVITIHLKCFAA

ENCHHYTEAERSLLFDKMPEVI

SGLEFDCYGGGLSKINTPLL

TIHLKCFAASGLEFDCYGGGLS

TPLKLSLEEWSTKPTNDSYG

KINTPLLTPLKLSLEEWSTKPT

LFAVVMHSGITISSGHYTAS

NDSYGLFAVVMHSGITISSGHY

VKVTDLNSLELDKGNFVVDQ

TASVKVTDLNSLELDKGNFVVD

MCEIGKPEPLNEEEARGVVE

QMCEIGKPEPLNEEEARGVVEN

NYNDEEVSIRVGGNTQPSKV

YNDEEVSIRVGGNTQPSKVLNK

LNKKNVEAIGLLGGQKSKAD

KNVEAIGLLGGQKSKADYELYN

YELYNKASNPDKVASTAFAE

KASNPDKVASTAFAENRNSETS

NRNSETSDTTGTHESDRNKE

DTTGTHESDRNKESSDQTGINI

SSDQTGINISGFENKISYVV

SGFENKISYVVQSLKEYEGKWL

QSLKEYEGKWLLFDDSEVKV

LFDDSEVKVTEEKDFLNSLSPS

TEEKDFLNSLSPSTSPTSTP

TSPTSTPYLLFYKKL

YLLFYKKL

UBP40_HUMAN
6
MFGDLFEEEYSTVSNNQYGKGK
118
FTNLSGIRNQGGTCYLNSLL

Ubiquitin

KLKTKALEPPAPREFTNLSGIR

QTLHFTPEFREALFSLGPEE

carboxyl-

NQGGTCYLNSLLQTLHFTPEFR

LGLFEDKDKPDAKVRIIPLQ

terminal

EALFSLGPEELGLFEDKDKPDA

LQRLFAQLLLLDQEAASTAD

hydrolase

KVRIIPLQLQRLFAQLLLLDQE

LTDSFGWTSNEEMRQHDVQE

40

AASTADLTDSFGWTSNEEMRQH

LNRILFSALETSLVGTSGHD

DVQELNRILFSALETSLVGTSG

LIYRLYHGTIVNQIVCKECK

HDLIYRLYHGTIVNQIVCKECK

NVSERQEDFLDLTVAVKNVS

NVSERQEDFLDLTVAVKNVSGL

GLEDALWNMYVEEEVFDCDN

EDALWNMYVEEEVFDCDNLYHC

LYHCGTCDRLVKAAKSAKLR

GTCDRLVKAAKSAKLRKLPPFL

KLPPFLTVSLLRFNFDFVKC

TVSLLRFNFDFVKCERYKETSC

ERYKETSCYTFPLRINLKPF

YTFPLRINLKPFCEQSELDDLE

CEQSELDDLEYIYDLFSVII

YIYDLFSVIIHKGGCYGGHYHV

HKGG

YIKDVDHLGNWQFQEEKSKPDV

CYGGHYHVYIKDVDHLGNWQ

NLKDLQSEEEIDHPLMILKAIL

FQEEKSKPDVNLKDLQSEEE

LEENNLIPVDQLGQKLLKKIGI

IDHPLMILKAILLEENNLIP

SWNKKYRKQHGPLRKFLQLHSQ

VDQLGQKLLKKIGISWNKKY

IFLLSSDESTVRLLKNSSLQAE

RKQHGPLRKFLQLHSQIFLL

SDFQRNDQQIFKMLPPESPGLN

SSDESTVRLLKNSSLQAESD

NSISCPHWFDINDSKVQPIREK

FQRNDQQIFKMLPPESPGLN

DIEQQFQGKESAYMLFYRKSQL

NSISCPHWFDINDSKVQPIR

QRPPEARANPRYGVPCHLLNEM

EKDIEQQFQGKESAYMLFYR

DAANIELQTKRAECDSANNTFE

KSQLQRPPEARANPRYGVPC

LHLHLGPQYHFENGALHPVVSQ

HLLNEMDAANIELQTKRAEC

TESVWDLTFDKRKTLGDLRQSI

DSANNTFELHLHLGPQYHFF

FQLLEFWEGDMVLSVAKLVPAG

NGALHPVVSQTESVWDLTFD

LHIYQSLGGDELTLCETEIADG

KRKTLGDLRQSIFQLLEFWE

EDIFVWNGVEVGGVHIQTGIDC

GDMVLSVAKLVPAGLHIYQS

EPLLLNVLHLDTSSDGEKCCQV

LGGDELTLCETEIADGEDIF

IESPHVFPANAEVGTVLTALAI

VWNGVEVGGVHIQTGIDCEP

PAGVIFINSAGCPGGEGWTAIP

LLLNVLHLDTSSDGEKCCQV

KEDMRKTFREQGLRNGSSILIQ

IESPHVFPANAEVGTVLTAL

DSHDDNSLLTKEEKWVTSMNEI

AIPAGVIFINSAGCPGGEGW

DWLHVKNLCQLESEEKQVKISA

TAIPKEDMRKTFREQGLRNG

TVNTMVFDIRIKAIKELKLMKE

SSILIQDSHDDNSLLTKEEK

LADNSCLRPIDRNGKLLCPVPD

WVTSMNEIDWLHVKNLCQLE

SYTLKEAELKMGSSLGLCLGKA

SEEKQVKISATVNTMVFDIR

PSSSQLFLFFAMGSDVQPGTEM

IKAIKELKLMKELADNSCLR

EIVVEETISVRDCLKLMLKKSG

PIDRNGKLLCPVPDSYTLKE

LQGDAWHLRKMDWCYEAGEPLC

AELKMGSSLGLCLGKAPSSS

EEDATLKELLICSGDTLLLIEG

QLFLFFAMGSDVQPGTEMEI

QLPPLGFLKVPIWWYQLQGPSG

VVEETISVRDCLKLMLKKSG

HWESHQDQTNCTSSWGRVWRAT

LQGDAWHLRKMDWCYEAGEP

SSQGASGNEPAQVSLLYLGDIE

LCEEDATLKELLICSGDTLL

ISEDATLAELKSQAMTLPPFLE

LIEGQLPPLGFLKVPIWWYQ

FGVPSPAHLRAWTVERKRPGRL

LQGPSGHWESHQDQTNCTSS

LRTDRQPLREYKLGRRIEICLE

WGRVWRATSSQGASGNEPAQ

PLQKGENLGPQDVLLRTQVRIP

VSLLYLGDIEISEDATLAEL

GERTYAPALDLVWNAAQGGTAG

KSQAMTLPPFLEFGVPSPAH

SLRQRVADFYRLPVEKIEIAKY

LRAWTVERKRPGRLLRTDRQ

FPEKFEWLPISSWNQQITKRKK

PLREYKLGRRIEICLEPLQK

KKKQDYLQGAPYYLKDGDTIGV

GENLGPQDVLLRTQVRIPGE

KNLLIDDDDDFSTIRDDTGKEK

RTYAPALDLVWNAAQGGTAG

QKQRALGRRKSQEALHEQSSYI

SLRQRVADFYRLPVEKIEIA

LSSAETPARPRAPETSLSIHVG

KYFPEKFEWLPISSWNQQIT

SFR

KRKKKKKQDYLQGAPYYLKD

GDTIGVKNLLIDDDDDFSTI

RDDTGKEKQKQRALGRRKSQ

UBP7_HUMAN
7
MNHQQQQQQQKAGEQQLSEPED
119
TGYVGLKNQGATCYMNSLLQ

Ubiquitin

MEMEAGDTDDPPRITQNPVING

TLFFTNQLRKAVYMMPTEGD

carboxyl-

NVALSDGHNTAEEDMEDDTSWR

DSSKSVPLALQRVFYELQHS

terminal

SEATFQFTVERFSRLSESVLSP

DKPVGTKKLTKSFGWETLDS

hydrolase

PCFVRNLPWKIMVMPRFYPDRP

FMQHDVQELCRVLLDNVENK

7

HQKSVGFFLQCNAESDSTSWSC

MKGTCVEGTIPKLFRGKMVS

HAQAVLKIINYRDDEKSFSRRI

YIQCKEVDYRSDRREDYYDI

SHLFFHKENDWGFSNFMAWSEV

QLSIKGKKNIFESFVDYVAV

TDPEKGFIDDDKVTFEVFVQAD

EQLDGDNKYDAGEHGLQEAE

APHGVAWDSKKHTGYVGLKNQG

KGVKFLTLPPVLHLQLMRFM

ATCYMNSLLQTLFFTNQLRKAV

YDPQTDQNIKINDRFEFPEQ

YMMPTEGDDSSKSVPLALQRVF

LPLDEFLQKTDPKDPANYIL

YELQHSDKPVGTKKLTKSFGWE

HAVLVHSGDNHGGHYVVYLN

TLDSFMQHDVQELCRVLLDNVE

PKGDGKWCKFDDDVVSRCTK

NKMKGTCVEGTIPKLFRGKMVS

EEAIEHNYGGHDDDLSVRHC

YIQCKEVDYRSDRREDYYDIQL

TNAYMLVYIRE

SIKGKKNIFESFVDYVAVEQLD

GDNKYDAGEHGLQEAEKGVKFL

TLPPVLHLQLMRFMYDPQTDQN

IKINDRFEFPEQLPLDEFLQKT

DPKDPANYILHAVLVHSGDNHG

GHYVVYLNPKGDGKWCKFDDDV

VSRCTKEEAIEHNYGGHDDDLS

VRHCTNAYMLVYIRESKLSEVL

QAVTDHDIPQQLVERLQEEKRI

EAQKRKERQEAHLYMQVQIVAE

DQFCGHQGNDMYDEEKVKYTVF

KVLKNSSLAEFVQSLSQTMGFP

QDQIRLWPMQARSNGTKRPAML

DNEADGNKTMIELSDNENPWTI

FLETVDPELAASGATLPKFDKD

HDVMLFLKMYDPKTRSLNYCGH

IYTPISCKIRDLLPVMCDRAGF

IQDTSLILYEEVKPNLTERIQD

YDVSLDKALDELMDGDIIVFQK

DDPENDNSELPTAKEYFRDLYH

RVDVIFCDKTIPNDPGFVVTLS

NRMNYFQVAKTVAQRLNTDPML

LQFFKSQGYRDGPGNPLRHNYE

GTLRDLLQFFKPRQPKKLYYQQ

LKMKITDFENRRSFKCIWLNSQ

FREEEITLYPDKHGCVRDLLEE

CKKAVELGEKASGKLRLLEIVS

YKIIGVHQEDELLECLSPATSR

TFRIEEIPLDQVDIDKENEMLV

TVAHFHKEVFGTFGIPFLLRIH

QGEHFREVMKRIQSLLDIQEKE

FEKFKFAIVMMGRHQYINEDEY

EVNLKDFEPQPGNMSHPRPWLG

LDHFNKAPKRSRYTYLEKAIKI

HN

U17L5_HUMAN
8
MEDDSLYLRGEWQFNHFSKLTS
120
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 5

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLAKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLAK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QPNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGA

EVTASSITSVLSQQAYVLFYIQ

EDTDRRATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGA

APEL

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKFL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSSTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

U17LL_HUMAN
9
MEEDSLYLGGEWQFNHESKLTS
121
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSNRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 21

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKMLTLLTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KMLTLLTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QPNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EWERHSESVSRGREPRALGA

EVTASSITSVLSQQAYVLFYIQ

EDTDRRATQGELKRDHPCLQ

KSEWERHSESVSRGREPRALGA

APEL

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKFL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSSTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

U17LA_HUMAN
10
MEDDSLYLGGEWQFNHFSKLTS
122
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYKPPLANYMLFREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KPPLSSRRPAAVGAGLQNMGNT

HIPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYKPPLANYMLF

KQEDAHEFLMFTVDAMRKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDRHSKDTTLIHQI

protein 10

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

ELDEHLVERATQESTLDHWKEF

QEQNKTKPEFNVRRVEGTVPPD

VLVIHQSKYKCRMKNHHPEQQS

SLLNLSSTTPTDQESMNTGTLA

SLRGRTRRSKGKNKHSKRALLV

CQ

UBP41_HUMAN
11
MDGVLFRAHQCQYVHPCVHVYV
123
WGLVGLHNIGQTCCLNSLIQ

Putative

TVGLMDPLCERKEKASKQEREN

VFVMNVDFARILKRITVPRG

ubiquitin

PLAHLAAWGLVGLHNIGQTCCL

ADEQRRSVPFQMLLLLEKMQ

carboxyl-

NSLIQVFVMNVDFARILKRITV

DSRQKAVWPLELAYCLQKYN

terminal

PRGADEQRRSVPFQMLLLLEKM

VPLFVQHDAAQLYLKLWNLI

hydrolase

QDSRQKAVWPLELAYCLQKYNV

KDQIADVHLVERLQALYMIR

41

PLFVQHDAAQLYLKLWNLIKDQ

MKDSLICLDCAMESSRNSSM

IADVHLVERLQALYMIRMKDSL

LTLRLSFFDVDSKPLKTLED

ICLDCAMESSRNSSMLTLRLSF

ALHCFFQPRELSSKSKCFCE

FDVDSKPLKTLEDALHCFFQPR

NCGKKTRGKQVLKLTHLPQT

ELSSKSKCFCENCGKKTRGKQV

LTIHLMRESIRNSQTRKICH

LKLTHLPQTLTIHLMRFSIRNS

SLYFPQSLDESQILPMKRES

QTRKICHSLYFPQSLDFSQILP

CDAEEQSGGQYELFAVIAHV

MKRESCDAEEQSGGQYELFAVI

GMADSGHYCVYIRNAVDGKW

AHVGMADSGHYCVYIRNAVDGK

FCFNDSNICLVSWEDIQCTY

WFCFNDSNICLVSWEDIQCTYG

GNPNYHW

NPNYHW

UBP38_HUMAN
12
MDKILEGLVSSSHPLPLKRVIV
124
SETGKTGLINLGNTCYMNSV

Ubiquitin

RKVVESAEHWLDEAQCEAMFDL

IQALFMATDFRRQVLSLNLN

carboxyl-

TTRLILEGQDPFQRQVGHQVLE

GCNSLMKKLQHLFAFLAHTQ

terminal

AYARYHRPEFESFFNKTFVLGL

REAYAPRIFFEASRPPWFTP

hydrolase

LHQGYHSLDRKDVAILDYIHNG

RSQQDCSEYLRFLLDRLHEE

38

LKLIMSCPSVLDLFSLLQVEVL

EKILKVQASHKPSEILECSE

RMVCERPEPQLCARLSDLLTDF

TSLQEVASKAAVLTETPRTS

VQCIPKGKLSITFCQQLVRTIG

DGEKTLIEKMFGGKLRTHIR

HFQCVSTQERELREYVSQVTKV

CLNCRSTSQKVEAFTDLSLA

SNLLQNIWKAEPATLLPSLQEV

FCPSSSLENMSVQDPASSPS

FASISSTDASFEPSVALASLVQ

IQDGGLMQASVPGPSEEPVV

HIPLQMITVLIRSLTTDPNVKD

YNPTTAAFICDSLVNEKTIG

ASMTQALCRMIDWLSWPLAQHV

SPPNEFYCSENTSVPNESNK

DTWVIALLKGLAAVQKFTILID

ILVNKDVPQKPGGETTPSVT

VTLLKIELVFNRLWFPLVRPGA

DLLNYFLAPEILTGDNQYYC

LAVLSHMLLSFQHSPEAFHLIV

ENCASLQNAEKTMQITEEPE

PHVVNLVHSFKNDGLPSSTAFL

YLILTLLRFSYDQKYHVRRK

VQLTELIHCMMYHYSGFPDLYE

ILDNVSLPLVLELPVKRITS

PILEAIKDFPKPSEEKIKLILN

FSSLSESWSVDVDFTDLSEN

QSAWTSQSNSLASCLSRLSGKS

LAKKLKPSGTDEASCTKLVP

ETGKTGLINLGNTCYMNSVIQA

YLLSSVVVHSGISSESGHYY

LFMATDFRRQVLSLNLNGCNSL

SYARNITSTDSSYQMYHQSE

MKKLQHLFAFLAHTQREAYAPR

ALALASSQSHLLGRDSPSAV

IFFEASRPPWFTPRSQQDCSEY

FEQDLENKEMSKEWFLFNDS

LRFLLDRLHEEEKILKVQASHK

RVTFTSFQSVQKITSRFPKD

PSEILECSETSLQEVASKAAVL

TAYVLLYKKQH

TETPRTSDGEKTLIEKMFGGKL

RTHIRCLNCRSTSQKVEAFTDL

SLAFCPSSSLENMSVQDPASSP

SIQDGGLMQASVPGPSEEPVVY

NPTTAAFICDSLVNEKTIGSPP

NEFYCSENTSVPNESNKILVNK

DVPQKPGGETTPSVTDLLNYFL

APEILTGDNQYYCENCASLQNA

EKTMQITEEPEYLILTLLRFSY

DQKYHVRRKILDNVSLPLVLEL

PVKRITSFSSLSESWSVDVDFT

DLSENLAKKLKPSGTDEASCTK

LVPYLLSSVVVHSGISSESGHY

YSYARNITSTDSSYQMYHQSEA

LALASSQSHLLGRDSPSAVFEQ

DLENKEMSKEWFLFNDSRVTFT

SFQSVQKITSRFPKDTAYVLLY

KKQHSTNGLSGNNPTSGLWING

DPPLQKELMDAITKDNKLYLQE

QELNARARALQAASASCSFRPN

GFDDNDPPGSCGPTGGGGGGGF

NTVGRLVF

UBP43_HUMAN
13
MDLGPGDAAGGGPLAPRPRRRR
125
RPPGAQGLKNHGNTCFMNAV

Ubiquitin

SLRRLFSRFLLALGSRSRPGDS

VQCLSNTDLLAEFLALGRYR

carboxyl-

PPRPQPGHCDGDGEGGFACAPG

AAPGRAEVTEQLAALVRALW

terminal

PVPAAPGSPGEERPPGPQPQLQ

TREYTPQLSAEFKNAVSKYG

hydrolase

LPAGDGARPPGAQGLKNHGNTC

SQFQGNSQHDALEFLLWLLD

43

FMNAVVQCLSNTDLLAEFLALG

RVHEDLEGSSRGPVSEKLPP

RYRAAPGRAEVTEQLAALVRAL

EATKTSENCLSPSAQLPLGQ

WTREYTPQLSAEFKNAVSKYGS

SFVQSHFQAQYRSSLTCPHC

QFQGNSQHDALEFLLWLLDRVH

LKQSNTFDPFLCVSLPIPLR

EDLEGSSRGPVSEKLPPEATKT

QTRFLSVTLVFPSKSQRFLR

SENCLSPSAQLPLGQSFVQSHF

VGLAVPILSTVAALRKMVAE

QAQYRSSLTCPHCLKQSNTFDP

EGGVPADEVILVELYPSGFQ

FLCVSLPIPLRQTRFLSVTLVF

RSFFDEEDLNTIAEGDNVYA

PSKSQRFLRVGLAVPILSTVAA

FQVPPSPSQGTLSAHPLGLS

LRKMVAEEGGVPADEVILVELY

ASPRLAAREGQRFSLSLHSE

PSGFQRSFFDEEDLNTIAEGDN

SKVLILFCNLVGSGQQASRF

VYAFQVPPSPSQGTLSAHPLGL

GPPFLIREDRAVSWAQLQQS

SASPRLAAREGQRFSLSLHSES

ILSKVRHLMKSEAPVQNLGS

KVLILFCNLVGSGQQASRFGPP

LFSIRVVGLSVACSYLSPKD

FLIREDRAVSWAQLQQSILSKV

SRPLCHWAVDRVLHLRRPGG

RHLMKSEAPVQNLGSLFSIRVV

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

PLQGTLTLLRSVFRKKENRRNE

RAEVSPQVPPVSLVSGGLSPAM

DGQAPGSPPALRIPEGLARGLG

SRLERDVWSAPSSLRLPRKASR

APRGSALGMSQRTVPGEQASYG

TFQRVKYHTLSLGRKKTLPESS

F

UBP2_HUMAN
14
MSQLSSTLKRYTESARYTDAHY
126
SAQGLAGLRNLGNTCFMNSI

Ubiquitin

AKSGYGAYTPSSYGANLAASLL

LQCLSNTRELRDYCLQRLYM

carboxyl-

EKEKLGFKPVPTSSFLTRPRTY

RDLHHGSNAHTALVEEFAKL

terminal

GPSSLLDYDRGRPLLRPDITGG

IQTIWTSSPNDVVSPSEFKT

hydrolase

GKRAESQTRGTERPLGSGLSGG

QIQRYAPRFVGYNQQDAQEF

2

SGFPYGVTNNCLSYLPINAYDQ

LRFLLDGLHNEVNRVTLRPK

GVTLTQKLDSQSDLARDFSSLR

SNPENLDHLPDDEKGRQMWR

TSDSYRIDPRNLGRSPMLARTR

KYLEREDSRIGDLFVGQLKS

KELCTLQGLYQTASCPEYLVDY

SLTCTDCGYCSTVFDPFWDL

LENYGRKGSASQVPSQAPPSRV

SLPIAKRGYPEVTLMDCMRL

PEIISPTYRPIGRYTLWETGKG

FTKEDVLDGDEKPTCCRCRG

QAPGPSRSSSPGRDGMNSKSAQ

RKRCIKKESIQRFPKILVLH

GLAGLRNLGNTCFMNSILQCLS

LKRFSESRIRTSKLTTFVNF

NTRELRDYCLQRLYMRDLHHGS

PLRDLDLREFASENTNHAVY

NAHTALVEEFAKLIQTIWTSSP

NLYAVSNHSGTTMGGHYTAY

NDVVSPSEFKTQIQRYAPRFVG

CRSPGTGEWHTENDSSVTPM

YNQQDAQEFLRFLLDGLHNEVN

SSSQVRTSDAYLLFYELAS

RVTLRPKSNPENLDHLPDDEKG

RQMWRKYLEREDSRIGDLFVGQ

LKSSLTCTDCGYCSTVFDPFWD

LSLPIAKRGYPEVTLMDCMRLF

TKEDVLDGDEKPTCCRCRGRKR

CIKKFSIQRFPKILVLHLKRFS

ESRIRTSKLTTFVNFPLRDLDL

REFASENTNHAVYNLYAVSNHS

GTTMGGHYTAYCRSPGTGEWHT

FNDSSVTPMSSSQVRTSDAYLL

FYELASPPSRM

UBP45_HUMAN
15
MRVKDPTKALPEKAKRSKRPTV
127
LSVRGITNLGNTCFFNAVMQ

Ubiquitin

PHDEDSSDDIAVGLTCQHVSHA

NLAQTYTLTDLMNEIKESST

carboxyl-

ISVNHVKRAIAENLWSVCSECL

KLKIFPSSDSQLDPLVVELS

terminal

KERRFYDGQLVLTSDIWLCLKC

RPGPLTSALFLFLHSMKETE

hydrolase

GFQGCGKNSESQHSLKHFKSSR

KGPLSPKVLFNQLCQKAPRF

45

TEPHCIIINLSTWIIWCYECDE

KDFQQQDSQELLHYLLDAVR

KLSTHCNKKVLAQIVDEFQKHA

TEETKRIQASILKAFNNPTT

SKTQTSAFSRIMKLCEEKCETD

KTADDETRKKVKAYGKEGVK

EIQKGGKCRNLSVRGITNLGNT

MNFIDRIFIGELTSTVMCEE

CFFNAVMQNLAQTYTLTDLMNE

CANISTVKDPFIDISLPIIE

IKESSTKLKIFPSSDSQLDPLV

ERVSKPLLWGRMNKYRSLRE

VELSRPGPLTSALFLFLHSMKE

TDHDRYSGNVTIENIHQPRA

TEKGPLSPKVLFNQLCQKAPRF

AKKHSSSKDKSQLIHDRKCI

KDFQQQDSQELLHYLLDAVRTE

RKLSSGETVTYQKNENLEMN

ETKRIQASILKAFNNPTTKTAD

GDSLMFASLMNSESRLNESP

DETRKKVKAYGKEGVKMNFIDR

TDDSEKEASHSESNVDADSE

IFIGELTSTVMCEECANISTVK

PSESESASKQTGLFRSSSGS

DPFIDISLPIIEERVSKPLLWG

GVQPDGPLYPLSAGKLLYTK

RMNKYRSLRETDHDRYSGNVTI

ETDSGDKEMAEAISELRLSS

ENIHQPRAAKKHSSSKDKSQLI

TVTGDQDFDRENQPLNISNN

HDRKCIRKLSSGETVTYQKNEN

LCFLEGKHLRSYSPQNAFQT

LEMNGDSLMFASLMNSESRLNE

LSQSYITTSKECSIQSCLYQ

SPTDDSEKEASHSESNVDADSE

FTSMELLMGNNKLLCENCTK

PSESESASKQTGLFRSSSGSGV

NKQKYQEETSFAEKKVEGVY

QPDGPLYPLSAGKLLYTKETDS

TNARKQLLISAVPAVLILHL

GDKEMAEAISELRLSSTVTGDQ

KRFHQAGLSLRKVNRHVDFP

DFDRENQPLNISNNLCFLEGKH

LMLDLAPFCSATCKNASVGD

LRSYSPQNAFQTLSQSYITTSK

KVLYGLYGIVEHSGSMREGH

ECSIQSCLYQFTSMELLMGNNK

YTAYVKVRTPSRKLSEHNTK

LLCENCTKNKQKYQEETSFAEK

KKNVPGLKAADNESAGQWVH

KVEGVYTNARKQLLISAVPAVL

VSDTYLQVVPESRALSAQAY

ILHLKRFHQAGLSLRKVNRHVD

LLFYERVL

FPLMLDLAPFCSATCKNASVGD

KVLYGLYGIVEHSGSMREGHYT

AYVKVRTPSRKLSEHNTKKKNV

PGLKAADNESAGQWVHVSDTYL

QVVPESRALSAQAYLLFYERVL

UBP32_HUMAN
16
MGAKESRIGFLSYEEALRRVTD
128
TEKGATGLSNLGNTCFMNSS

Ubiquitin

VELKRLKDAFKRTCGLSYYMGQ

IQCVSNTQPLTQYFISGRHL

carboxyl-

HCFIREVLGDGVPPKVAEVIYC

YELNRTNPIGMKGHMAKCYG

terminal

SFGGTSKGLHFNNLIVGLVLLT

DLVQELWSGTQKNVAPLKLR

hydrolase

RGKDEEKAKYIFSLFSSESGNY

WTIAKYAPRFNGFQQQDSQE

32

VIREEMERMLHVVDGKVPDTLR

LLAFLLDGLHEDLNRVHEKP

KCFSEGEKVNYEKFRNWLFLNK

YVELKDSDGRPDWEVAAEAW

DAFTFSRWLLSGGVYVTLTDDS

DNHLRRNRSIVVDLFHGQLR

DTPTFYQTLAGVTHLEESDIID

SQVKCKTCGHISVRFDPFNF

LEKRYWLLKAQSRTGRFDLETF

LSLPLPMDSYMHLEITVIKL

GPLVSPPIRPSLSEGLFNAFDE

DGTTPVRYGLRLNMDEKYTG

NRDNHIDFKEISCGLSACCRGP

LKKQLSDLCGLNSEQILLAE

LAERQKFCFKVFDVDRDGVLSR

VHGSNIKNFPQDNQKVRLSV

VELRDMVVALLEVWKDNRTDDI

SGFLCAFEIPVPVSPISASS

PELHMDLSDIVEGILNAHDTTK

PTQTDFSSSPSTNEMFTLTT

MGHLTLEDYQIWSVKNVLANEF

NGDLPRPIFIPNGMPNTVVP

LNLLFQVCHIVLGLRPATPEEE

CGTEKNFTNGMVNGHMPSLP

GQIIRGWLERESRYGLQAGHNW

DSPFTGYIIAVHRKMMRTEL

FIISMQWWQQWKEYVKYDANPV

YFLSSQKNRPSLFGMPLIVP

VIEPSSVLNGGKYSFGTAAHPM

CTVHTRKKDLYDAVWIQVSR

EQVEDRIGSSLSYVNTTEEKFS

LASPLPPQEASNHAQDCDDS

DNISTASEASETAGSGFLYSAT

MGYQYPFTLRVVQKDGNSCA

PGADVCFARQHNTSDNNNQCLL

WCPWYRFCRGCKIDCGEDRA

GANGNILLHLNPQKPGAIDNQP

FIGNAYIAVDWDPTALHLRY

LVTQEPVKATSLTLEGGRLKRT

QTSQERVVDEHESVEQSRRA

PQLIHGRDYEMVPEPVWRALYH

QAEPINLDSCLRAFTSEEEL

WYGANLALPRPVIKNSKTDIPE

GENEMYYCSKCKTHCLATKK

LELFPRYLLFLRQQPATRTQQS

LDLWRLPPILIIHLKRFQFV

NIWVNMGNVPSPNAPLKRVLAY

NGRWIKSQKIVKFPRESFDP

TGCFSRMQTIKEIHEYLSQRLR

SAFLVPRDPALCQHKPLTPQ

IKEEDMRLWLYNSENYLTLLDD

GDELSEPRILAREVKKVDAQ

EDHKLEYLKIQDEQHLVIEVRN

SSAGEEDVLLSKSPSSLSAN

KDMSWPEEMSFIANSSKIDRHK

IISSPKGSPSSSRKSGTSCP

VPTEKGATGLSNLGNTCFMNSS

SSKNSSPNSSPRTLGRSKGR

IQCVSNTQPLTQYFISGRHLYE

LRLPQIGSKNKLSSSKENLD

LNRTNPIGMKGHMAKCYGDLVQ

ASKENGAGQICELADALSRG

ELWSGTQKNVAPLKLRWTIAKY

HVLGGSQPELVTPQDHEVAL

APRFNGFQQQDSQELLAFLLDG

ANGFLYEHEACGNGYSNGQL

LHEDLNRVHEKPYVELKDSDGR

GNHSEEDSTDDQREDTRIKP

PDWEVAAEAWDNHLRRNRSIVV

IYNLYAISCHSGILGGGHYV

DLFHGQLRSQVKCKTCGHISVR

TYAKNPNCKWYCYNDSSCKE

FDPFNFLSLPLPMDSYMHLEIT

LHPDEIDTDSAYILFYEQQG

VIKLDGTTPVRYGLRLNMDEKY

IDYAQFLPKTDGKKMADTSS

TGLKKQLSDLCGLNSEQILLAE

MDEDFESDYKKYCVLQ

VHGSNIKNFPQDNQKVRLSVSG

FLCAFEIPVPVSPISASSPTQT

DFSSSPSTNEMFTLTINGDLPR

PIFIPNGMPNTVVPCGTEKNFT

NGMVNGHMPSLPDSPFTGYIIA

VHRKMMRTELYFLSSQKNRPSL

FGMPLIVPCTVHTRKKDLYDAV

WIQVSRLASPLPPQEASNHAQD

CDDSMGYQYPFTLRVVQKDGNS

CAWCPWYRFCRGCKIDCGEDRA

FIGNAYIAVDWDPTALHLRYQT

SQERVVDEHESVEQSRRAQAEP

INLDSCLRAFTSEEELGENEMY

YCSKCKTHCLATKKLDLWRLPP

ILIIHLKRFQFVNGRWIKSQKI

VKFPRESFDPSAFLVPRDPALC

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

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 6

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QQNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EVTASSITSVLSQQAYVLFYIQ

KSEWERHSESVSRGREPRALGS

ED

UBP42_HUMAN
18
MTIVDKASESSDPSAYQNQPGS
130
RVGAGLQNLGNTCFANAALQ

Ubiquitin

SEAVSPGDMDAGSASWGAVSSL

CLTYTPPLANYMLSHEHSKT

carboxyl-

NDVSNHTLSLGPVPGAVVYSSS

CHAEGFCMMCTMQAHITQAL

terminal

SVPDKSKPSPQKDQALGDGIAP

SNPGDVIKPMFVINEMRRIA

hydrolase

PQKVLFPSEKICLKWQQTHRVG

RHFRFGNQEDAHEFLQYTVD

42

AGLQNLGNTCFANAALQCLTYT

AMQKACLNGSNKLDRHTQAT

PPLANYMLSHEHSKTCHAEGFC

TLVCQIFGGYLRSRVKCLNC

MMCTMQAHITQALSNPGDVIKP

KGVSDTFDPYLDITLEIKAA

MFVINEMRRIARHERFGNQEDA

QSVNKALEQFVKPEQLDGEN

HEFLQYTVDAMQKACLNGSNKL

SYKCSKCKKMVPASKRFTIH

DRHTQATTLVCQIFGGYLRSRV

RSSNVLTLSLKRFANFTGGK

KCLNCKGVSDTFDPYLDITLEI

IAKDVKYPEYLDIRPYMSQP

KAAQSVNKALEQFVKPEQLDGE

NGEPIVYVLYAVLVHTGFNC

NSYKCSKCKKMVPASKRFTIHR

HAGHYFCYIKASNGLWYQMN

SSNVLTLSLKRFANFTGGKIAK

DSIVSTSDIRSVLSQQAYVL

DVKYPEYLDIRPYMSQPNGEPI

FYIRSHDVKNGGE

VYVLYAVLVHTGFNCHAGHYFC

YIKASNGLWYQMNDSIVSTSDI

RSVLSQQAYVLFYIRSHDVKNG

GELTHPTHSPGQSSPRPVISQR

VVTNKQAAPGFIGPQLPSHMIK

NPPHLNGTGPLKDTPSSSMSSP

NGNSSVNRASPVNASASVQNWS

VNRSSVIPEHPKKQKITISIHN

KLPVRQCQSQPNLHSNSLENPT

KPVPSSTITNSAVQSTSNASTM

SVSSKVTKPIPRSESCSQPVMN

GKSKLNSSVLVPYGAESSEDSD

EESKGLGKENGIGTIVSSHSPG

QDAEDEEATPHELQEPMTLNGA

NSADSDSDPKENGLAPDGASCQ

GQPALHSENPFAKANGLPGKLM

PAPLLSLPEDKILETFRLSNKL

KGSTDEMSAPGAERGPPEDRDA

EPQPGSPAAESLEEPDAAAGLS

STKKAPPPRDPGTPATKEGAWE

AMAVAPEEPPPSAGEDIVGDTA

PPDLCDPGSLTGDASPLSQDAK

GMIAEGPRDSALAEAPEGLSPA

PPARSEEPCEQPLLVHPSGDHA

RDAQDPSQSLGAPEAAERPPAP

VLDMAPAGHPEGDAEPSPGERV

EDAAAPKAPGPSPAKEKIGSLR

KVDRGHYRSRRERSSSGEPARE

SRSKTEGHRHRRRRTCPRERDR

QDRHAPEHHPGHGDRLSPGERR

SLGRCSHHHSRHRSGVELDWVR

HHYTEGERGWGREKFYPDRPRW

DRCRYYHDRYALYAARDWKPFH

GGREHERAGLHERPHKDHNRGR

RGCEPARERERHRPSSPRAGAP

HALAPHPDRFSHDRTALVAGDN

CNLSDRFHEHENGKSRKRRHDS

VENSDSHVEKKARRSEQKDPLE

EPKAKKHKKSKKKKKSKDKHRD

RDSRHQQDSDLSAACSDADLHR

HKKKKKKKKRHSRKSEDFVKDS

ELHLPRVTSLETVAQFRRAQGG

FPLSGGPPLEGVGPFREKTKHL

RMESRDDRCRLFEYGQGKRRYL

ELGR

U17L7_HUMAN
19
MEDDSLYLGGDWQFNHFSKLTS
131
AVGAGLQKIGNTFYVNVSLQ

Inactive

SRLDAAFAEIQRTSLSEKSPLS

CLTYTLPLSNYMLSREDSQT

ubiquitin

SETRFDLCDDLAPVARQLAPRE

CHLHKCCMFCTMQAHITWAL

carboxyl-

KLPLSSRRPAAVGAGLQKIGNT

HSPGHVIQPSQVLAAGFHRG

terminal

FYVNVSLQCLTYTLPLSNYMLS

EQEDAHEFLMFTVDAMKKAC

hydrolase

REDSQTCHLHKCCMFCTMQAHI

LPGHKQLDHHSKDTTLIHQI

17-like

TWALHSPGHVIQPSQVLAAGFH

FGAYWRSQIKYLHCHGVSDT

protein 7

RGEQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQLDHHSKDTTLIHQIFG

LEQLVKPKELNGENAYHCGL

AYWRSQIKYLHCHGVSDTFDPY

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
MEDDSLYLGGEWQFNHFSKLTS
132
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 17

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

ELDEHLVERATQESTLDHWKFL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSSTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

UBP13_HUMAN
21
MQRRGALFGMPGGSGGRKMAAG
133
YGPGYTGLKNLGNSCYLSSV

Ubiquitin

DIGELLVPHMPTIRVPRSGDRV

MQAIFSIPEFQRAYVGNLPR

carboxyl-

YKNECAFSYDSPNSEGGLYVCM

IFDYSPLDPTQDFNTQMTKL

terminal

NTFLAFGREHVERHFRKTGQSV

GHGLLSGQYSKPPVKSELIE

hydrolase

YMHLKRHVREKVRGASGGALPK

QVMKEEHKPQQNGISPRMFK

13

RRNSKIFLDLDTDDDLNSDDYE

AFVSKSHPEFSSNRQQDAQE

YEDEAKLVIFPDHYEIALPNIE

FFLHLVNLVERNRIGSENPS

ELPALVTIACDAVLSSKSPYRK

DVFRFLVEERIQCCQTRKVR

QDPDTWENELPVSKYANNLTQL

YTERVDYLMQLPVAMEAATN

DNGVRIPPSGWKCARCDLRENL

KDELIAYELTRREAEANRRP

WLNLTDGSVLCGKWFFDSSGGN

LPELVRAKIPFSACLQAFSE

GHALEHYRDMGYPLAVKLGTIT

PENVDDFWSSALQAKSAGVK

PDGADVYSFQEEEPVLDPHLAK

TSRFASFPEYLVVQIKKFTF

HLAHFGIDMLHMHGTENGLQDN

GLDWVPKKFDVSIDMPDLLD

DIKLRVSEWEVIQESGTKLKPM

INHLRARGLQPGEEELPDIS

YGPGYTGLKNLGNSCYLSSVMQ

PPIVIPDDSKDRLMNQLIDP

AIFSIPEFQRAYVGNLPRIFDY

SDIDESSVMQLAEMGFPLEA

SPLDPTQDFNTQMTKLGHGLLS

CRKAVYFTGNMGAEVAFNWI

GQYSKPPVKSELIEQVMKEEHK

IVHMEEPDFAEPLTMPGYGG

PQQNGISPRMFKAFVSKSHPEF

AASAGASVFGASGLDNQPPE

SSNRQQDAQEFFLHLVNLVERN

EIVAIITSMGFQRNQAIQAL

RIGSENPSDVFRFLVEERIQCC

RATNNNLERALDWIFSHPEF

QTRKVRYTERVDYLMQLPVAME

EEDSDFVIEMENNANANIIS

AATNKDELIAYELTRREAEANR

EAKPEGPRVKDGSGTYELFA

RPLPELVRAKIPFSACLQAFSE

FISHMGTSTMSGHYICHIKK

PENVDDEWSSALQAKSAGVKTS

EGRWVIYNDHKVCASERPPK

RFASFPEYLVVQIKKFTFGLDW

DLGYMYFYRRIPS

VPKKFDVSIDMPDLLDINHLRA

RGLQPGEEELPDISPPIVIPDD

SKDRLMNQLIDPSDIDESSVMQ

LAEMGFPLEACRKAVYFTGNMG

AEVAFNWIIVHMEEPDFAEPLT

MPGYGGAASAGASVFGASGLDN

QPPEEIVAIITSMGFQRNQAIQ

ALRATNNNLERALDWIFSHPEF

EEDSDFVIEMENNANANIISEA

KPEGPRVKDGSGTYELFAFISH

MGTSTMSGHYICHIKKEGRWVI

YNDHKVCASERPPKDLGYMYFY

RRIPS

UBP11_HUMAN
22
MAVAPRLFGGLCFRFRDQNPEV
134
KGQPGICGLTNLGNTCFMNS

Ubiquitin

AVEGRLPISHSCVGCRRERTAM

ALQCLSNVPQLTEYFLNNCY

carboxyl-

ATVAANPAAAAAAVAAAAAVTE

LEELNFRNPLGMKGEIAEAY

terminal

DREPQHEELPGLDSQWRQIENG

ADLVKQAWSGHHRSIVPHVF

hydrolase

ESGRERPLRAGESWFLVEKHWY

KNKVGHFASQFLGYQQHDSQ

11

KQWEAYVQGGDQDSSTFPGCIN

ELLSFLLDGLHEDLNRVKKK

NATLFQDEINWRLKEGLVEGED

EYVELCDAAGRPDQEVAQEA

YVLLPAAAWHYLVSWYGLEHGQ

WQNHKRRNDSVIVDTFHGLF

PPIERKVIELPNIQKVEVYPVE

KSTLVCPDCGNVSVTFDPFC

LLLVRHNDLGKSHTVQFSHTDS

YLSVPLPISHKRVLEVFFIP

IGLVLRTARERELVEPQEDTRL

MDPRRKPEQHRLVVPKKGKI

WAKNSEGSLDRLYDTHITVLDA

SDLCVALSKHTGISPERMMV

ALETGQLIIMETRKKDGTWPSA

ADVFSHRFYKLYQLEEPLSS

QLHVMNNNMSEEDEDFKGQPGI

ILDRDDIFVYEVSGRIEAIE

CGLTNLGNTCFMNSALQCLSNV

GSREDIVVPVYLRERTPARD

PQLTEYFLNNCYLEELNFRNPL

YNNSYYGLMLFGHPLLVSVP

GMKGEIAEAYADLVKQAWSGHH

RDRFTWEGLYNVLMYRLSRY

RSIVPHVFKNKVGHFASQFLGY

VTKPNSDDEDDGDEKEDDEE

QQHDSQELLSFLLDGLHEDLNR

DKDDVPGPSTGGSLRDPEPE

VKKKEYVELCDAAGRPDQEVAQ

QAGPSSGVTNRCPFLLDNCL

EAWQNHKRRNDSVIVDTFHGLF

GTSQWPPRRRRKQLFTLQTV

KSTLVCPDCGNVSVTFDPFCYL

NSNGTSDRTTSPEEVHAQPY

SVPLPISHKRVLEVFFIPMDPR

IAIDWEPEMKKRYYDEVEAE

RKPEQHRLVVPKKGKISDLCVA

GYVKHDCVGYVMKKAPVRLQ

LSKHTGISPERMMVADVESHRF

ECIELFTTVETLEKENPWYC

YKLYQLEEPLSSILDRDDIFVY

PSCKQHQLATKKLDLWMLPE

EVSGRIEAIEGSREDIVVPVYL

ILIIHLKRFSYTKESREKLD

RERTPARDYNNSYYGLMLFGHP

TLVEFPIRDLDESFFVIQPQ

LLVSVPRDRFTWEGLYNVLMYR

NESNPELYKYDLIAVSNHYG

LSRYVTKPNSDDEDDGDEKEDD

GMRDGHYTTFACNKDSGQWH

EEDKDDVPGPSTGGSLRDPEPE

YFDDNSVSPVNENQIESKAA

QAGPSSGVTNRCPFLLDNCLGT

YVLFYQRQD

SQWPPRRRRKQLFTLQTVNSNG

TSDRTTSPEEVHAQPYIAIDWE

PEMKKRYYDEVEAEGYVKHDCV

GYVMKKAPVRLQECIELFTTVE

TLEKENPWYCPSCKQHQLATKK

LDLWMLPEILIIHLKRFSYTKF

SREKLDTLVEFPIRDLDFSEFV

IQPQNESNPELYKYDLIAVSNH

YGGMRDGHYTTFACNKDSGQWH

YFDDNSVSPVNENQIESKAAYV

LFYQRQDVARRLLSPAGSSGAP

ASPACSSPPSSEFMDVN

U17L1_HUMAN
23
MGDDSLYLGGEWQFNHESKLTS
135
AVGAGLQNMGNTCYENASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTLPLANYMLSREHSQT

carboxyl-

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

hydrolase

CYENASLQCLTYTLPLANYMLS

KQEDVHEFLMFTVDAMKKAC

17-like

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHCKDTTLIHQI

protein 1

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDVHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHCKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTFDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVAGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHDGHYF

AGNKLAKNVQYPECLDMQPYMS

SYVKAQEVQWYKMDDAEVTV

QQNTGPLVYVLYAVLVHAGWSC

CSIISVLSQQAYVLFYIQKS

HDGHYFSYVKAQEVQWYKMDDA

EVTVCSIISVLSQQAYVLFYIQ

KSEWERHSESVSRGREPRALGA

EDTDRRAKQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKFL

QEQNKTKPEFNVGKVEGTLPPN

ALVIHQSKYKCGMKNHHPEQQS

SLLNLSSTTRTDQESMNTGTLA

SLQGRTRRAKGKNKHSKRALLV

CQ

UBP14_HUMAN
24
MPLYSVTVKWGKEKFEGVELNT
136
ASAMELPCGLTNLGNTCYMN

Ubiquitin

DEPPMVFKAQLFALTGVQPARQ

ATVQCIRSVPELKDALKRYA

carboxyl-

KVMVKGGTLKDDDWGNIKIKNG

GALRASGEMASAQYITAALR

terminal

MTLLMMGSADALPEEPSAKTVF

DLFDSMDKTSSSIPPIILLQ

hydrolase

VEDMTEEQLASAMELPCGLTNL

FLHMAFPQFAEKGEQGQYLQ

14

GNTCYMNATVQCIRSVPELKDA

QDANECWIQMMRVLQQKLEA

LKRYAGALRASGEMASAQYITA

IEDDSVKETDSSSASAATPS

ALRDLFDSMDKTSSSIPPIILL

KKKSLIDQFFGVEFETTMKC

QFLHMAFPQFAEKGEQGQYLQQ

TESEEEEVTKGKENQLQLSC

DANECWIQMMRVLQQKLEAIED

FINQEVKYLFTGLKLRLQEE

DSVKETDSSSASAATPSKKKSL

ITKQSPTLQRNALYIKSSKI

IDQFFGVEFETTMKCTESEEEE

SRLPAYLTIQMVRFFYKEKE

VTKGKENQLQLSCFINQEVKYL

SVNAKVLKDVKFPLMLDMYE

FTGLKLRLQEEITKQSPTLQRN

LCTPELQEKMVSFRSKFKDL

ALYIKSSKISRLPAYLTIQMVR

EDKKVNQQPNTSDKKSSPQK

FFYKEKESVNAKVLKDVKFPLM

EVKYEPFSFADDIGSNNCGY

LDMYELCTPELQEKMVSFRSKF

YDLQAVLTHQGRSSSSGHYV

KDLEDKKVNQQPNTSDKKSSPQ

SWVKRKQDEWIKFDDDKVSI

KEVKYEPFSFADDIGSNNCGYY

VTPEDILRLSGGGDWHIAYV

DLQAVLTHQGRSSSSGHYVSWV

LLYGPRR

KRKQDEWIKFDDDKVSIVTPED

ILRLSGGGDWHIAYVLLYGPRR

VEIMEEESEQ

Q13107|UBP4
25
MAEGGGCRERPDAETQKSELGP
137
SHIQPGLCGLGNLGNTCFMN

_HUMAN

LMRTTLQRGAQWYLIDSRWFKQ

SALQCLSNTAPLTDYFLKDE

Ubiquitin

WKKYVGFDSWDMYNVGEHNLFP

YEAEINRDNPLGMKGEIAEA

carboxyl-

GPIDNSGLFSDPESQTLKEHLI

YAELIKQMWSGRDAHVAPRM

terminal

DELDYVLVPTEAWNKLLNWYGC

FKTQVGRFAPQFSGYQQQDS

hydrolase

VEGQQPIVRKVVEHGLFVKHCK

QELLAFLLDGLHEDLNRVKK

4

VEVYLLELKLCENSDPTNVLSC

KPYLELKDANGRPDAVVAKE

HFSKADTIATIEKEMRKLFNIP

AWENHRLRNDSVIVDTFHGL

AERETRLWNKYMSNTYEQLSKL

FKSTLVCPECAKVSVTEDPF

DNTVQDAGLYQGQVLVIEPQNE

CYLTLPLPLKKDRVMEVFLV

DGTWPRQTLQSKSSTAPSRNFT

PADPHCRPTQYRVTVPLMGA

TSPKSSASPYSSVSASLIANGD

VSDLCEALSRLSGIAAENMV

STSTCGMHSSGVSRGGSGFSAS

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

DPWYCPNCKKHQQATKKFDL

DGSECVTLPVYFRERKSRPSST

WSLPKILVVHLKRFSYNRYW

SSASALYGQPLLLSVPKHKLTL

RDKLDTVVEFPIRGLNMSEF

ESLYQAVCDRISRYVKQPLPDE

VCNLSARPYVYDLIAVSNHY

FGSSPLEPGACNGSRNSCEGED

GAMGVGHYTAYAKNKLNGKW

EEEMEHQEEGKEQLSETEGSGE

YYFDDSNVSLASEDQIVTKA

DEPGNDPSETTQKKIKGQPCPK

AYVLFYQRRD

RLFTFSLVNSYGTADINSLAAD

GKLLKLNSRSTLAMDWDSETRR

LYYDEQESEAYEKHVSMLQPQK

KKKTTVALRDCIELFTTMETLG

EHDPWYCPNCKKHQQATKKFDL

WSLPKILVVHLKRFSYNRYWRD

KLDTVVEFPIRGLNMSEFVCNL

SARPYVYDLIAVSNHYGAMGVG

HYTAYAKNKLNGKWYYFDDSNV

SLASEDQIVTKAAYVLFYQRRD

DEFYKTPSLSSSGSSDGGTRPS

SSQQGFGDDEACSMDTN

UBP26_HUMAN
26
MAALFLRGFVQIGNCKTGISKS
138
KICHGLPNLGNTCYMNAVLQ

Ubiquitin

KEAFIEAVERKKKDRLVLYFKS

SLLSIPSFADDLLNQSFPWG

carboxyl-

GKYSTFRLSDNIQNVVLKSYRG

KIPLNALTMCLARLLFFKDT

terminal

NQNHLHLTLQNNNGLFIEGLSS

YNIEIKEMLLLNLKKAISAA

hydrolase

TDAEQLKIFLDRVHQNEVQPPV

AEIFHGNAQNDAHEFLAHCL

26

RPGKGGSVFSSTTQKEINKTSF

DQLKDNMEKLNTIWKPKSEF

HKVDEKSSSKSFEIAKGSGTGV

GEDNFPKQVFADDPDTSGFS

LQRMPLLTSKLTLTCGELSENQ

CPVITNFELELLHSIACKAC

HKKRKRMLSSSSEMNEEFLKEN

GQVILKTELNNYLSINLPQR

NSVEYKKSKADCSRCVSYNREK

IKAHPSSIQSTEDLFFGAEE

QLKLKELEENKKLECESSCIMN

LEYKCAKCEHKTSVGVHSFS

ATGNPYLDDIGLLQALTEKMVL

RLPRILIVHLKRYSLNEFCA

VFLLQQGYSDGYTKWDKLKLFF

LKKNDQEVIISKYLKVSSHC

ELFPEKICHGLPNLGNTCYMNA

NEGTRPPLPLSEDGEITDFQ

VLQSLLSIPSFADDLLNQSFPW

LLKVIRKMTSGNISVSWPAT

GKIPLNALTMCLARLLFFKDTY

KESKDILAPHIGSDKESEQK

NIEIKEMLLLNLKKAISAAAEI

KGQTVFKGASRRQQQKYLGK

FHGNAQNDAHEFLAHCLDQLKD

NSKPNELESVYSGDRAFIEK

NMEKLNTIWKPKSEFGEDNFPK

EPLAHLMTYLEDTSLCQFHK

QVFADDPDTSGFSCPVITNFEL

AGGKPASSPGTPLSKVDFQT

ELLHSIACKACGQVILKTELNN

VPENPKRKKYVKTSKFVAFD

YLSINLPQRIKAHPSSIQSTFD

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
LPGFTGLVNLGNTCFMNSVI

Ubiquitin

KKKQKDRANQESKDGDPRKETG

QSLSNTRELRDFFHDRSFEA

carboxyl-

SRYVAQAGLEPLASGDPSASAS

EINYNNPLGTGGRLAIGFAV

terminal

HAAGITGSRHRTRLFFPSSSGS

LLRALWKGTHHAFQPSKLKA

hydrolase

ASTPQEEQTKEGACEDPHDLLA

IVASKASQFTGYAQHDAQEF

19

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

SFEAEINYNNPLGTGGRLAIGF

PGYQHPSEAMNAHTPQFFIY

AVLLRALWKGTHHAFQPSKLKA

KIDSSNREQRLEDKGDTPLE

IVASKASQFTGYAQHDAQEFMA

LGDDCSLA

FLLDGLHEDLNRIQNKPYTETV

LVWRNNERLQEFVLVASKEL

DSDGRPDEVVAEEAWQRHKMRN

ECAEDPGSAGEAARAGHFTL

DSFIVDLFQGQYKSKLVCPVCA

DQCLNLFTRPEVLAPEEAWY

KVSITFDPFLYLPVPLPQKQKV

CPQCKQHREASKQLLLWRLP

LPVFYFAREPHSKPIKFLVSVS

NVLIVQLKRFSFRSFIWRDK

KENSTASEVLDSLSQSVHVKPE

INDLVEFPVRNLDLSKFCIG

NLRLAEVIKNRFHRVFLPSHSL

QKEEQLPSYDLYAVINHYGG

DTVSPSDTLLCFELLSSELAKE

MIGGHYTACARLPNDRSSQR

RVVVLEVQQRPQVPSVPISKCA

SDVGWRLFDDSTVTTVDESQ

ACQRKQQSEDEKLKRCTRCYRV

VVTRYAYVLFYRRRN

GYCNQLCQKTHWPDHKGLCRPE

NIGYPFLVSVPASRLTYARLAQ

LLEGYARYSVSVFQPPFQPGRM

ALESQSPGCTTLLSTGSLEAGD

SERDPIQPPELQLVTPMAEGDT

GLPRVWAAPDRGPVPSTSGISS

EMLASGPIEVGSLPAGERVSRP

EAAVPGYQHPSEAMNAHTPQFF

IYKIDSSNREQRLEDKGDTPLE

LGDDCSLALVWRNNERLQEFVL

VASKELECAEDPGSAGEAARAG

HFTLDQCLNLFTRPEVLAPEEA

WYCPQCKQHREASKQLLLWRLP

NVLIVQLKRFSFRSFIWRDKIN

DLVEFPVRNLDLSKFCIGQKEE

QLPSYDLYAVINHYGGMIGGHY

TACARLPNDRSSQRSDVGWRLF

DDSTVTTVDESQVVTRYAYVLF

YRRRNSPVERPPRAGHSEHHPD

LGPAAEAAASQASRIWQELEAE

EEPVPEGSGPLGPWGPQDWVGP

LPRGPTTPDEGCLRYFVLGTVA

ALVALVLNVFYPLVSQSRWR

UBP10_HUMAN
28
MALHSPQYIFGDFSPDEFNQFF
140
SLQPRGLINKGNWCYINATL

Ubiquitin

VTPRSSVELPPYSGTVLCGTQA

QALVACPPMYHLMKFIPLYS

carboxyl-

VDKLPDGQEYQRIEFGVDEVIE

KVQRPCTSTPMIDSFVRLMN

terminal

PSDTLPRTPSYSISSTLNPQAP

EFTNMPVPPKPRQALGDKIV

hydrolase

EFILGCTASKITPDGITKEASY

RDIRPGAAFEPTYIYRLLTV

10

GSIDCQYPGSALALDGSSNVEA

NKSSLSEKGRQEDAEEYLGF

EVLENDGVSGGLGQRERKKKKK

ILNGLHEEMLNLKKLLSPSN

RPPGYYSYLKDGGDDSISTEAL

EKLTISNGPKNHSVNEEEQE

VNGHANSAVPNSVSAEDAEFMG

EQGEGSEDEWEQVGPRNKTS

DMPPSVTPRTCNSPQNSTDSVS

VTRQADFVQTPITGIFGGHI

DIVPDSPFPGALGSDTRTAGQP

RSVVYQQSSKESATLQPFFT

EGGPGADFGQSCFPAEAGRDTL

LQLDIQSDKIRTVQDALESL

SRTAGAQPCVGTDTTENLGVAN

VARESVQGYTTKTKQEVEIS

GQILESSGEGTATN

RRVTLEKLPPVLVLHLKRFV

GVELHTTESIDLDPTKPESASP

YEKTGGCQKLIKNIEYPVDL

PADGTGSASGTLPVSQPKSWAS

EISKELLSPGVKNKNFKCHR

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

EGDLKLLRSSLLAVRGQKQDTP

DYVLNDNPEGDLKLLRSSLL

49

VRRGRTLRSMASGEDVVLPQRA

AVRGQKQDTPVRRGRTLRSM

PQGQPQMLTALWYRRQRLLART

ASGEDVVLPQRAPQGQPQML

LRLWFEKSSRGQAKLEQRRQEE

TALWYRRQRLLARTLRLWFE

ALERKKEEARRRRREVKRRLLE

KSSRGQAKLEQRRQEEALER

ELASTPPRKSARLLLHTPRDAG

KKEEARRRRREVKRRLLEEL

PAASRPAALPTSRRVPAATLKL

ASTPPRKSARLLLHTPRDAG

RRQPAMAPGVTGLRNLGNTCYM

PAASRPAALPTSRRVPAATL

NSILQVLSHLQKFRECFLNLDP

KLRRQPAMAPGVTGLRNLGN

SKTEHLFPKATNGK

TCYMNSILQVLSHLQKFREC

TQLSGKPTNSSATELSLRNDRA

FLNLDPSKTEHLFPKATNGK

EACEREGFCWNGRASISRSLEL

TQLSGKPTNSSATELSLRND

IQNKEPSSKHISLCRELHTLFR

RAEACEREGFCWNGRASISR

VMWSGKWALVSPFAMLHSVWSL

SLELIQNKEPSSKHISLCRE

IPAFRGYDQQDAQEFLCELLHK

LHTLFRVMWSGKWALVSPFA

VQQELESEGTTRRILIPFSQRK

MLHSVWSLIPAFRGYDQQDA

LTKQVLKVVNTIFHGQLLSQVT

QEFLCELLHKVQQELESEGT

CISCNYKSNTIEPFWDLSLEFP

TRRILIPFSQRKLTKQVLKV

ERYHCIEKGFVPLNQTECLLTE

VNTIFHGQLLSQVTCISCNY

MLAKFTETEALEGRIYACDQCN

KSNTIEPFWDLSLEFPERYH

SKRRKSNPKPLVLSEARKQLMI

CIEKGFVPLNQTECLLTEML

YRLPQVLRLHLKRFRWSGRNHR

AKFTETEALEGRIYACDQCN

EKIGVHVVFDQVLTMEPYCCRD

SKRRKSNPKPLVLSEARKQL

MLSSLDKETFAYDL

MIYRLPQVLRLHLKRFRWSG

SAVVMHHGKGFGSGHYTAYCYN

RNHREKIGVHVVFDQVLTME

TEGGFWVHCNDSKLNVCSVEEV

PYCCRDMLSSLDKETFAYDL

CKTQAYILFYTQRTVQGNARIS

SAVVMHHGKGFGSGHYTAYC

ETHLQAQVQSSNNDEGRPQTFS

YNTEGGFWVHCNDSKLNVCS

VEEVCKTQAYILFYTQRT

U17L8_HUMAN
30
MEDDSLYLGGEWQFNHFSKLTS
142
AVGAGLQNMGNTCYLNASLQ

Inactive

PRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

ubiquitin

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

carboxyl-

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

terminal

CYLNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

hydrolase

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

17-like

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

protein 8

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYPCGL

GCWRSQIKCLHCHGISDTFDPY

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

KPVGTKKLTKSFGWETLDSFMQ

DKPVGTKKLTKSFGWETLDS

HDVQELCRVLLDNVENKMKGTC

FMQHDVQELCRVLLDNVENK

VEGTIPKLFRGKMVSYIQCKEV

MKGTCVEGTIPKLFRGKMVS

DYRSDRREDYYDIQLSIKGKKN

YIQCKEVDYRSDRREDYYDI

IFESFVDYVAVEQLDGDNKYDA

QLSIKGKKNIFESFVDYVAV

GEHGLQEAEKGVKFLTLPPVLH

EQLDGDNKYDAGEHGLQEAE

LQLMRFMYDPQTDQNIKINDRF

KGVKFLTLPPVLHLQLMRFM

EFPEQLPLDEFLQKTDPKDPAN

YDPQTDQNIKINDRFEFPEQ

YILHAVLVHSGDNHGGHYVVYL

LPLDEFLQKTDPKDPANYIL

NPKGDGKWCKFDDDVVSRCTKE

HAVLVHSGDNHGGHYVVYLN

EAIEHNYGGHDDDLSVRHCTNA

PKGDGKWCKFDDDVVSRCTK

YMLVYIRESKLSEVLQAVTDHD

EEAIEHNYGGHDDDLSVRHC

IPQQLVERLQEEKRIEAQKR

TNAYMLVYIRE

6DGF_1
32
AQGLAGLRNLGNTCFMNSILQC
144
AQGLAGLRNLGNTCFMNSIL

LSNTRELRDYCLQRLYMRDLHH

QCLSNTRELRDYCLQRLYMR

GSNAHTALVEEFAKLIQTIWTS

DLHHGSNAHTALVEEFAKLI

SPNDVVSPSEFKTQIQRYAPRF

QTIWTSSPNDVVSPSEFKTQ

VGYNQQDAQEFLRFLLDGLHNE

IQRYAPRFVGYNQQDAQEFL

VNRVTLRPKSNPENLDHLPDDE

RFLLDGLHNEVNRVTLRPKS

KGRQMWRKYLEREDSRIGDLFV

NPENLDHLPDDEKGRQMWRK

GQLKSSLTCTDCGYCSTVEDPF

YLEREDSRIGDLFVGQLKSS

WDLSLPIAKRGYPEVTLMDCMR

LTCTDCGYCSTVFDPFWDLS

LFTKEDVLDGDEKPTCCRCRGR

LPIAKRGYPEVTLMDCMRLF

KRCIKKFSIQRFPKILVLHLKR

TKEDVLDGDEKPTCCRCRGR

FSESRIRTSKLTTFVNFPLRDL

KRCIKKFSIQRFPKILVLHL

DLREFASENTNHAVYNLYAVSN

KRFSESRIRTSKLTTFVNFP

HSGTTMGGHYTAYCRSPGTGEW

LRDLDLREFASENTNHAVYN

HTFNDSSVTPMSSSQVRTSDAY

LYAVSNHSGTTMGGHYTAYC

LLFYELASPPSRM

RSPGTGEWHTFNDSSVTPMS

SSQVRTSDAYLLFYELAS

2VHF_1
33
GLEIMIGKKKGIQGHYNSCYLD
145
MIGKKKGIQGHYNSCYLDST

STLFCLFAFSSVLDTVLLRPKE

LFCLFAFSSVLDTVLLRPKE

KNDVEYYSETQELLRTEIVNPL

KNDVEYYSETQELLRTEIVN

RIYGYVCATKIMKLRKILEKVE

PLRIYGYVCATKIMKLRKIL

AASGFTSEEKDPEEFLNILFHH

EKVEAASGFTSEEKDPEEFL

ILRVEPLLKIRSAGQKVQDCYF

NILFHHILRVEPLLKIRSAG

YQIFMEKNEKVGVPTIQQLLEW

QKVQDCYFYQIFMEKNEKVG

SFINSNLKFAEAPSCLIIQMPR

VPTIQQLLEWSFINSNLKFA

FGKDFKLFKKIFPSLELNITDL

EAPSCLIIQMPRFGKDEKLF

LEDTPRQCRICGGLAMYECREC

KKIFPSLELNITDLLEDTPR

YDDPDISAGKIKQFCKTCNTQV

QCRICGGLAMYECRECYDDP

HLHPKRLNHKYNPVSLPKDLPD

DISAGKIKQFCKTCNTQVHL

WDWRHGCIPCQNMELFAVLCIE

HPKRLNHKYNPVSLPKDLPD

TSHYVAFVKYGKDDSAWLFFDS

WDWRHGCIPCQNMELFAVLC

MADRDGGQNGFNIPQVTPCPEV

IETSHYVAFVKYGKDDSAWL

GEYLKMSLEDLHSLDSRRIQGC

FFDSMADRDGGQNGFNIPQV

ARRLLCDAYMCMYQSPTMSLYK

TPCPEVGEYLKMSLEDLHSL

DSRRIQGCARRLLCDAYMCM

YQS

U17LI_HUMAN
34
MEDDSLYLGGEWQFNHFSKLTS
146
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 18

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

HIHEHAKAKRHNLAIDLMYGGI

QDAHEFLIAALDVLHRHCKG

22

YCFLCQDYIYDKDMEIIAKEEQ

DDNGKKANNPNHCNCIIDQI

RKAWKMQGVGEKFSTWEPTKRE

FTGGLQSDVTCQVCHGVSTT

LELLKHNPKRRKITSNCTIGLR

IDPFWDISLDLPGSSTPFWP

GLINLGNTCFMNCIVQALTHTP

LSPGSEGNVVNGESHVSGTT

LLRDFFLSDRHRCEMQSPSSCL

TLTDCLRRFTRPEHLGSSAK

VCEMSSLFQEFYSGHRSPHIPY

IKCSGCHSYQESTKQLTMKK

KLLHLVWTHARHLAGYEQQDAH

LPIVACFHLKRFEHSAKLRR

EFLIAALDVLHRHCKGDDNGKK

KITTYVSFPLELDMTPFMAS

ANNPNHCNCIIDQIFTGGLQSD

SKESRMNGQYQQPTDSLNND

VTCQVCHGVSTTIDPFWDISLD

NKYSLFAVVNHQGTLESGHY

LPGSSTPFWPLSPGSEGNVVNG

TSFIRQHKDQWFKCDDAIIT

ESHVSGTTTLTDCLRRFTRPEH

KASIKDVLDSEGYLLFYHKQ

LGSSAKIKCSGCHSYQESTKQL

F

TMKKLPIVACFHLKRFEHSAKL

RRKITTYVSFPLELDMTPEMAS

SKESRMNGQYQQPTDSLNNDNK

YSLFAVVNHQGTLESGHYTSFI

RQHKDQWFKCDDAIITKASIKD

VLDSEGYLLFYHKQFLEYE

UBP18_HUMAN
36
MSKAFGLLRQICQSILAESSQS
148
KGLVPGLVNLGNTCFMNSLL

Ubl

PADLEEKKEEDSNMKREQPRER

QGLSACPAFIRWLEEFTSQY

carboxyl-

PRAWDYPHGLVGLHNIGQTCCL

SRDQKEPPSHQYLSLTLLHL

terminal

NSLIQVFVMNVDFTRILKRITV

LKALSCQEVTDDEVLDASCL

hydrolase

PRGADEQRRSVPFQMLLLLEKM

LDVLRMYRWQISSFEEQDAH

18

QDSRQKAVRPLELAYCLQKCNV

ELFHVITSSLEDERDRQPRV

PLFVQHDAAQLYLKLWNLIKDQ

THLFDVHSLEQQSEITPKQI

ITDVHLVERLQALYTIRVKDSL

TCRTRGSPHPTSNHWKSQHP

ICVDCAMESSRNSSMLTLPLSL

FHGRLTSNMVCKHCEHQSPV

FDVDSKPLKTLEDALHCFFQPR

RFDTFDSLSLSIPAATWGHP

ELSSKSKCFCENCGKKTRGKQV

LTLDHCLHHFISSESVRDVV

LKLTHLPQTLTIHLMRESIRNS

CDNCTKIEAKGTLNGEKVEH

QTRKICHSLYFPQSLDESQILP

QRTTFVKQLKLGKLPQCLCI

MKRESCDAEEQSGG

HLQRLSWSSHGTPLKRHEHV

QYELFAVIAHVGMADSGHYCVY

QFNEFLMMDIYKYHLLGHKP

IRNAVDGKWFCFNDSNICLVSW

SQHNPKLNKNPGPTLELQDG

EDIQCTYGNPNYHWQETAYLLV

PGAPTPVLNQPGAPKTQIFM

YMKMEC

NGACSPSLLPTLSAPMPFPL

PVVPDYSSSTYLFRLMAVVV

HHGDMHSGHFVTYRRSPPSA

RNPLSTSNQWLWVSDDTVRK

ASLQEVLSSSAYLLFYERVL

UBP28_HUMAN
37
MTAELQQDDAAGAADGHGSSCQ
149
GWPVGLKNVGNTCWFSAVIQ

Ubiquitin

MLLNQLREITGIQDPSFLHEAL

SLFQLPEFRRLVLSYSLPQN

carboxyl-

KASNGDITQAVSLLTDERVKEP

VLENCRSHTEKRNIMFMQEL

terminal

SQDTVATEPSEVEGSAANKEVL

QYLFALMMGSNRKFVDPSAA

hydrolase

AKVIDLTHDNKDDLQAAIALSL

LDLLKGAFRSSEEQQQDVSE

28

LESPKIQADGRDLNRMHEATSA

FTHKLLDWLEDAFQLAVNVN

ETKRSKRKRCEVWGENPNPNDW

SPRNKSENPMVQLFYGTFLT

RRVDGWPVGLKNVGNTCWFSAV

EGVREGKPFCNNETFGQYPL

IQSLFQLPEFRRLVLSYSLPQN

QVNGYRNLDECLEGAMVEGD

VLENCRSHTEKRNIMFMQELQY

VELLPSDHSVKYGQERWFTK

LFALMMGSNRKFVDPSAALDLL

LPPVLTFELSRFEFNQSLGQ

KGAFRSSEEQQQDVSEFTHKLL

PEKIHNKLEFPQIIYMDRYM

DWLEDAFQLAVNVNSPRNKSEN

YRSKELIRNKRECIRKLKEE

PMVQLFYGTFLTEG

IKILQQKLERYVKYGSGPAR

VREGKPFCNNETFGQYPLQVNG

FPLPDMLKYVIEFASTKPAS

YRNLDECLEGAMVEGDVELLPS

ESCPPESDTHMTLPLSSVHC

DHSVKYGQERWFTKLPPVLTFE

SVSDQTSKESTSTESSSQDV

LSRFEFNQSLGQPEKIHNKLEF

ESTFSSPEDSLPKSKPLTSS

PQIIYMDRYMYRSKELIRNKRE

RSSMEMPSQPAPRTVTDEEI

CIRKLKEEIKILQQKLERYVKY

NFVKTCLQRWRSEIEQDIQD

GSGPARFPLPDMLKYVIEFAST

LKTCIASTTQTIEQMYCDPL

KPASESCPPESDTHMTLPLSSV

LRQVPYRLHAVLVHEGQANA

HCSVSDQTSKESTSTESSSQDV

GHYWAYIYNQPRQSWLKYND

ESTFSSPEDSLPKSKPLTSSRS

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
MEDDSLYLGGEWQFNHFSKLTS
150
AVGAGLQNMGNTCYENASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

SEARVDLCDDLAPVARQLAPRK

CQRPKCCMLCTMQAHITWAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

hydrolase

CYENASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVTGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHDGHYF

TGNKLAKNVQYPEC

SYVKAQEGQWYKMDDAKVTA

LDMQPYMSQQNTGPLVYVLYAV

CSITSVLSQQAYVLFYIQKS

LVHAGWSCHDGHYFSYVKAQEG

QWYKMDDAKVTACSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDERLVERATQES

TLDHWKFPQEQNKTKPEFNVRK

VEGTLPPNVLVIHQSKYKCGMK

NHHPEQQSSLLNLSSTTRTDQE

SVNTGTLASLQGRTRRSKGKNK

HSKRALLVCQ

UBP31_HUMAN
39
MSKVTAPGSGPPAAASGKEKRS
151
PVPGVAGLRNHGNTCFMNAT

Ubiquitin

FSKRLFRSGRAGGGGAGGPGAS

LQCLSNTELFAEYLALGQYR

carboxyl-

GPAAPSSPSSPSSARSVGSEMS

AGRPEPSPDPEQPAGRGAQG

terminal

RVLKTLSTLSHLSSEGAAPDRG

QGEVTEQLAHLVRALWTLEY

hydrolase

GLRSCFPPGPAAAPTPPPCPPP

TPQHSRDFKTIVSKNALQYR

31

PASPAPPACAAEPVPGVAGLRN

GNSQHDAQEFLLWLLDRVHE

HGNTCFMNATLQCLSNTELFAE

DLNHSVKQSGQPPLKPPSET

YLALGQYRAGRPEPSPDPEQPA

DMMPEGPSFPVCSTFVQELF

GRGAQGQGEVTEQLAHLVRALW

QAQYRSSLTCPHCQKQSNTF

TLEYTPQHSRDFKTIVSKNALQ

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

DKETRDFLFVNTEDEYIPDA

KYFLRPTVCIQVCPFSLRVVSV

ESVRLQRERHHQPQTCTLSQ

VGITYLLPQEEQPLCHPIVERA

CFQLYTKEERLAPDDAWRCP

LKSCGPGGTAHVKLVVEWDKET

HCKQLQQGSITLSLWTLPDV

RDFLFVNTEDEYIPDAESVRLQ

LIIHLKRFRQEGDRRMKLQN

RERHHQPQTCTLSQ

MVKFPLTGLDMTPHVVKRSQ

CFQLYTKEERLAPDDAWRCPHC

SSWSLPSHWSPWRRPYGLGR

KQLQQGSITLSLWTLPDVLIIH

DPEDYIYDLYAVCNHHGTMQ

LKRFRQEGDRRMKLQNMVKFPL

GGHYTAYCKNSVDGLWYCFD

TGLDMTPHVVKRSQSSWSLPSH

DSDVQQLSEDEVCTQTAYIL

WSPWRRPYGLGRDPEDYIYDLY

FYQRRT

AVCNHHGTMQGGHYTAYCKNSV

DGLWYCFDDSDVQQLSEDEVCT

QTAYILFYQRRTAIPSWSANSS

VAGSTSSSLCEHWVSRLPGSKP

ASVTSAASSRRTSLASLSESVE

MTGERSEDDGGFSTRPFVRSVQ

RQSLSSRSSVTSPLAVNENCMR

PSWSLSAKLQMRSNSPSRFSGD

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
MEEDSLYLGGEWQFNHFSKLTS
152
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 19

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
MEDDSLYLGGEWQFNHFSKLTS
153
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 15

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

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
MVPGEENQLVPKEDVFWRCRQN
154
ETGYVGLVNQAMTCYLNSLL

Ubiquitin

IFDEMKKKFLQIENAAEEPRVL

QTLFMTPEFRNALYKWEFEE

carboxyl-

CIIQDTTNSKTVNERITLNLPA

SEEDPVTSIPYQLQRLFVLL

terminal

STPVRKLFEDVANKVGYINGTF

QTSKKRAIETTDVTRSFGWD

hydrolase

DLVWGNGINTADMAPLDHTSDK

SSEAWQQHDVQELCRVMFDA

47

SLLDANFEPGKKNFLHLTDKDG

LEQKWKQTEQADLINELYQG

EQPQILLEDSSAGEDSVHDRFI

KLKDYVRCLECGYEGWRIDT

GPLPREGSGGSTSDYVSQSYSY

YLDIPLVIRPYGSSQAFASV

SSILNKSETGYVGLVNQAMTCY

EEALHAFIQPEILDGPNQYF

LNSLLQTLFMTPEFRNALYKWE

CERCKKKCDARKGLRFLHFP

FEESEEDPVTSIPYQLQRLFVL

YLLTLQLKRFDFDYTTMHRI

LQTSKKRAIETTDVTRSFGWDS

KLNDRMTFPEELDMSTFIDV

SEAWQQHDVQELCRVMFDALEQ

EDEKSPQTESCTDSGAENEG

KWKQTEQADLINEL

SCHSDQMSNDFSNDDGVDEG

YQGKLKDYVRCLECGYEGWRID

ICLETNSGTEKISKSGLEKN

TYLDIPLVIRPYGSSQAFASVE

SLIYELFSVMVHSGSAAGGH

EALHAFIQPEILDGPNQYFCER

YYACIKSFSDEQWYSFNDQH

CKKKCDARKGLRFLHFPYLLTL

VSRITQEDIKKTHGGSSGSR

QLKRFDFDYTTMHRIKLNDRMT

GYYSSAFASSTNAYMLIYRL

FPEELDMSTFIDVEDEKSPQTE

KD

SCTDSGAENEGSCHSDQMSNDF

SNDDGVDEGICLETNSGTEKIS

KSGLEKNSLIYELFSVMVHSGS

AAGGHYYACIKSFSDEQWYSFN

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

SSHFKVFRVYASNQEFESVRLN

ETLSSFSDDNKITIRLGRALKK

GEYRVKVYQLLVNEQEPCKFLL

DAVFAKGMTVRQSKEELIPQLR

EQCGLELSIDRFRLRKKTWKNP

GTVFLDYHIYEEDI

NISSNWEVFLEVLDGVEKMKSM

SQLAVLSRRWKPSEMKLDPFQE

VVLESSSVDELREKLSEISGIP

LDDIEFAKGRGTFPCDISVLDI

HQDLDWNPKVSTLNVWPLYICD

DGAVIFYRDKTEELMELTDEQR

NELMKKESSRLQKTGHRVTYSP

RKEKALKIYLDGAPNKDLTQD

UBP51_HUMAN
43
MAQVRETSLPSGSGVRWISGGG
155
YTVGLRGLINLGNTCFMNCI

Ubiquitin

GGASPEEAVEKAGKMEEAAAGA

VQALTHIPLLKDFFLSDKHK

carboxyl-

TKASSRREAEEMKLEPLQEREP

CIMTSPSLCLVCEMSSLFHA

terminal

APEENLTWSSSGGDEKVLPSIP

MYSGSRTPHIPYKLLHLIWI

hydrolase

LRCHSSSSPVCPRRKPRPRPQP

HAEHLAGYRQQDAHEFLIAI

51

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

TYESCGDGVPAPQKVLFPTERL

RHFREGNQEDAHEFLRYTID

36

SLRWERVFRVGAGLHNLGNTCF

AMQKACLNGCAKLDRQTQAT

LNATIQCLTYTPPLANYLLSKE

TLVHQIFGGYLRSRVKCSVC

HARSCHQGSFCMLCVMQNHIVQ

KSVSDTYDPYLDVALEIRQA

AFANSGNAIKPVSFIRDLKKIA

ANIVRALELFVKADVLSGEN

RHFRFGNQEDAHEFLRYTIDAM

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

PEASEPPQSPSEKRKKTFVGEP

QRLGSETRLPQHIREATAAPHG

KRKRKKKKRPEDTAASALQEGQ

TQRQPGSPMYRREGQAQLPAVR

RQEDGTQPQVNGQQ

VGCVTDGHHASSRKRRRKGAEG

LGEEGGLHQDPLRHSCSPMGDG

DPEAMEESPRKKKKKKRKQETQ

RAVEEDGHLKCPRSAKPQDAVV

PESSSCAPSANGWCPGDRMGLS

QAPPVSWNGERESDVVQELLKY

SSDKAYGRKVLTWDGKMSAVSQ

DAIEDSRQARTETVVDDWDEEF

DRGKEKKIKKEKREKRRNFNAF

QKLQTRRNFWSVTHPAKAASLS

YRR

UBP44_HUMAN
45
MLAMDTCKHVGQLQLAQDHSSL
157
TPGVTGLRNLGNTCYMNSVL

Ubiquitin

NPQKWHCVDCNTTESIWACLSC

QVLSHLLIFRQCFLKLDLNQ

carboxyl-

SHVACGRYIEEHALKHFQESSH

WLAMTASEKTRSCKHPPVTD

terminal

PVALEVNEMYVFCYLCDDYVLN

TVVYQMNECQEKDTGFVCSR

hydrolase

DNTTGDLKLLRRTLSAIKSQNY

QSSLSSGLSGGASKGRKMEL

44

HCTTRSGRFLRSMGTGDDSYFL

IQPKEPTSQYISLCHELHTL

HDGAQSLLQSEDQLYTALWHRR

FQVMWSGKWALVSPFAMLHS

RILMGKIFRTWFEQSPIGRKKQ

VWRLIPAFRGYAQQDAQEFL

EEPFQEKIVVKREVKKRRQELE

CELLDKIQRELETTGTSLPA

YQVKAELESMPPRKSLRLQGLA

LIPTSQRKLIKQVLNVVNNI

QSTIIEIVSVQVPAQTPASPAK

FHGQLLSQVTCLACDNKSNT

DKVLSTSENEISQKVSDSSVKR

IEPFWDLSLEFPERYQCSGK

RPIVTPGVTGLRNLGNTCYMNS

DIASQPCLVTEMLAKFTETE

VLQVLSHLLIFRQC

ALEGKIYVCDQCNSKRRRFS

FLKLDLNQWLAMTASEKTRSCK

SKPVVLTEAQKQLMICHLPQ

HPPVTDTVVYQMNECQEKDTGF

VLRLHLKRFRWSGRNNREKI

VCSRQSSLSSGLSGGASKGRKM

GVHVGFEEILNMEPYCCRET

ELIQPKEPTSQYISLCHELHTL

LKSLRPECFIYDLSAVVMHH

FQVMWSGKWALVSPFAMLHSVW

GKGFGSGHYTAYCYNSEGGF

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

CLCNAPHLADYFNRNCYQDD

carboxyl-

KTAEECRLDRDEERAYVLYMKY

INRSNLLGHKGEVAEEFGII

terminal

VTVYNLIKKRPDFKQQQDYFHS

MKALWTGQYRYISPKDEKIT

hydrolase

ILGPGNIKKAVEEAERLSESLK

IGKINDQFAGYSQQDSQELL

8

LRYEEAEVRKKLEEKDRQEEAQ

LFLMDGLHEDLNKADNRKRY

RLQQKRQETGREDGGTLAKGSL

KEENNDHLDDFKAAEHAWQK

ENVLDSKDKTQKSNGEKNEKCE

HKQLNESIIVALFQGQFKST

TKEKGAITAKELYTMMTDKNIS

VQCLTCHKKSRTFEAFMYLS

LIIMDARRMQDYQDSCILHSLS

LPLASTSKCTLQDCLRLFSK

VPEEAISPGVTASWIEAHLPDD

EEKLTDNNRFYCSHCRARRD

SKDTWKKRGNVEYVVLLDWFSS

SLKKIEIWKLPPVLLVHLKR

AKDLQIGTTLRSLKDALFKWES

FSYDGRWKQKLQTSVDFPLE

KTVLRNEPLVLEGG

NLDLSQYVIGPKNNLKKYNL

YENWLLCYPQYTTNAKVTPPPR

FSVSNHYGGLDGGHYTAYCK

RQNEEVSISLDFTYPSLEESIP

NAARQRWFKFDDHEVSDISV

SKPAAQTPPASIEVDENIELIS

SSVKSSAAYILFYTSLG

GQNERMGPLNISTPVEPVAASK

SDVSPIIQPVPSIKNVPQIDRT

KKPAVKLPEEHRIKSESTNHEQ

QSPQSGKVIPDRSTKPVVFSPT

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

LKRFSYDGRWKQKLQTSVDEPL

ENLDLSQYVIGPKNNLKKYNLF

SVSNHYGGLDGGHYTAYCKNAA

RQRWFKFDDHEVSDISVSSVKS

SAAYILFYTSLGPRVTDVAT

UBP37_HUM
47
MSPLKIHGPIRIRSMQTGITKW
159
QQLQGFSNLGNTCYMNAILQ

AN Ubiquitin

KEGSFEIVEKENKVSLVVHYNT

SLFSLQSFANDLLKQGIPWK

carboxyl-

GGIPRIFQLSHNIKNVVLRPSG

KIPLNALIRRFAHLLVKKDI

terminal

AKQSRLMLTLQDNSFLSIDKVP

CNSETKKDLLKKVKNAISAT

hydrolase 37

SKDAEEMRLFLDAVHQNRLPAA

AERFSGYMQNDAHEFLSQCL

MKPSQGSGSFGAILGSRTSQKE

DQLKEDMEKLNKTWKTEPVS

TSRQLSYSDNQASAKRGSLETK

GEENSPDISATRAYTCPVIT

DDIPFRKVLGNPGRGSIKTVAG

NLEFEVQHSIICKACGEIIP

SGIARTIPSLTSTSTPLRSGLL

KREQFNDLSIDLPRRKKPLP

ENRTEKRKRMISTGSELNEDYP

PRSIQDSLDLFFRAEELEYS

KENDSSSNNKAMTDPSRKYLTS

CEKCGGKCALVRHKFNRLPR

SREKQLSLKQSEENRTSGLLPL

VLILHLKRYSFNVALSLNNK

QSSSFYGSRAGSKEHSSGGTNL

IGQQVIIPRYLTLSSHCTEN

DRTNVSSQTPSAKR

TKP

SLGFLPQPVPLSVKKLRCNQDY

PFTLGWSAHMAISRPLKASQ

TGWNKPRVPLSSHQQQQLQGFS

MVNSCITSPSTPSKKFTFKS

NLGNTCYMNAILQSLFSLQSFA

KSSLALCLDSDSEDELKRSV

NDLLKQGIPWKKIPLNALIRRF

ALSQRLCEMLGNEQQQEDLE

AHLLVKKDICNSETKKDLLKKV

KDSKLCPIEPDKSELENSGF

KNAISATAERFSGYMQNDAHEF

DRMSEEELLAAVLEISKRDA

LSQCLDQLKEDMEKLNKTWKTE

SPSLSHEDDDKPTSSPDTGF

PVSGEENSPDISATRAYTCPVI

AEDDIQEMPENPDTMETEKP

TNLEFEVQHSIICKACGEIIPK

KTITELDPASFTEITKDCDE

REQFNDLSIDLPRRKKPLPPRS

NKENKTPEGSQGEVDWLQQY

IQDSLDLFFRAEELEYSCEKCG

DMEREREEQELQQALAQSLQ

GKCALVRHKFNRLPRVLILHLK

EQEAWEQKEDDDLKRATELS

RYSFNVALSLNNKIGQQVIIPR

LQEFNNSFVDALGSDEDSGN

YLTLSSHCTENTKP

EDVFDMEYTEAEAEELKRNA

PFTLGWSAHMAISRPLKASQMV

ETGNLPHSYRLISVVSHIGS

NSCITSPSTPSKKFTFKSKSSL

TSSSGHYISDVYDIKKQAWF

ALCLDSDSEDELKRSVALSQRL

TYNDLEVSKIQEAAVQSDRD

CEMLGNEQQQEDLEKDSKLCPI

RSGYIFFYMHK

EPDKSELENSGFDRMSEEELLA

AVLEISKRDASPSLSHEDDDKP

TSSPDTGFAEDDIQEMPENPDT

METEKPKTITELDPASFTEITK

DCDENKENKTPEGSQGEVDWLQ

QYDMEREREEQELQQALAQSLQ

EQEAWEQKEDDDLKRATELSLQ

EFNNSFVDALGSDEDSGNEDVF

DMEYTEAEAEELKRNAETGNLP

HSYRLISVVSHIGS

TSSSGHYISDVYDIKKQAWFTY

NDLEVSKIQEAAVQSDRDRSGY

IFFYMHKEIFDELLETEKNSQS

LSTEVGKTTRQAL

U17LD_HUMAN
48
MEEDSLYLGGEWQFNHESKLTS
160
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRLDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLVPEARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHPSKDTTLIHQI

protein 13

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHPSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

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

CYENASLQCLTYTLPLANYMLS

KQEDVHEFLMFTVDAMKKAC

17-like

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 3

TWALHSPGHVIQPSQALASGFH

FGGCWRSQIKCLHCHGISDT

RGKQEDVHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTFDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVAGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHDGHYF

AGNKLAKNVQYPEC

SYVKAQEGQWYKMDDAEVTV

LDMQPYMSQQNTGPLVYVLYAV

CSITSVLSQQAYVLFYIQKS

LVHAGWSCHDGHYFSYVKAQEG

QWYKMDDAEVTVCSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRAKQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVGK

VEGTLPPNALVIHQSKYKCGMK

NHHPEQQSSLLNLSSTTRTDQE

SMNTGTLASLQGRTRRAKGKNK

HSKRALLVCQ

UBP54_HUMAN
50
MSWKRNYFSGGRGSVQGMFAPR
162
APSKGLSNEPGQNSCFLNSA

Inactive

SSTSIAPSKGLSNEPGQNSCFL

LQVLWHLDIFRRSFRQLTTH

ubiquitin

NSALQVLWHLDIFRRSFRQLTT

KCMGDSCIFCALKGIFNQFQ

carboxyl-

HKCMGDSCIFCALKGIFNQFQC

CSSEKVLPSDTLRSALAKTF

terminal

SSEKVLPSDTLRSALAKTFQDE

QDEQRFQLGIMDDAAECFEN

hydrolase

QRFQLGIMDDAAECFENLLMRI

LLMRIHFHIADETKEDICTA

54

HFHIADETKEDICTAQHCISHQ

QHCISHQKFAMTLFEQCVCT

KFAMTLFEQCVCTSCGATSDPL

SCGATSDPLPFIQ

PFIQMVHYISTTSLCNQAICML

MVHYISTTSLCNQAICMLER

ERREKPSPSMFGELLQNASTMG

REKPSPSMFGELLQNASTMG

DLRNCPSNCGERIRIRRVLMNA

DLRNCPSNCGERIRIRRVLM

PQIITIGLVWDSDHSDLAEDVI

NAPQIITIGLVWDSDHSDLA

HSLGTCLKLGDLFFRVTDDRAK

EDVIHSLGTCLKLGDLFFRV

QSELYLVGMICYYG

TDDRAKQSELYLVGMICYYG

KHYSTFFFQTKIRKWMYFDDAH

KHYSTFFFQTKIRKWMYFDD

VKEIGPKWKDVVTKCIKGHYQP

AHVKEIGPKWKDVVTKCIKG

LLLLYADPQGTPVSTQDLPPQA

HYQPLLLLYADPQGTPVSTQ

EFQSYSRTCYDSEDSGREPSIS

DLPPQAEFQSYSRTCYDSED

SDTRTDSSTESYPYKHSHHESV

SGREPSISSDTRTDSSTESY

VSHFSSDSQGTVIYNVENDSMS

PYKHSHHESVVSHFSSDSQG

QSSRDTGHLTDSECNQKHTSKK

TVIYNVEND

GSLIERKRSSGRVRRKGDEPQA

SGYHSEGETLKEKQAPRNASKP

SSSTNRLRDFKETVSNMIHNRP

SLASQTNVGSHCRGRGGDQPDK

KPPRTLPLHSRDWEIESTSSES

KSSSSSKYRPTWRPKRESLNID

SIFSKDKRKHCGYT

QLSPFSEDSAKEFIPDEPSKPP

SYDIKFGGPSPQYKRWGPARPG

SHLLEQHPRLIQRMESGYESSE

RNSSSPVSLDAALPESSNVYRD

PSAKRSAGLVPSWRHIPKSHSS

SILEVDSTASMGGWTKSQPFSG

EEISSKSELDELQEEVARRAQE

QELRRKREKELEAAKGENPHPS

RFMDLDELQNQGRSDGFERSLQ

EAESVFEESLHLEQKGDCAAAL

ALCNEAISKLRLALHGASCSTH

SRALVDKKLQISIRKARSLQDR

MQQQQSPQQPSQPSACLPTQAG

TLSQPTSEQPIPLQ

VLLSQEAQLESGMDTEFGASSF

FHSPASCHESHSSLSPESSAPQ

HSSPSRSALKLLTSVEVDNIEP

SAFHRQGLPKAPGWTEKNSHHS

WEPLDAPEGKLQGSRCDNSSCS

KLPPQEGRGIAQEQLFQEKKDP

ANPSPVMPGIATSERGDEHSLG

CSPSNSSAQPSLPLYRTCHPIM

PVASSFVLHCPDPVQKTNQCLQ

GQSLKTSLTLKVDRGSEETYRP

EFPSTKGLVRSLAEQFQRMQGV

SMRDSTGFKDRSLSGSLRKNSS

PSDSKPPESQGQEKGHWPWAKQ

QSSLEGGDRPLSWE

ESTEHSSLALNSGLPNGETSSG

GQPRLAEPDIYQEKLSQVRDVR

SKDLGSSTDLGTSLPLDSWVNI

TRFCDSQLKHGAPRPGMKSSPH

DSHTCVTYPERNHILLHPHWNQ

DTEQETSELESLYQASLQASQA

GCSGWGQQDTAWHPLSQTGSAD

GMGRRLHSAHDPGLSKTSTAEM

EHGLHEARTVRTSQATPCRGLS

RECGEDEQYSAENLRRISRSLS

GTVVSEREEAPVSSHSEDSSNV

RKPLETGHRCSSSSSLPVIHDP

SVFLLGPQLYLPQPQFLSPDVL

MPTMAGEPNRLPGT

SRSVQQFLAMCDRGETSQGAKY

TGRTLNYQSLPHRSRTDNSWAP

WSETNQHIGTRFLTTPGCNPQL

TYTATLPERSKGLQVPHTQSWS

DLFHSPSHPPIVHPVYPPSSSL

HVPLRSAWNSDPVPGSRTPGPR

RVDMPPDDDWRQSSYASHSGHR

RTVGEGFLFVLSDAPRREQIRA

RVLQHSQW

SNUT2_HUMAN
51
MSGRSKRESRGSTRGKRESESR
163
LPGIVGLNNIKANDYANAVL

U4/U6.U5

GSSGRVKRERDREREPEAASSR

QALSNVPPLRNYFLEEDNYK

tri-snRNP-

GSPVRVKREFEPASAREAPASV

NIKRPPGDIMFLLVQRFGEL

associated

VPFVRVKREREVDEDSEPEREV

MRKLWNPRNFKAHVSPHEML

protein 2

RAKNGRVDSEDRRSRHCPYLDT

QAVVLCSKKTFQITKQGDGV

INRSVLDEDFEKLCSISLSHIN

DFLSWFLNALHSALGGTKKK

AYACLVCGKYFQGRGLKSHAYI

KKTIVTDVFQGSMRIFTKKL

HSVQFSHHVFLNLHTLKFYCLP

PHPDLPAEEKEQLLHNDEYQ

DNYEIIDSSLEDITYVLKPTFT

ETMVESTFMYLTLDLPTAPL

KQQIANLDKQAKLSRAYDGTTY

YKDEKEQLIIPQVPLENILA

LPGIVGLNNIKANDYANAVLQA

KFNGITEKEYKTYKENFLKR

LSNVPPLRNYFLEEDNYKNIKR

FQLTKLPPYLIFCIKRFTKN

PPGDIMFLLVQRFGELMRKLWN

NFFVEKNPTIVNFPITNVDL

PRNFKAHVSPHEML

REYLSEEVQAVHKNTTYDLI

QAVVLCSKKTFQITKQGDGVDF

ANIVHDGKPSEGSYRIHVLH

LSWFLNALHSALGGTKKKKKTI

HGTGKWYELQDLQVTDILPQ

VTDVFQGSMRIFTKKLPHPDLP

MITLSEAYIQIWKRRD

AEEKEQLLHNDEYQETMVESTF

MYLTLDLPTAPLYKDEKEQLII

PQVPLFNILAKFNGITEKEYKT

YKENFLKRFQLTKLPPYLIFCI

KRFTKNNFFVEKNPTIVNEPIT

NVDLREYLSEEVQAVHKNTTYD

LIANIVHDGKPSEGSYRIHVLH

HGTGKWYELQDLQVTDILPQMI

TLSEAYIQIWKRRDNDETNQQG

A

UBP35_HUMAN
52
MDKILEAVVTSSYPVSVKQGLV
164
SDTGKIGLINLGNTCYVNSI

Ubiquitin

RRVLEAARQPLEREQCLALLAL

LQALFMASDERHCVLRLTEN

carboxyl-

GARLYVGGAEELPRRVGCQLLH

NSQPLMTKLQWLFGFLEHSQ

terminal

VAGRHHPDVFAEFFSARRVLRL

RPAISPENFLSASWTPWESP

hydrolase

LQGGAGPPGPRALACVQLGLQL

GTQQDCSEYLKYLLDRLHEE

35

LPEGPAADEVFALLRREVLRTV

EKTGTRICQKLKQSSSPSPP

CERPGPAACAQVARLLARHPRC

EEPPAPSSTSVEKMFGGKIV

VPDGPHRLLFCQQLVRCLGRFR

TRICCLCCLNVSSREEAFTD

CPAEGEEGAVEFLEQAQQVSGL

LSLAFPPPERCRRRRLGSVM

LAQLWRAQPAAILPCLKELFAV

RPTEDITARELPPPTSAQGP

ISCAEEEPPSSALASVVQHLPL

GRVGPRRQRKHCITEDTPPT

ELMDGVVRNLSNDDSVTDSQML

SLYIEGLDSKEAGGQSSQEE

TAISRMIDWVSWPLGKNIDKWI

RIEREEEGKEERTEKEEVGE

IALLKGLAAVKKFS

EEESTRGEGEREKEEEVEEE

ILIEVSLTKIEKVESKLLYPIV

EEKVE

RGAALSVLKYMLLTFQHSHEAF

KETEKEAEQEKEEDSLGAGT

HLLLPHIPPMVASLVKEDSNSG

HPDAAIPSGERTCGSEGSRS

TSCLEQLAELVHCMVFRFPGFP

VLDLVNYFLSPEKLTAENRY

DLYEPVMEAIKDLHVPNEDRIK

YCESCASLQDAEKVVELSQG

QLLGQDAWTSQKSELAGFYPRL

PCYLILTLLRFSFDLRTMRR

MAKSDTGKIGLINLGNTCYVNS

RKILDDVSIPLLLRLPLAGG

ILQALFMASDFRHCVLRLTENN

RGQAYDLCSVVVHSGVSSES

SQPLMTKLQWLFGFLEHSQRPA

GHYYCYAREGAARPAASLGT

ISPENFLSASWTPWFSPGTQQD

ADRPEPENQWYLFNDTRVSF

CSEYLKYLLDRLHEEEKTGTRI

SSFESVSNVTSFFPKDTAYV

CQKLKQSSSPSPPEEPPAPSST

LFYRQRP

SVEKMFGGKIVTRICCLCCLNV

SSREEAFTDLSLAF

PPPERCRRRRLGSVMRPTEDIT

ARELPPPTSAQGPGRVGPRRQR

KHCITEDTPPTSLYIEGLDSKE

AGGQSSQEERIEREEEGKEERT

EKEEVGEEEESTRGEGEREKEE

EVEEEEEKVEKETEKEAEQEKE

EDSLGAGTHPDAAIPSGERTCG

SEGSRSVLDLVNYFLSPEKLTA

ENRYYCESCASLQDAEKVVELS

QGPCYLILTLLRFSFDLRTMRR

RKILDDVSIPLLLRLPLAGGRG

QAYDLCSVVVHSGVSSESGHYY

CYAREGAARPAASLGTADRPEP

ENQWYLFENDTRVSF

SSFESVSNVTSFFPKDTAYVLF

YRQRPREGPEAELGSSRVRTEP

TLHKDLMEAISKDNILYLQEQE

KEARSRAAYISALPTSPHWGRG

FDEDKDEDEGSPGGCNPAGGNG

GDFHRLVF

UBP15_HUMAN
53
MAEGGAADLDTQRSDIATLLKT
165
EQPGLCGLSNLGNTCFMNSA

Ubiquitin

SLRKGDTWYLVDSRWFKQWKKY

IQCLSNTPPLTEYFLNDKYQ

carboxyl-

VGFDSWDKYQMGDQNVYPGPID

EELNFDNPLGMRGEIAKSYA

terminal

NSGLLKDGDAQSLKEHLIDELD

ELIKQMWSGKFSYVTPRAFK

hydrolase

YILLPTEGWNKLVSWYTLMEGQ

TQVGRFAPQFSGYQQQDCQE

15

EPIARKVVEQGMFVKHCKVEVY

LLAFLLDGLHEDLNRIRKKP

LTELKLCENGNMNNVVTRRFSK

YIQLKDADGRPDKVVAEEAW

ADTIDTIEKEIRKIFSIPDEKE

ENHLKRNDSIIVDIFHGLFK

TRLWNKYMSNTFEPLNKPDSTI

STLVCPECAKISVTFDPFCY

QDAGLYQGQVLVIEQKNEDGTW

LTLPLPMKKERTLEVYLVRM

PRGPSTPKSPGASNFSTLPKIS

DPLTKPMQYKVVVPKIGNIL

PSSLSNNYNNMNNRNVKNSNYC

DLCTALSALSGIPADKMIVT

LPSYTAYKNYDYSEPGRNNEQP

DIYNHRFHRIFAMDENLSSI

GLCGLSNLGNTCFM

MERDDIYVFEININRTEDTE

NSAIQCLSNTPPLTEYFLNDKY

HVIIPVCLREKFRHSSYTHH

QEELNFDNPLGMRGEIAKSYAE

TGSSLFGQPFLMAVPRNNTE

LIKQMWSGKFSYVTPRAFKTQV

DKLYNLLLLRMCRYVKISTE

GRFAPQFSGYQQQDCQELLAFL

TEETEGSLHCCKDQNINGNG

LDGLHEDLNRIRKKPYIQLKDA

PNGIHEEGSPSEMETDEPDD

DGRPDKVVAEEAWENHLKRNDS

ESSQDQELPSENENSQSEDS

IIVDIFHGLFKSTLVCPECAKI

VGGDNDSENGLCTEDTCKGQ

SVTFDPFCYLTLPLPMKKERTL

LTGHKKRLFTFQFNNLGNTD

EVYLVRMDPLTKPMQYKVVVPK

INYIKDDTRHIRFDDRQLRL

IGNILDLCTALSALSGIPADKM

DERSFLALDWDPDLKKRYFD

IVTDIYNHRFHRIFAMDENLSS

ENAAEDFEKHESVEYKPPKK

IMERDDIYVFEININRTEDTEH

PFVKLKDCIELFTTKEKLGA

VIIPVCLREKFRHSSYTHHTGS

EDPWYCPNCKEHQQATKKLD

SLFGQPFLMAVPRN

LWSLPPVLVVHLKRFSYSRY

NTEDKLYNLLLLRMCRYVKIST

MRDKLDTLVDFPINDLDMSE

ETEETEGSLHCCKDQNINGNGP

FLINPNAGPCRYNLIAVSNH

NGIHEEGSPSEMETDEPDDESS

YGGMGGGHYTAFAKNKDDGK

QDQELPSENENSQSEDSVGGDN

WYYFDDSSVSTASEDQIVSK

DSENGLCTEDTCKGQLTGHKKR

AAYVLFYQRQD

LFTFQFNNLGNTDINYIKDDTR

HIRFDDRQLRLDERSFLALDWD

PDLKKRYFDENAAEDFEKHESV

EYKPPKKPFVKLKDCIELFTTK

EKLGAEDPWYCPNCKEHQQATK

KLDLWSLPPVLVVHLKRFSYSR

YMRDKLDTLVDFPINDLDMSEF

LINPNAGPCRYNLIAVSNHYGG

MGGGHYTAFAKNKD

DGKWYYFDDSSVSTASEDQIVS

KAAYVLFYQRQDTFSGTGFFPL

DRETKGASAATGIPLESDEDSN

DNDNDIENENCMHTN

UBP29_HUMAN
54
MISLKVCGFIQIWSQKTGMTKL
166
QLQQGFPNLGNTCYMNAVLQ

Ubiquitin

KEALIETVQRQKEIKLVVTFKS

SLFAIPSFADDLLTQGVPWE

carboxyl-

GKFIRIFQLSNNIRSVVLRHCK

YIPFEALIMTLTQLLALKDF

terminal

KRQSHLRLTLKNNVFLFIDKLS

CSTKIKRELLGNVKKVISAV

hydrolase

YRDAKQLNMFLDIIHQNKSQQP

AEIFSGNMQNDAHEFLGQCL

29

MKSDDDWSVFESRNMLKEIDKT

DQLKEDMEKLNATLNTGKEC

SFYSICNKPSYQKMPLFMSKSP

GDENSSPQMHVGSAATKVFV

THVKKGILENQGGKGQNTLSSD

CPVVANFEFELQLSLICKAC

VQTNEDILKEDNPVPNKKYKTD

GHAVLKVEPNNYLSINLHQE

SLKYIQSNRKNPSSLEDLEKDR

TKPLPLSIQNSLDLFFKEEE

DLKLGPSFNTNCNGNPNLDETV

LEYNCQMCKQKSCVARHTFS

LATQTLNAKNGLTSPLEPEHSQ

RLSRVLIIHLKRYSFNNAWL

GDPRCNKAQVPLDSHSQQLQQG

LVKNNEQVYIPKSLSLSSYC

FPNLGNTCYMNAVL

NESTKPPLPLSSSAPVGKCE

QSLFAIPSFADDLLTQGVPWEY

VLEVSQEMISEINSPLTPSM

IPFEALIMTLTQLLALKDFCST

KLTSESSDSLVLPVEPDKNA

KIKRELLGNVKKVISAVAEIFS

DLQRFQRDCGDASQEQHQRD

GNMQNDAHEFLGQCLDQLKEDM

LENGSALESELVHFRDRAIG

EKLNATLNTGKECGDENSSPQM

EKELPVADSLMDQGDISLPV

HVGSAATKVFVCPVVANFEFEL

MYEDGGKLISSPDTRLVEVH

QLSLICKACGHAVLKVEPNNYL

LQEVPQHPELQKYEKTNTFV

SINLHQETKPLPLSIQNSLDLF

EFNFDSVTESTNGFYDCKEN

FKEEELEYNCQMCKQKSCVARH

RIPEGSQGMAEQLQQCIEES

TFSRLSRVLIIHLKRYSFNNAW

IIDEFLQQAPPPGVRKLDAQ

LLVKNNEQVYIPKSLSLSSYCN

EHTEETLNQSTELRLQKADL

ESTKPPLPLSSSAPVGKCEVLE

NHLGALGSDNPGNKNILDAE

VSQEMISEINSPLTPSMKLTSE

NTRGEAKELTRNVKMGDPLQ

SSDSLVLPVEPDKN

AYRLISVVSHIGSSPNSGHY

ADLQRFQRDCGDASQEQHQRDL

ISDVYDFQKQAWFTYNDLCV

ENGSALESELVHFRDRAIGEKE

SEISETKMQEARLHSGYIFF

LPVADSLMDQGDISLPVMYEDG

YMHN

GKLISSPDTRLVEVHLQEVPQH

PELQKYEKTNTFVEFNFDSVTE

STNGFYDCKENRIPEGSQGMAE

QLQQCIEESIIDEFLQQAPPPG

VRKLDAQEHTEETLNQSTELRL

QKADLNHLGALGSDNPGNKNIL

DAENTRGEAKELTRNVKMGDPL

QAYRLISVVSHIGSSPNSGHYI

SDVYDFQKQAWFTYNDLCVSEI

SETKMQEARLHSGYIFFYMHNG

IFEELLRKAENSRLPSTQAGVI

PQGEYEGDSLYRPA

UBP6_HUMAN
55
MDMVENADSLQAQERKDILMKY
167
KGATGLSNLGNTCFMNSSIQ

Ubiquitin

DKGHRAGLPEDKGPEPVGINSS

CVSNTQPLTQYFISGRHLYE

carboxyl-

IDRFGILHETELPPVTAREAKK

LNRTNPIGMKGHMAKCYGDL

terminal

IRREMTRTSKWMEMLGEWETYK

VQELWSGTQKSVAPLKLRRT

hydrolase

HSSKLIDRVYKGIPMNIRGPVW

IAKYAPKFDGFQQQDSQELL

6

SVLLNIQEIKLKNPGRYQIMKE

AFLLDGLHEDLNRVHEKPYV

RGKRSSEHIHHIDLDVRTTLRN

ELKDSDGRPDWE

HVFFRDRYGAKQRELFYILLAY

VAAEAWDNHLRRNRSIIVDL

SEYNPEVGYCRDLSHITALFLL

FHGQLRSQVKCKTCGHISVR

YLPEEDAFWALVQLLASERHSL

FDPNFLSLPLPMDSYMDLEI

PGFHSPNGGTVQGLQDQQEHVV

TVIKLDGTTPVRYGLRLNMD

PKSQPKTMWHQDKEGLCGQCAS

EKYTGLKKQLRDLCGLNSEQ

LGCLLRNLIDGISLGLTLRLWD

ILLAEVHDSNIKNFPQDNQK

VYLVEGEQVLMPIT

VQLSVSGELCAFEIPVPSSP

SIALKVQQKRLMKTSRCGLWAR

ISASSPTQIDFSSSPSTNGM

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

APLKLRRTIAKYAPKFDGFQQQ

RFQFVNDQWIKSQKIVRFLR

DSQELLAFLLDGLHEDLNRVHE

ESFDPSAFLVPRDPALCQHK

KPYVELKDSDGRPDWEVAAEAW

PLTPQGDELSKPRILAREVK

DNHLRRNRSIIVDLFHGQLRSQ

KVDAQSSAGKEDMLLSKSPS

VKCKTCGHISVRFDPFNFLSLP

SLSANISSSPKGSPSSSRKS

LPMDSYMDLEITVIKLDGTTPV

GTSCPSSKNSSPNSSPRTLG

RYGLRLNMDEKYTGLKKQLRDL

RSKGRLRLPQIGSKNKPSSS

CGLNSEQILLAEVHDSNIKNFP

KKNLDASKENGAGQICELAD

QDNQKVQLSVSGFLCAFEIPVP

ALSRGHMRGGSQPELVTPQD

SSPISASSPTQIDFSSSPSTNG

HEVALANGFLYEHEACGNGC

MFTLTINGDLPKPIFIPNGMPN

GDGYSNGQLGNHSEEDSTDD

TVVPCGTEKNFTNGMVNGHMPS

QREDTHIKPIYNLYAISCHS

LPDSPFTGYIIAVHRKMMRTEL

GILSGGHYITYAKNPNCKWY

YFLSPQENRPSLFG

CYNDSSCEELHPDEIDTDSA

MPLIVPCTVHTRKKDLYDAVWI

YILFYEQQG

QVSWLARPLPPQEASIHAQDRD

NCMGYQYPFTLRVVQKDGNSCA

WCPQYRFCRGCKIDCGEDRAFI

GNAYIAVDWHPTALHLRYQTSQ

ERVVDKHESVEQSRRAQAEPIN

LDSCLRAFTSEEELGESEMYYC

SKCKTHCLATKKLDLWRLPPFL

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

RFQLGLMDDAAECFENMLERIH

MLERIHFHIVPSRDADMCTS

53

FHIVPSRDADMCTSKSCITHQK

KSCITHQKFAMTLYEQCVCR

FAMTLYEQCVCRSCGASSDPLP

SCGASSDPLPFTEFVRYIST

FTEFVRYISTTALCNEVERMLE

TALCNEVERMLERHERFKPE

RHERFKPEMFAELLQAANTTDD

MFAELLQAANTTDDYRKCPS

YRKCPSNCGQKIKIRRVLMNCP

NCGQKIKIRRVLMNCPEIVT

EIVTIGLVWDSEHSDLTEAVVR

IGLVWDSEHSDLTEAVVRNL

NLATHLYLPGLFYRVTDENAKN

ATHLYLPGLFYRVTDENAKN

SELNLVGMICYTSQ

SELNLVGMICYTSQHYCAFA

HYCAFAFHTKSSKWVFFDDANV

FHTKSSKWVFFDDANVKEIG

KEIGTRWKDVVSKCIRCHFQPL

TRWKDVVSKCIRCHFQPLLL

LLFYANPDGTAVSTEDALRQVI

FYANPDGTAVSTEDALRQVI

SWSHYKSVAENMGCEKPVIHKS

SWSHYKSVAENMGCEKPVIH

DNLKENGFGDQAKQRENQKFPT

KSDNLKENGFGDQAKQRENQ

DNISSSNRSHSHTGVGKGPAKL

KFPTDNISSSNRSHSHTGVG

SHIDQREKIKDISRECALKAIE

KGPAKLSHIDQREKIKDISR

QKNLLSSQRKDLEKGQRKDLGR

ECALKAIEQKNLLSSQRKDL

HRDLVDEDLSHFQSGSPPAPNG

EKGQRK

FKQHGNPHLYHSQGKGSYKHDR

VVPQSRASAQIISSSKSQILAP

GEKITGKVKSDNGTGYDTDSSQ

DSRDRGNSCDSSSKSRNRGWKP

MRETLNVDSIFSES

EKRQHSPRHKPNISNKPKSSKD

PSFSNWPKENPKQKGLMTIYED

EMKQEIGSRSSLESNGKGAEKN

KGLVEGKVHGDNWQMQRTESGY

ESSDHISNGSTNLDSPVIDGNG

TVMDISGVKETVCFSDQITTSN

LNKERGDCTSLQSQHHLEGFRK

ELRNLEAGYKSHEFHPESHLQI

KNHLIKRSHVHEDNGKLFPSSS

LQIPKDHNAREHIHQSDEQKLE

KPNECKFSEWLNIENSERTGLP

FHVDNSASGKRVNSNEPSSLWS

SHLRTVGLKPETAPLIQQQNIM

DQCYFENSLSTECI

IRSASRSDGCQMPKLFCQNLPP

PLPPKKYAITSVPQSEKSESTP

DVKLTEVFKATSHLPKHSLSTA

SEPSLEVSTHMNDERHKETFQV

RECFGNTPNCPSSSSTNDFQAN

SGAIDAFCQPELDSISTCPNET

VSLTTYFSVDSCMTDTYRLKYH

QRPKLSFPESSGFCNNSLS

U17LO_HUMAN
57
MEDDSLYLRGEWQFNHFSKLTS
169
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSSRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 24

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KTLTLHTSAKVLILVLKRFSDV

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

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 22

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQQNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPEC

SYVKAQEGQWYKMDDAEVTA

LDMQPYMSQQNTGPLVYVLYAV

SSITSVLSQQAYVLFYIQKS

LVHAGWSCHNGHYFSYVKAQEG

QWYKMDDAEVTASSITSVLSQQ

AYVLFYIQKSEWERHSESVSRG

REPRALGAEDTDRRATQGELKR

DHPCLQAPELDEHLVERATQES

TLDHWKFLQEQNKTKPEFNVRK

VEGTLPPDVLVIHQSKYKCGMK

NHHPEQQSSLLKLSSTTPTHQE

SMNTGTLASLRGRARRSKGKNK

HSKRALLVCQ

UBP5_HUMAN
58
MAELSEEALLSVLPTIRVPKAG
170
FGPGYTGIRNLGNSCYLNSV

Ubiquitin

DRVHKDECAFSFDTPESEGGLY

VQVLESIPDFQRKYVDKLEK

carboxyl-

ICMNTFLGFGKQYVERHENKTG

IFQNAPTDPTQDFSTQVAKL

terminal

QRVYLHLRRTRRPKEEDPATGT

GHGLLSGEYSKPVPESGDGE

hydrolase

GDPPRKKPTRLAIGVEGGFDLS

RVPEQKEVQDGIAPRMFKAL

5

EEKFELDEDVKIVILPDYLEIA

IGKGHPEFSTNRQQDAQEFF

RDGLGGLPDIVRDRVTSAVEAL

LHLINMVERNCRSSENPNEV

LSADSASRKQEVQAWDGEVRQV

FRFLVEEKIKCLATEKVKYT

SKHAFSLKQLDNPARIPPCGWK

QRVDYIMQLPVPMDAALNKE

CSKCDMRENLWLNLTDGSILCG

ELLEYEEKKRQAEEEKMALP

RRYFDGSGGNNHAVEHYRETGY

ELVRAQVPFSSCLEAYGAPE

PLAVKLGTITPDGADVYSYDED

QVDDFWSTALQAKSVAVKTT

DMVLDPSLAEHLSHFGIDMLKM

RFASFPDYLVIQIKKFTFGL

QKTDKTMTELEIDM

DWVPKKLDVSIEMPEELDIS

NQRIGEWELIQESGVPLKPLFG

QLRGTGLQPGEEELPDIAPP

PGYTGIRNLGNSCYLNSVVQVL

LVTPDEPKGSLGFYGNEDED

FSIPDFQRKYVDKLEKIFQNAP

SFCSPHFSSPTSPMLDESVI

TDPTQDFSTQVAKLGHGLLSGE

IQLVEMGFPMDACRKAVYYT

YSKPVPESGDGERVPEQKEVQD

GNSGAEAAMNWVMSHMDDPD

GIAPRMFKALIGKGHPEFSTNR

FANPLILPGSSGPGSTSAAA

QQDAQEFFLHLINMVERNCRSS

DPPPEDCVTTIVSMGFSRDQ

ENPNEVFRFLVEEKIKCLATEK

ALKALRATNNSLERAVDWIF

VKYTQRVDYIMQLPVPMDAALN

SHIDDLDAEAAMDISEGRSA

KEELLEYEEKKRQAEEEKMALP

ADSISESVPVGPKVRDGPGK

ELVRAQVPESSCLEAYGAPEQV

YQLFAFISHMGTSTMCGHYV

DDFWSTALQAKSVAVKTTRFAS

CHIKKEGRWVIYNDQKVCAS

FPDYLVIQIKKFTFGLDWVPKK

EKPPKDLGYIYFYQRVA

LDVSIEMPEELDIS

QLRGTGLQPGEEELPDIAPPLV

TPDEPKGSLGFYGNEDEDSFCS

PHFSSPTSPMLDESVIIQLVEM

GFPMDACRKAVYYTGNSGAEAA

MNWVMSHMDDPDFANPLILPGS

SGPGSTSAAADPPPEDCVTTIV

SMGFSRDQALKALRATNNSLER

AVDWIFSHIDDLDAEAAMDISE

GRSAADSISESVPVGPKVRDGP

GKYQLFAFISHMGTSTMCGHYV

CHIKKEGRWVIYNDQKVCASEK

PPKDLGYIYFYQRVAS

UBP25_HUMAN
59
MTVEQNVLQQSAAQKHQQTFLN

KAPVGLKNVGNTCWFSAVIQ

Ubiquitin

QLREITGINDTQILQQALKDSN

SLFNLLEFRRLVLNYKPPSN

carboxyl-

GNLELAVAFLTAKNAKTPQQEE

AQDLPRNQKEHRNLPFMREL

terminal

TTYYQTALPGNDRYISVGSQAD

RYLFALLVGTKRKYVDPSRA

hydrolase

TNVIDLTGDDKDDLQRAIALSL

VEILKDAFKSNDSQQQDVSE

25

AESNRAFRETGITDEEQAISRV

FTHKLLDWLEDAFQMKAEEE

LEASIAENKACLKRTPTEVWRD

TDEEKPKNPMVELFYGRFLA

SRNPYDRKRQDKAPVGLKNVGN

VGVLEGKKFENTEMFGQYPL

TCWFSAVIQSLFNLLEFRRLVL

QVNGFKDLHECLEAAMIEGE

NYKPPSNAQDLPRNQKEHRNLP

IESLHSENSGKSGQEHWFTE

FMRELRYLFALLVGTKRKYVDP

LPPVLTFELSRFEFNQALGR

SRAVEILKDAFKSNDSQQQDVS

PEKIHNKLEFPQVLYLDRYM

EFTHKLLDWLEDAFQMKAEEET

HRNREITRIKREEIKRLKDY

DEEKPKNPMVELFY

LTVLQQRLERYLSYGSGPKR

GRFLAVGVLEGKKFENTEMFGQ

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

QAAGDPEYLEQPSRSDESKHLK

EETIQIITKASHEHEDKSPETV

LQSAIKLEYARLVKLAQEDTPP

ETDYRLHHVVVYFIQNQAPKKI

IEKTLLEQFGDRNLSFDERCHN

IMKVAQAKLEMIKPEEVNLEEY

EEWHQDYRKFRETTMYLIIGLE

NFQRESYIDSLLFL

ICAYQNNKELLSKGLYRGHDEE

LISHYRRECLLKLNEQAAELFE

SGEDREVNNGLIIMNEFIVPEL

PLLLVDEMEEKDILAVEDMRNR

WCSYLGQEMEPHLQEKLTDFLP

KLLDCSMEIKSFHEPPKLPSYS

THELCERFARIMLSLSRTPADG

R

UBP33_HUMAN
60
MTGSNSHITILTLKVLPHFESL
171
ARGLTGLKNIGNTCYMNAAL

Ubiquitin

GKQEKIPNKMSAFRNHCPHLDS

QALSNCPPLTQFFLDCGGLA

carboxyl-

VGEITKEDLIQKSLGTCQDCKV

RTDKKPAICKSYLKLMTELW

terminal

QGPNLWACLENRCSYVGCGESQ

HKSRPGSVVPTTLFQGIKTV

hydrolase

VDHSTIHSQETKHYLTVNLTTL

NPTFRGYSQQDAQEFLRCLM

33

RVWCYACSKEVFLDRKLGTQPS

DLLHEELKEQVMEVEEDPQT

LPHVRQPHQIQENSVQDFKIPS

ITTEETMEEDKSQSDVDFQS

NTTLKTPLVAVFDDLDIEADEE

CESCSNSDRAENENGSRCFS

DELRARGLTGLKNIGNTCYMNA

EDNNETTMLIQDDENNSEMS

ALQALSNCPPLTQFFLDCGGLA

KDWQKEKMCNKINKVNSEGE

RTDKKPAICKSYLKLMTELWHK

FDKDRDSISETVDLNNQETV

SRPGSVVPTTLFQGIKTVNPTF

KVQIHSRASEYITDVHSNDL

RGYSQQDAQEFLRCLMDLLHEE

STPQILPSNEGVNPRLSASP

LKEQVMEVEEDPQT

PKSGNLWPGLAPPHKKAQSA

ITTEETMEEDKSQSDVDFQSCE

SPKRKKQHKKYRSVISDIFD

SCSNSDRAENENGSRCFSEDNN

GTIISSVQCLTCDRVSVTLE

ETTMLIQDDENNSEMSKDWQKE

TFQDLSLPIPGKEDLAKLHS

KMCNKINKVNSEGEFDKDRDSI

SSHPTSIVKAGSCGEAYAPQ

SETVDLNNQETVKVQIHSRASE

GWIAFFMEYVKRFVVSCVPS

YITDVHSNDLSTPQILPSNEGV

WFWGPVVTLQDCLAAFFARD

NPRLSASPPKSGNLWPGLAPPH

ELKGDNMYSCEKCKKLRNGV

KKAQSASPKRKKQHKKYRSVIS

KFCKVQNFPEILCIHLKRFR

DIFDGTIISSVQCLTCDRVSVT

HELMFSTKISTHVSFPLEGL

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

LQCLSSTRPLRDFCLRRDFR

carboxyl-

PNPMLRPLPPRPGLPDERLKKL

QEVPGGGRAQELTEAFADVI

terminal

ELGRGRTSGPRPRGPLRADHGV

GALWHPDSCEAVNPTRFRAV

hydrolase

PLPGSPPPTVALPLPSRTNLAR

FQKYVPSFSGYSQQDAQEFL

21

SKSVSSGDLRPMGIALGGHRGT

KLLMERLHLEINRRGRRAPP

GELGAALSRLALRPEPPTLRRS

ILANGPVPSPPRRGGALLEE

TSLRRLGGFPGPPTLFSIRTEP

PELSDDDRANLMWK

PASHGSFHMISARSSEPFYSDD

RYLEREDSKIVDLFVGQLKS

KMAHHTLLLGSGHVGLRNLGNT

CLKCQACGYRSTTFEVFCDL

CFLNAVLQCLSSTRPLRDFCLR

SLPIPKKGFAGGKVSLRDCF

RDFRQEVPGGGRAQELTEAFAD

NLFTKEEELESENAPVCDRC

VIGALWHPDSCEAVNPTRFRAV

RQKTRSTKKLTVQRFPRILV

FQKYVPSFSGYSQQ

LHLNRFSASRGSIKKSSVGV

DAQEFLKLLMERLHLEINRRGR

DFPLQRLSLGDFASDKAGSP

RAPPILANGPVPSPPRRGGALL

VYQLYALCNHSGSVHYGHYT

EEPELSDDDRANLMWKRYLERE

ALCRCQTGWHVYNDSRVSPV

DSKIVDLFVGQLKSCLKCQACG

SENQVASSEGYVLFYQLMQ

YRSTTFEVFCDLSLPIPKKGFA

GGKVSLRDCENLFTKEEELESE

NAPVCDRCRQKTRSTKKLTVQR

FPRILVLHLNRFSASRGSIKKS

SVGVDFPLQRLSLGDFASDKAG

SPVYQLYALCNHSGSVHYGHYT

ALCRCQTGWHVYNDSRVSPVSE

NQVASSEGYVLFYQLMQEPPRC

L

U17L4_HUMAN
62
MGDDSLYLGGEWQENHFSKLTS
173
AVGAGLQNMGNTCYENASLQ

Inactive

SRPDAAFAEIQRTSLPEKSPLS

CLTYTLPLANYMLSREHSQT

ubiquitin

SETRVDLCDDLAPVARQLAPRE

CQRPKCCMLCTMQAHITWAL

carboxyl-

KLPLSSRRPAAVGAGLQNMGNT

HSPGHVIQPSQALAAGFHRG

terminal

CYENASLQCLTYTLPLANYMLS

KQEDVHEFLMFTVDAMKKAC

hydrolase

REHSQTCQRPKCCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

17-like

TWALHSPGHVIQPSQALAAGFH

FGGCWRSQIKCLHCHGISDT

protein 4

RGKQEDVHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVKQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGL

GCWRSQIKCLHCHGISDTFDPY

CLQRAPASNTLTLHTSAKVL

LDIALDIQAAQSVKQALEQLVK

ILVLKRFSDVAGNKLAKNVQ

PEELNGENAYHCGLCLQRAPAS

YPECLDMQPYMSQQNTGPLV

NTLTLHTSAKVLILVLKRFSDV

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

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 20

TRALHNPGHVIQPSQALAAGFH

FGGYWRSQIKCLHCHGISDT

RGKQEDAHEFLMFTVDAMKKAC

FDPYLDIALDIQAAQSVQQA

LPGHKQVDHHSKDTTLIHQIFG

LEQLVKPEELNGENAYHCGV

GYWRSQIKCLHCHGISDTFDPY

CLQRAPASKTLTLHTSAKVL

LDIALDIQAAQSVQQALEQLVK

ILVLKRFSDVTGNKIAKNVQ

PEELNGENAYHCGVCLQRAPAS

YPECLDMQPYMSQPNTGPLV

KTLTLHTSAKVLILVLKRFSDV

YVLYAVLVHAGWSCHNGHYF

TGNKIAKNVQYPECLDMQPYMS

SYVKAQEGQWYKMDDAEVTA

QPNTGPLVYVLYAVLVHAGWSC

SSITSVLSQQAYVLFYIQKS

HNGHYFSYVKAQEGQWYKMDDA

EVTASSITSVLSQQAYVLFYIQ

KSEWERHSESVSRGREPRALGA

EDTDRRATQGELKRDHPCLQAP

ELDEHLVERATQESTLDHWKFL

QEQNKTKPEFNVRKVEGTLPPD

VLVIHQSKYKCGMKNHHPEQQS

SLLNLSSTTPTHQESMNTGTLA

SLRGRARRSKGKNKHSKRALLV

CQ

UBP12_HUMAN
64
MEILMTVSKFASICTMGANASA
175
EHYFGLVNFGNTCYCNSVLQ

Ubiquitin

LEKEIGPEQFPVNEHYFGLVNF

ALYFCRPFREKVLAYKSQPR

carboxyl-

GNTCYCNSVLQALYFCRPFREK

KKESLLTCLADLFHSIATQK

terminal

VLAYKSQPRKKESLLTCLADLF

KKVGVIPPKKFITRLRKENE

hydrolase

HSIATQKKKVGVIPPKKFITRL

LFDNYMQQDAHEFLNYLLNT

12

RKENELFDNYMQQDAHEFLNYL

IADILQEERKQEKQNGRLPN

LNTIADILQEERKQEKQNGRLP

GNIDNENNNSTPDPTWVHEI

NGNIDNENNNSTPDPTWVHEIF

FQGTLTNETRCLTCETISSK

QGTLTNETRCLTCETISSKDED

DEDFLDLSVDVEQNTSITHC

FLDLSVDVEQNTSITHCLRGFS

LRGFSNTETLCSEYKYYCEE

NTETLCSEYKYYCEECRSKQEA

CRSKQEAHKRMKVKKLPMIL

HKRMKVKKLPMILALHLKRFKY

ALHLKRFKYMDQLHRYTKLS

MDQLHRYTKLSYRVVFPLELRL

YRVVFPLELRLFNTSGDATN

FNTSGDATNPDRMY

PDRMYDLVAVVVHCGSGPNR

DLVAVVVHCGSGPNRGHYIAIV

GHYIAIVKSHDFWLLFDDDI

KSHDFWLLFDDDIVEKIDAQAI

VEKIDAQAIEEFYGLTSDIS

EEFYGLTSDISKNSESGYILFY

KNSESGYILFYQSR

QSRD

UL17C_HUMAN
65
MEEDSLYLGGEWQFNHFSKLTS
176
AVGAGLQNMGNTCYVNASLQ

Ubiquitin

SRPDAAFAEIQRTSLPEKSPLS

CLTYTPPLANYMLSREHSQT

carboxyl-

CETRVDLCDDLAPVARQLAPRE

CHRHKGCMLCTMQAHITRAL

terminal

KLPLSNRRPAAVGAGLQNMGNT

HNPGHVIQPSQALAAGFHRG

hydrolase

CYVNASLQCLTYTPPLANYMLS

KQEDAHEFLMFTVDAMKKAC

17-like

REHSQTCHRHKGCMLCTMQAHI

LPGHKQVDHHSKDTTLIHQI

protein 12

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

EVFLEQRLAAPLLGSSSKFSEQ

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

KRFRHEVMYSFKIN

FYRKSS

SHVSFPLEGLDLRPFLAKECTS

QITTYDLLSVICHHGTAGSGHY

IAYCQNVINGQWYEFDDQYVTE

VHETVVQNAEGYVLFYRKSSEE

AMRERQQVVSLAAMREPSLLRF

YVSREWLNKFNTFAEPGPITNQ

TFLCSHGGIPPHKYHYIDDLVV

ILPQNVWEHLYNRFGGGPAVNH

LYVCSICQVEIEALAKRRRIEI

DTFIKLNKAFQAEESPGVIYCI

SMQWFREWEAFVKGKDNEPPGP

IDNSRIAQVKGSGHVQLKQGAD

YGQISEETWTYLNSLYGGGPEI

AIRQSVAQPLGPENLHGEQKIE

AETRAV

UBP46_HUMAN
67
MTVRNIASICNMGTNASALEKD
178
EHYFGLVNFGNTCYCNSVLQ

Ubiquitin

IGPEQFPINEHYFGLVNFGNTC

ALYFCRPFRENVLAYKAQQK

carboxyl-

YCNSVLQALYFCRPFRENVLAY

KKENLLTCLADLFHSIATQK

terminal

KAQQKKKENLLTCLADLFHSIA

KKVGVIPPKKFISRLRKEND

hydrolase

TQKKKVGVIPPKKFISRLRKEN

LFDNYMQQDAHEFLNYLLNT

46

DLFDNYMQQDAHEFLNYLLNTI

IADILQEEKKQEKQNGKLKN

ADILQEEKKQEKQNGKLKNGNM

GNMNEPAENNKPELTWVHEI

NEPAENNKPELTWVHEIFQGTL

FQGTLTNETRCLNCETVSSK

TNETRCLNCETVSSKDEDFLDL

DEDFLDLSVDVEQNTSITHC

SVDVEQNTSITHCLRDESNTET

LRDFSNTETLCSEQKYYCET

LCSEQKYYCETCCSKQEAQKRM

CCSKQEAQKRMRVKKLPMIL

RVKKLPMILALHLKRFKYMEQL

ALHLKRFKYMEQLHRYTKLS

HRYTKLSYRVVFPLELRLFNTS

YRVVFPLELRLFNTSSDAVN

SDAVNLDRMYDLVA

LDRMYDLVAVVVHCGSGPNR

VVVHCGSGPNRGHYITIVKSHG

GHYITIVKSHGFWLLFDDDI

FWLLFDDDIVEKIDAQAIEEFY

VEKIDAQAIEEFYGLTSDIS

GLTSDISKNSESGYILFYQSRE

KNSESGYILFYQSR

CYLD_HUMAN
68
MSSGLWSQEKVTSPYWEERIFY
179
GKKKGIQGHYNSCYLDSTLF

Ubiquitin

LLLQECSVTDKQTQKLLKVPKG

CLFAFSSVLDTVLLRPKEKN

carboxyl-

SIGQYIQDRSVGHSRIPSAKGK

DVEYYSETQELLRTEIVNPL

terminal

KNQIGLKILEQPHAVLFVDEKD

RIYGYVCATKIMKLRKILEK

hydrolase

VVEINEKFTELLLAITNCEERF

VEAASGFTSEEKDPEEFLNI

CYLD

SLFKNRNRLSKGLQIDVGCPVK

LFHHILRVEPLLKIRSAGQK

VQLRSGEEKFPGVVRFRGPLLA

VQDCYFYQIFME

ERTVSGIFFGVELLEEGRGQGF

KNEKVGVPTIQQLLEWSFIN

TDGVYQGKQLFQCDEDCGVFVA

SNLKFAEAPSCLIIQMPRFG

LDKLELIEDDDTALESDYAGPG

KDFKLEKKIFPSLELNITDL

DTMQVELPPLEINSRVSLKVGE

LEDTPRQCRICGGLAMYECR

TIESGTVIFCDVLPGKESLGYF

ECYDDPDISAGKIKQFCKTC

VGVDMDNPIGNWDGRFDGVQLC

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

FFDSMADRDGGQNGFNIPQVTP

CPEVGEYLKMSLEDLHSLDSRR

IQGCARRLLCDAYMCMYQSPTM

SLYK

UBP16_HUMAN
69
MGKKRTKGKTVPIDDSSETLEP
180
ITVKGLSNLGNTCFFNAVMQ

Ubiquitin

VCRHIRKGLEQGNLKKALVNVE

NLSQTPVLRELLKEVKMSGT

carboxyl-

WNICQDCKTDNKVKDKAEEETE

IVKIEPPDLALTEPLEINLE

terminal

EKPSVWLCLKCGHQGCGRNSQE

PPGPLTLAMSQFLNEMQETK

hydrolase

QHALKHYLTPRSEPHCLVLSLD

KGVVTPKELFSQVCKKAVRF

16

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

PETAFCTLANRFVENTDECS

EDSEYEAEMSLQGEVNIKSNHI

IQHCLYQFTRNEKLRDANKL

SQEGVMHKEYCVNQKDLNGQAK

LCEVCTRRQCNGPKANIKGE

MIESVTDNQKSTEEVDMKNINM

RKHVYTNAKKQMLISLAPPV

DNDLEVLTSSPTRNLNGAYLTE

LTLHLKRFQQAGFNLRKVNK

GSNGEVDISNGFKNLNLNAALH

HIKFPEIL

PDEINIEILNDSHT

DLAPFCTLKCKNVAEENTRV

PGTKVYEVVNEDPETAFCTLAN

LYSLYGVVEHSGTMRSGHYT

REVFNTDECSIQHCLYQFTRNE

AYAKARTANSHLSNLVLHGD

KLRDANKLLCEVCTRRQCNGPK

IPQDFEMESKGQWFHISDTH

ANIKGERKHVYTNAKKQMLISL

VQAVPTTKVLNSQAYLLFYE

APPVLTLHLKRFQQAGFNLRKV

RIL

NKHIKFPEILDLAPFCTLKCKN

VAEENTRVLYSLYGVVEHSGTM

RSGHYTAYAKARTANSHLSNLV

LHGDIPQDFEMESKGQWFHISD

THVQAVPTTKVLNSQAYLLFYE

RIL

ALG13_HUMAN
70
MKCVFVTVGTTSEDDLIACVSA
181
YRYKDSLKEDIQKADLVISH

Putative

PDSLQKIESLGYNRLILQIGRG

AGAGSCLETLEKGKPLVVVI

bifunctional

TVVPEPFSTESFTLDVYRYKDS

NEKLMNNHQLELAKQLHKEG

UDP-N-

LKEDIQKADLVISHAGAGSCLE

HLFYCTCRVLTCPGQAKSIA

acetylgluco-

TLEKGKPLVVVINEKLMNNHQL

SAPGKCQDSAALTSTAFSGL

samine

ELAKQLHKEGHLFYCTCRVLTC

DFGLLSGYLHKQALVTATHP

transferase

PGQAKSIASAPGKCQDSAALTS

TCTLLFPSCHAFFPLPLTPT

and

TAFSGLDFGLLSGYLHKQALVT

LYKMHKGWKNYCSQKSLNEA

deubiquitinase

ATHPTCTLLFPSCHAFFPLPLT

SMDEYLGSLGLFRKLTAKDA

ALG13

PTLYKMHKGWKNYCSQKSLNEA

SCLFRAISEQLFCSQVHHLE

SMDEYLGSLGLFRKLTAKDASC

IRKACVSYMRENQQTFESYV

LFRAISEQLFCSQVHHLEIRKA

EGSFEKYLERLGDPKESAGQ

CVSYMRENQQTFESYVEGSFEK

LEIRALSLIYNRDFILYREP

YLERLGDPKESAGQ

GKPPTYVTDNGYEDKILLCY

LEIRALSLIYNRDFILYRFPGK

SSSGHYDSVYS

PPTYVTDNGYEDKILLCYSSSG

HYDSVYSKQFQSSAAVCQAVLY

EILYKDVFVVDEEELKTAIKLF

RSGSKKNRNNAVTGSEDAHTDY

KSSNQNRMEEWGACYNAENIPE

GYNKGTEETKSPENPSKMPFPY

KVLKALDPEIYRNVEFDVWLDS

RKELQKSDYMEYAGRQYYLGDK

CQVCLESEGRYYNAHIQEVGNE

NNSVTVFIEELAEKHVVPLANL

KPVTQVMSVPAWNAMPSRKGRG

YQKMPGGYVPEIVISEMDIKQQ

KKMFKKIRGKEVYM

TMAYGKGDPLLPPRLQHSMHYG

HDPPMHYSQTAGNVMSNEHFHP

QHPSPRQGRGYGMPRNSSRFIN

RHNMPGPKVDFYPGPGKRCCQS

YDNFSYRSRSFRRSHRQMSCVN

KESQYGFTPGNGQMPRGLEETI

TFYEVEEGDETAYPTLPNHGGP

STMVPATSGYCVGRRGHSSGKQ

TLNLEEGNGQSENGRYHEEYLY

RAEPDYETSGVYSTTASTANLS

LQDRKSCSMSPQDTVTSYNYPQ

KMMGNIAAVAASCANNVPAPVL

SNGAAANQAISTTSVSSQNAIQ

PLFVSPPTHGRPVI

ASPSYPCHSAIPHAGASLPPPP

PPPPPPPPPPPPPPPPPPPPPP

PALDVGETSNLQPPPPLPPPPY

SCDPSGSDLPQDTKVLQYYENL

GLQCYYHSYWHSMVYVPQMQQQ

LHVENYPVYTEPPLVDQTVPQC

YSEVRREDGIQAEASANDTFPN

ADSSSVPHGAVYYPVMSDPYGQ

PPLPGFDSCLPVVPDYSCVPPW

HPVGTAYGGSSQIHGAINPGPI

GCIAPSPPASHYVPQGM

OTU1_HUMAN
71
MFGPAKGRHFGVHPAPGFPGGV
182
QGLSSRTRVRELQGQIAAIT

Ubiquitin

SQQAAGTKAGPAGAWPVGSRTD

GIAPGGQRILVGYPPECLDL

thioesterase

TMWRLRCKAKDGTHVLQGLSSR

SNGDTILEDLPIQSGDMLII

OTU1

TRVRELQGQIAAITGIAPGGQR

EEDQTRPRSSPAFTKRGASS

ILVGYPPECLDLSNGDTILEDL

YVRETLPVLTRTVVPADNSC

PIQSGDMLIIEEDQTRPRSSPA

LFTSVYYVVEGGVLNPACAP

FTKRGASSYVRETLPVLTRTVV

EMRRLIAQIVASDPDFYSEA

PADNSCLFTSVYYVVEGGVLNP

ILGKTNQEYCDWIKRDDTWG

ACAPEMRRLIAQIVASDPDFYS

GAIEISILSKFYQCEICVVD

EAILGKTNQEYCDWIKRDDTWG

TQTVRIDRFGEDAGYTKRVL

GAIEISILSKFYQCEICVVDTQ

LIYDGIHYDPLQ

TVRIDRFGEDAGYTKRVLLIYD

GIHYDPLQRNFPDPDTPPLTIF

SSNDDIVLVQALELADEARRRR

QFTDVNRFTLRCMVCQKGLTGQ

AEAREHAKETGHTNFGEV

OTUD1_HUMAN
72
MQLYSSVCTHYPAGAPGPTAAA
183
HREAAAVPAAKMPAFSSCFE

OTU

PAPPAAATPFKVSLQPPGAAGA

VVSGAAAPASAAAGPPGASC

domain-

APEPETGECQPAAAAEHREAAA

KPPLPPHYTSTAQITVRALG

containing

VPAAKMPAFSSCFEVVSGAAAP

ADRLLLHGPDPVPGAAGSAA

protein 1

ASAAAGPPGASCKPPLPPHYTS

APRGRCLLLAPAPAAPVPPR

TAQITVRALGADRLLLHGPDPV

RGSSAWLLEELLRPDCPEPA

PGAAGSAAAPRGRCLLLAPAPA

GLDATREGPDRNRRLSEHRQ

APVPPRRGSSAWLLEELLRPDC

ALAAAKHRGPAATPGSPDPG

PEPAGLDATREGPDRNFRLSEH

PGPWGEEHLAERGPRGWERG

RQALAAAKHRGPAATPGSPDPG

GDRCDAPGGDAARRPDPEAE

PGPWGEEHLAERGPRGWERGGD

APPAGSIEAAPSSAAEPVIV

RCDAPGGDAARRPDPEAEAPPA

SRSDPRDEKLALYLAEVEKQ

GSIEAAPSSAAEPVIVSRSDPR

DKYLRQRNKYRFHIIPDGNC

DEKLALYLAEVEKQ

LYRAVSKTVYGDQSLHRELR

DKYLRQRNKYRFHIIPDGNCLY

EQTVHYIADHLDHFSPLIEG

RAVSKTVYGDQSLHRELREQTV

DVGEFIIAAAQDGAWAGYPE

HYIADHLDHFSPLIEGDVGEFI

LLAMGQMLNVNIHLTTGGRL

IAAAQDGAWAGYPELLAMGQML

ESPTVSTMIHYLGPEDSLRP

NVNIHLTTGGRLESPTVSTMIH

SIWLSWLSNGHYDAV

YLGPEDSLRPSIWLSWLSNGHY

DAVFDHSYPNPEYDNWCKQTQV

QRKRDEELAKSMAISLSKMYIE

QNACS

OTU6B_HUMAN
73
MEAVLTEELDEEEQLLRRHRKE
184
QKHREELEQLKLTTKENKID

Deubiquitinase

KKELQAKIQGMKNAVPKNDKKR

SVAVNISNLVLENQPPRISK

OTUD6B

RKQLTEDVAKLEKEMEQKHREE

AQKRREKKAALEKEREERIA

LEQLKLTTKENKIDSVAVNISN

EAEIENLTGARHMESEKLAQ

LVLENQPPRISKAQKRREKKAA

ILAARQLEIKQIPSDGHCMY

LEKEREERIAEAEIENLTGARH

KAIEDQLKEKDCALTVVALR

MESEKLAQILAARQLEIKQIPS

SQTAEYMQSHVEDFLPFLTN

DGHCMYKAIEDQLKEKDCALTV

PNTGDMYTPEEFQKYCEDIV

VALRSQTAEYMQSHVEDFLPFL

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

YIRKTRPDGNCFYRAFGFSH

LQRFKAVSAKSKEDLVSQGFTE

LEALLDDSKELQRFKAVSAK

FTIEDFHNTFMDLIEQVEKQTS

SKEDLVSQGFTEFTIEDFHN

VADLLASFNDQSTSDYLVVYLR

TFMDLIEQVEKQTSVADLLA

LLTSGYLQRESKFFEHFIEGGR

SENDQSTSDYLVVYLRLLTS

TVKEFCQQEVEPMCKESDHIHI

GYLQRESKFFEHFIEGGRTV

IALAQALSVSIQVEYMDRGEGG

KEFCQQEVEPMCKESDHIHI

TTNPHIFPEGSEPKVYLLYRPG

IALAQALSVSIQVEYMDRGE

HYDILYK

GGTTNPHIFPEGSEPKVYLL

YRPGHYDILYK

OTU7A_HUMAN
76
MVSSVLPNPTSAECWAALLHDP
186
SDYEQLRQVHTANLPHVFNE

OTU

MTLDMDAVLSDFVRSTGAEPGL

GRGPKQPEREPQPGHKVERP

domain-

ARDLLEGKNWDLTAALSDYEQL

CLQRQDDIAQEKRLSRGISH

containing

RQVHTANLPHVENEGRGPKQPE

ASSAIVSLARSHVASECNNE

protein 7A

REPQPGHKVERPCLQRQDDIAQ

QFPLEMPIYTFQLPDLSVYS

EKRLSRGISHASSAIVSLARSH

EDERSFIERDLIEQATMVAL

VASECNNEQFPLEMPIYTFQLP

EQAGRLNWWSTVCTSCKRLL

DLSVYSEDFRSFIERDLIEQAT

PLATTGDGNCLLHAASLGMW

MVALEQAGRLNWWSTVCTSCKR

GFHDRDLVLRKALYTMMRTG

LLPLATTGDGNCLLHAASLGMW

AEREALKRRWRWQQTQQNKE

GFHDRDLVLRKALYTMMRTGAE

EEWEREWTELLKLASSEPRT

REALKRRWRWQQTQQNKEEEWE

HFSKNGGTGGGVDNSEDPVY

REWTELLKLASSEPRTHFSKNG

ESLEEFHVFVLAHILRRPIV

GTGGGVDNSEDPVY

VVADTMLRDSGGEAFAPIPF

ESLEEFHVFVLAHILRRPIVVV

GGIYLPLEVPPNRCHCSPLV

ADTMLRDSGGEAFAPIPFGGIY

LAYDQAHFSAL

LPLEVPPNRCHCSPLVLAYDQA

HFSALVSMEQRDQQREQAVIPL

TDSEHKLLPLHFAVDPGKDWEW

GKDDNDNARLAHLILSLEAKLN

LLHSYMNVTWIRIPSETRAPLA

QPESPTASAGEDVQSLADSLDS

DRDSVCSNSNSNNGKNGKDKEK

EKQRKEKDKTRADSVANKLGSF

SKTLGIKLKKNMGGLGGLVHGK

MGRANSANGKNGDSAERGKEKK

AKSRKGSKEESGASASTSPSEK

TTPSPTDKAAGASP

AEKGGGPRGDAWKYSTDVKLSL

NILRAAMQGERKFIFAGLLLTS

HRHQFHEEMIGYYLTSAQERFS

AEQEQRRRDAATAAAAAAAAAA

ATAKRPPRRPETEGVPVPERAS

PGPPTQLVLKLKERPSPGPAAG

RAARAAAGGTASPGGGARRASA

SGPVPGRSPPAPARQSVIHVQA

SGARDEACAPAVGALRPCATYP

QQNRSLSSQSYSPARAAALRTV

NTVESLARAVPGALPGAAGTAG

AAEHKSQTYTNGFGALRDGLEF

ADADAPTARSNGECGRGGPGPV

QRRCQRENCAFYGRAETEHYCS

YCYREELRRRREARGARP

OTUD4_HUMAN
77
MEAAVGVPDGGDQGGAGPREDA
187
MEAAVGVPDGGDQGGAGPRE

OTU

TPMDAYLRKLGLYRKLVAKDGS

DATPMDAYLRKLGLYRKLVA

domain-

CLFRAVAEQVLHSQSRHVEVRM

KDGSCLFRAVAEQVLHSQSR

containing

ACIHYLRENREKFEAFIEGSFE

HVEVRMACIHYLRENREKFE

protein 4

EYLKRLENPQEWVGQVEISALS

AFIEGSFEEYLKRLENPQEW

LMYRKDFIIYREPNVSPSQVTE

VGQVEISALSLMYRKDFIIY

NNFPEKVLLCFSNGNHYDIVYP

REPNVSPSQVTENNFPEKVL

IKYKESSAMCQSLLYELLYEKV

LCFSNGNHYDIVYP

FKTDVSKIVMELDTLEVADEDN

SEISDSEDDSCKSKTAAAAADV

NGFKPLSGNEQLKNNGNSTSLP

LSRKVLKSLNPAVYRNVEYEIW

LKSKQAQQKRDYSIAAGLQYEV

GDKCQVRLDHNGKF

LNADVQGIHSENGPVLVEELGK

KHTSKNLKAPPPESWNTVSGKK

MKKPSTSGQNFHSDVDYRGPKN

PSKPIKAPSALPPRLQHPSGVR

QHAFSSHSSGSQSQKFSSEHKN

LSRTPSQIIRKPDRERVEDFDH

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
MSETSFNLISEKCDILSILR

Ubiquitin

PENRIYRRKIEELSKRFTAIRK

DHPENRIYRRKIEELSKRFT

thioesterase

TKGDGNCFYRALGYSYLESLLG

AIRKTKGDGNCFYRALGYSY

OTUB2

KSREIFKFKERVLQTPNDLLAA

LESLLGKSREIFKFKERVLQ

GFEEHKERNFFNAFYSVVELVE

TPNDLLAAGFEEHKERNFFN

KDGSVSSLLKVFNDQSASDHIV

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

SRNHLKHRQETVDYMIKQREDF

LGDQLEGHSRNHLKHRQETV

EPFVEDDIPFEKHVASLAKPGT

DYMIKQREDFEPFVEDDIPF

FAGNDAIVAFARNHQLNVVIHQ

EKHVASLAKPGTFAGNDAIV

LNAPLWQIRGTEKSSVRELHIA

AFARNHQLNVVIHQLNAPLW

YRYGEHYDSVRRINDNSEAPAH

QIRGTEKSSVRELHIAYRYG

LQTDFQMLHQDESNKREKIKTK

EHYDSVRR

GMDSEDDLRDEVEDAVQKVCNA

TGCSDFNLIVQNLEAENYNIES

AIIAVLRMNQGKRNNAEENLEP

SGRVLKQCGPLWEE

GGSGARIFGNQGLNEGRTENNK

AQASPSEENKANKNQLAKVTNK

QRREQQWMEKKKRQEERHRHKA

LESRGSHRDNNRSEAEANTQVT

LVKTFAALNI

OTU7B_HUMAN
80
MTLDMDAVLSDFVRSTGAEPGL
189
MTLDMDAVLSDFVRSTGAEP

OTU

ARDLLEGKNWDVNAALSDFEQL

GLARDLLEGKNWDVNAALSD

domain-

RQVHAGNLPPSFSEGSGGSRTP

FEQLRQVHAGNLPPSFSEGS

containing

EKGFSDREPTRPPRPILQRQDD

GGSRTPEKGFSDREPTRPPR

protein 7B

IVQEKRLSRGISHASSSIVSLA

PILQRQDDIVQEKRLSRGIS

(Also referred

RSHVSSNGGGGGSNEHPLEMPI

HASSSIVSLARSHVSSNGGG

to herein as

CAFQLPDLTVYNEDERSFIERD

GGSNEHPLEMPICAFQLPDL

Cezanne)

LIEQSMLVALEQAGRLNWWVSV

TVYNEDFRSFIERDLIEQSM

DPTSQRLLPLATTGDGNCLLHA

LVALEQAGRLNWWVSVDPTS

ASLGMWGFHDRDLMLRKALYAL

QRLLPLATTGDGNCLLHAAS

MEKGVEKEALKRRWRWQQTQQN

LGMWGFHDRDLMLRKALYAL

KESGLVYTEDEWQKEWNELIKL

MEKGVEKEALKRRWRWQQTQ

ASSEPRMHLGTNGANCGGVESS

QNKESGLVYTEDEWQKEWNE

EEPVYESLEEFHVFVLAHVLRR

LIKLASSEPRMHLGTNGANC

PIVVVADTMLRDSGGEAFAPIP

GGVESSEEPVYESLEEFHVF

FGGIYLPLEVPASQCHRSPLVL

VLAHVLRRPIVVVADTMLRD

AYDQAHFSALVSMEQKENTKEQ

SGGEAFAPIPFGGIYLPLEV

AVIPLTDSEYKLLPLHFAVDPG

PASQCHRSPLVLAYDQAHFS

KGWEWGKDDSDNVRLASVILSL

AL

EVKLHLLHSYMNVKWIPLSSDA
270
PPSFSEGSGGSRTPEKGFSD

QAPLAQPESPTASAGDEPRSTP

REPTRPPRPILQRQDDIVQE

ESGDSDKESVGSSSTSNEGGRR

KRLSRGISHASSSIVSLARS

KEKSKRDREKDKKRADSVANKL

HVSSNGGGGGSNEHPLEMPI

GSFGKTLGSKLKKNMGGLMHSK

CAFQLPDLTVYNEDFRSFIE

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

ELLVHRF

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

RYTLEMFRTCQFCPQFREIIHK

KTMHRYTLEMFRTCQFCPQF

factor

ALIDRNIQATLESQKKLNWCRE

REIIHKALIDRNIQATLESQ

alpha-induced

VRKLVALKTNGDGNCLMHATSQ

KKLNWCREVRKLVALKTNGD

protein 3

YMWGVQDTDLVLRKALFSTLKE

GNCLMHATSQYMWGVQDTDL

TDTRNFKFRWQLESLKSQEFVE

VLRKALFSTLKETDTRNFKF

TGLCYDTRNWNDEWDNLIKMAS

RWQLESLKSQEFVETGLCYD

TDTPMARSGLQYNSLEEIHIFV

TRNWNDEWDNLIKMASTDTP

LCNILRRPIIVISDKMLRSLES

MARSGLQYNSLEEIHIFVLC

GSNFAPLKVGGIYLPLHWPAQE

NILRRPIIVISDKMLRSLES

CYRYPIVLGYDSHHFVPLVTLK

GSNFAPLKVGGIYLPLHWPA

DSGPEIRAVPLVNRDRGRFEDL

QECYRYPIVLGYDSHHFVPL

KVHELTDPENEMKE

KLLKEYLMVIEIPVQGWDHGTT

HLINAAKLDEANLPKEINLVDD

YFELVQHEYKKWQENSEQGRRE

GHAQNPMEPSVPQLSLMDVKCE

TPNCPFFMSVNTQPLCHECSER

RQKNQNKLPKLNSKPGPEGLPG

MALGASRGEAYEPLAWNPEEST

GGPHSAPPTAPSPFLFSETTAM

KCRSPGCPFTLNVQHNGFCERC

HNARQLHASHAPDHTRHLDPGK

CQACLQDVTRTFNGICSTCFKR

TTAEASSSLSTSLPPSCHQRSK

SDPSRLVRSPSPHSCHRAGNDA

PAGCLSQAARTPGD

RTGTSKCRKAGCVYFGTPENKG

FCTLCFIEYRENKHFAAASGKV

SPTASRFQNTIPCLGRECGTLG

STMFEGYCQKCFIEAQNQRFHE

AKRTEEQLRSSQRRDVPRTTQS

TSRPKCARASCKNILACRSEEL

CMECQHPNQRMGPGAHRGEPAP

EDPPKQRCRAPACDHFGNAKCN

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

SKEELEVDFKKLKQIKNRMK

SGGDIARQLTADEV

KTDWLFLNACVGVVEGDLAA

RLLNRPSAFDVGYTLVHLAIRF

IEAYKSSGGDIARQLTADEV

QRQDMLAILLTEVSQQAAKCIP

RLLNRPSAFDVGYTLVHLAI

AMVCPELTEQIRREIAASLHQR

RFQRQDMLAILLTEVSQQAA

KGDFACYFLTDLVTFTLPADIE

KCIPAMVCPELTEQIRREIA

DLPPTVQEKLFDEVLDRDVQKE

ASLHQRKGDFACYFLTDLVT

LEEESPIINWSLELATRLDSRL

FTLPADIEDLPPTVQEKLFD

YALWNRTAGDCLLDSVLQATWG

EVLDRDVQKELEEESPIINW

IYDKDSVLRKALHDSLHDCSHW

SLELATRLDSRLYALWNRTA

FYTRWKDWESWYSQSFGLHFSL

GDCLLDSVLQATWGIYDKDS

REEQWQEDWAFILSLASQPGAS

VLRKALHDSLHDCSHWFYTR

LEQTHIFVLAHILRRPIIVYGV

WKDWESWYSQSFGLHFSLRE

KYYKSFRGETLGYTRFQGVYLP

EQWQEDWAFILSLASQPGAS

LLWEQSFCWKSPIALGYTRGHF

LEQTHIFVLAHILRRPIIVY

SALVAMENDGYGNR

GVKYYKSFRGETLGYTRFQG

GAGANLNTDDDVTITFLPLVDS

VYLPLLWEQSFCWKSPIALG

ERKLLHVHFLSAQELGNEEQQE

YTRGHFSAL

KLLREWLDCCVTEGGVLVAMQK

SSRRRNHPLVTQMVEKWLDRYR

QIRPCTSLSDGEEDEDDEDE

VCIP1_HUMAN
84
MSQPPPPPPPLPPPPPPPEAPQ
193
PASGSVSIECTECGQRHEQQ

Deubiquiti-

TPSSLASAAASGGLLKRRDRRI

QLLGVEEVTDPDVVLHNLLR

nating

LSGSCPDPKCQARLFFPASGSV

NALLGVTGAPKKNTELVKVM

protein

SIECTECGQRHEQQQLLGVEEV

GLSNYHCKLLSPILARYGMD

VCIP135

TDPDVVLHNLLRNALLGVTGAP

KQTGRAKLLRDMNQGELFDC

KKNTELVKVMGLSNYHCKLLSP

ALLGDRAFLIEPEHVNTVGY

ILARYGMDKQTGRAKLLRDMNQ

GKDRSGSLLYLHDTLEDIKR

GELFDCALLGDRAFLIEPEHVN

ANKSQECLIPVHVDGDGHCL

TVGYGKDRSGSLLYLHDTLEDI

VHAVSRALVGRELFWHALRE

KRANKSQECLIPVHVDGDGHCL

NLKQHFQQHLARYQALFHDF

VHAVSRALVGRELFWHALRENL

IDAAEWEDIINECDPLFVPP

KQHFQQHLARYQALFHDFIDAA

EGVPLGLRNIHIFGLANVLH

EWEDIINECDPLFVPPEGVPLG

RPIILLDSLSGMRSSGDYSA

LRNIHIFGLANVLH

TFLPGLIPAEKCTGKDGHLN

RPIILLDSLSGMRSSGDYSATF

KPICIAWSSSGRNHYIPL

LPGLIPAEKCTGKDGHLNKPIC

IAWSSSGRNHYIPLVGIKGAAL

PKLPMNLLPKAWGVPQDLIKKY

IKLEEDGGCVIGGDRSLQDKYL

LRLVAAMEEVFMDKHGIHPSLV

ADVHQYFYRRTGVIGVQPEEVT

AAAKKAVMDNRLHKCLLCGALS

ELHVPPEWLAPGGKLYNLAKST

HGQLRTDKNYSFPLNNLVCSYD

SVKDVLVPDYGMSNLTACNWCH

GTSVRKVRGDGSIVYLDGDRTN

SRSTGGKCGCGFKHFWDGKEYD

NLPEAFPITLEWGG

RVVRETVYWFQYESDSSLNSNV

YDVAMKLVTKHFPGEFGSEILV

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-

VPRPVCAVLLLFPITEKYEVFR

MVPRPVCAVLLLFPITEKYE

terminal

TEEEEKIKSQGQDVTSSVYFMK

VFRTEEEEKIKSQGQDVTSS

hydrolase

QTISNACGTIGLIHAIANNKDK

VYFMKQTISNACGTIGLIHA

isozyme L3

MHFESGSTLKKFLEESVSMSPE

IANNKDKMHFESGSTLKKFL

ERARYLENYDAIRVTHETSAHE

EESVSMSPEERARYLENYDA

GQTEAPSIDEKVDLHFIALVHV

IRVTHETSAHEGQTEAPSID

DGHLYELDGRKPFPINHGETSD

EKVDLHFIALVHVDGHLYEL

ETLLEDAIEVCKKFMERDPDEL

DGRKPFPINHGETSDETLLE

RFNAIALSAA

DAIEVCKKFMERDPDELRFN

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

DDKVNFHFILFNNVDGHLYELD

AAHDAVAQEGQCRVDDKVNF

GRMPFPVNHGASSEDTLLKDAA

HFILFNNVDGHLYELDGRMP

KVCREFTEREQGEVRFSAVALC

FPVNHGASSEDTLLKDAAKV

KAA

CREFTEREQGEVRFSAVALC

KAA

UCHL5_HUMAN
87
MTGNAGEWCLMESDPGVFTELI
195
GEWCLMESDPGVFTELIKGF

Ubiquitin

KGFGCRGAQVEEIWSLEPENFE

GCRGAQVEEIWSLEPENFEK

carboxyl-

KLKPVHGLIFLFKWQPGEEPAG

LKPVHGLIFLFKWQPGEEPA

terminal

SVVQDSRLDTIFFAKQVINNAC

GSVVQDSRLDTIFFAKQVIN

hydrolase

ATQAIVSVLLNCTHQDVHLGET

NACATQAIVSVLLNCTHQDV

isozyme L5

LSEFKEFSQSFDAAMKGLALSN

HLGETLSEFKEFSQSEDAAM

SDVIRQVHNSFARQQMFEFDTK

KGLALSNSDVIRQVHNSFAR

TSAKEEDAFHFVSYVPVNGRLY

QQMFEFDTKTSAKEEDAFHF

ELDGLREGPIDLGACNQDDWIS

VSYVPVNGRLYELDGLREGP

AVRPVIEKRIQKYSEGEIRFNL

IDLGACNQDDWISAVRPVIE

MAIVSDRKMIYEQKIAELQRQL

KRIQKYSEGEIRFNLMAIVS

AEEEPMDTDQGNSMLSAIQSEV

DRK

AKNQMLIEEEVQKLKRYKIENI

RRKHNYLPFIMELLKTLAEHQQ

LIPLVEKAKEKQNAKKAQETK

ATX3_HUMAN
88
MESIFHEKQEGSLCAQHCLNNL
196
ESIFHEKQEGSLCAQHCLNN

Ataxin-3

LQGEYFSPVELSSIAHQLDEEE

LLQGEYFSPVELSSIAHQLD

RMRMAEGGVTSEDYRTFLQQPS

EEERMRMAEGGVTSEDYRTF

GNMDDSGFFSIQVISNALKVWG

LQQPSGNMDDSGFFSIQVIS

LELILFNSPEYQRLRIDPINER

NALKVWGLELILFNSPEYQR

SFICNYKEHWFTVRKLGKQWFN

LRIDPINERSFICNYKEHWF

LNSLLTGPELISDTYLALFLAQ

TVRKLGKQWFNLNSLLTGPE

LQQEGYSIFVVKGDLPDCEADQ

LISDTYLALFLAQLQQEGYS

LLQMIRVQQMHRPKLIGEELAQ

IFVVK

LKEQRVHKTDLERVLEANDGSG

MLDEDEEDLQRALALSRQEIDM

EDEEADLRRAIQLSMQGSSRNI

SQDMTQTSGTNLTSEELRKRRE

AYFEKQQQKQQQQQQQQQQGDL

SGQSSHPCERPATSSGALGSDL

GDAMSEEDMLQAAVTMSLETVR

NDLKTEGKK

JOS2_HUMAN
89
MSQAPGAQPSPPTVYHERQRLE
197
PTVYHERQRLELCAVHALNN

Josephin-2

LCAVHALNNVLQQQLFSQEAAD

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

RMRMAEGGVTSEEYLAFLQQPS

EEERMRMAEGGVTSEEYLAF

protein

ENMDDTGFFSIQVISNALKFWG

LQQPSENMDDTGFFSIQVIS

LEIIHENNPEYQKLGIDPINER

NALKFWGLEIIHFNNPEYQK

SFICNYKQHWFTIRKFGKHWFN

LGIDPINERSFICNYKQHWF

LNSLLAGPELISDTCLANFLAR

TIRKFGKHWFNLNSLLAGPE

LQQQAYSVFVVKGDLPDCEADQ

LISDTCLANFLARLQQQAYS

LLQIISVEEMDTPKLNGKKLVK

VFVVK

QKEHRVYKTVLEKVSEESDESG

TSDQDEEDFQRALELSRQETNR

EDEHLRSTIELSMQGSSGNTSQ

DLPKTSCVTPASEQPKKIKEDY

FEKHQQEQKQQQQQSDLPGHSS

YLHERPTTSSRAIESDLSDDIS

EGTVQAAVDTILEIMRKNLKIK

GEK

MINY3_HUMAN
92
MSELTKELMELVWGTKSSPGLS
200
CRWTQGFVFSESEGSALEQF

Ubiquitin

DTIFCRWTQGFVFSESEGSALE

EGGPCAVIAPVQAFLLKKLL

carboxyl-

QFEGGPCAVIAPVQAFLLKKLL

FSSEKSSWRDCSEEEQKELL

terminal

FSSEKSSWRDCSEEEQKELLCH

CHTLCDILESACCDHSGSYC

hydrolase

TLCDILESACCDHSGSYCLVSW

LVSWLRGKTTEETASISGSP

MINDY-3

LRGKTTEETASISGSPAESSCQ

AESSCQVEHSSALAVEELGF

VEHSSALAVEELGFERFHALIQ

ERFHALIQKRSFRSLPELKD

KRSFRSLPELKDAVLDQYSMWG

AVLDQYSMWGNKFG

NKFGVLLFLYSVLLTKGIENIK

VLLFLYSVLLTKGIENIKNE

NEIEDASEPLIDPVYGHGSQSL

IEDASEPLIDPVYGHGSQSL

INLLLTGHAVSNVWDGDRECSG

INLLLTGHAVSNVWDGDREC

MKLLGIHEQAAVGFLTLMEALR

SGMKLLGIHEQAAVGFLTLM

YCKVGSYLKSPKFPIWIVGSET

EALRYCKVGSYLKSPKFPIW

HLTVFFAKDMALVA

IVGSETHLTVFFAKDMALVA

PEAPSEQARRVFQTYDPEDNGF

PEAPSEQARRVFQTYDPEDN

IPDSLLEDVMKALDLVSDPEYI

GFIPDSLLEDVMKALDLVSD

NLMKNKLDPEGLGIILLGPFLQ

PEYINLMKNKLDPEGLGIIL

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

FTGVSDFEYTPECSVFDLLG

TNGPCPLLAIMNILFLQWKVKL

IPLYHGWLVDPQSPEAVRAV

PPQKEVITSDELMAHLGNCLLS

GKLSYNQLVERIITCKHSSD

IKPQEKSEGLQLNFQQNVDDAM

TNLVTEGLIAEQFLETTAAQ

TVLPKLATGLDVNVRFTGVSDF

LTYHGLCELTAAAKEGELSV

EYTPECSVFDLLGIPLYHGWLV

FFRNNHFSTMTKHKSHLYLL

DPQSPEAVRAVGKLSYNQLVER

VTDQGFLQEEQVVWESLHNV

IITCKHSSDTNLVTEGLIAEQF

DGDSCFCDSDFHLSHSLGKG

LETTAAQLTYHGLC

PGAEGGSGSPETQLQVDQDY

ELTAAAKEGELSVFFRNNHFST

LIALSLQQQQPRGPLGLTDL

MTKHKSHLYLLVTDQGFLQEEQ

ELAQQLQQEEYQQQQAAQPV

VVWESLHNVDGDSCFCDSDFHL

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

FTGVRVFEYTPECIVFDLLD

PDLAGTCQAELTAAGSEEPSSA

IPLYHGWLVDPQIDDIVKAV

GGLSSSCSDPSPPGESPSLDSL

GNCSYNQLVEKIISCKQSDN

ESFSNLHSFPSSCEFNSEEGAE

SELVSEGFVAEQFLNNTATQ

NRVPEEEEGAAVLPGAVPLCKE

LTYHGLCELTSTVQEGELCV

EEGEETAQVLAASKERFPGQSV

FFRNNHFSTMTKYKGQLYLL

YHIKWIQWKEENTPIITQNENG

VTDQGFLTEEKVVWESLHNV

PCPLLAILNVLLLAWKVKLPPM

DGDGNFCDSEFHLRPPSDPE

MEIITAEQLMEYLG

TVYKGQQDQIDQDYLMALSL

DYMLDAKPKEISEIQRLNYEQN

QQEQQSQEINWEQIPEGISD

MSDAMAILHKLQTGLDVNVRFT

LELAKKLQEEEDRRASQYYQ

GVRVFEYTPECIVFDLLDIPLY

EQEQAAAAAAAASTQAQQGQ

HGWLVDPQIDDIVKAVGNCSYN

PAQASPSSGRQSGNSERKRK

QLVEKIISCKQSDNSELVSEGF

EPREKDKEKEKEKNSCVIL

VAEQFLNNTATQLTYHGLCELT

STVQEGELCVFFRNNHFSTMTK

YKGQLYLLVTDQGFLTEEKVVW

ESLHNVDGDGNFCDSEFHLRPP

SDPETVYKGQQDQIDQDYLMAL

SLQQEQQSQEINWEQIPEGISD

LELAKKLQEEEDRRASQYYQEQ

EQAAAAAAAASTQAQQGQPAQA

SPSSGRQSGNSERKRKEPREKD

KEKEKEKNSCVIL

MINY4_HUMAN
95
MDSLFVEEVAASLVREFLSRKG
203
FCCFNEEWKLQSFSFSNTAS

Probable

LKKTCVTMDQERPRSDLSINNR

LKYGIVQNKGGPCGVLAAVQ

ubiquitin

NDLRKVLHLEFLYKENKAKENP

GCVLQKLLFEGDSKADCAQG

carboxyl-

LKTSLELITRYFLDHFGNTANN

LQPSDAHRTRCLVLALADIV

terminal

FTQDTPIPALSVPKKNNKVPSR

WRAGGRERAVVALASRTQQF

hydrolase

CSETTLVNIYDLSDEDAGWRTS

SPTGKYKADGVLETLTLHSL

MINDY-4

LSETSKARHDNLDGDVLGNFVS

TCYEDLVTFLQQSIHQFEVG

SKRPPHKSKPMQTVPGETPVLT

PYGCILLTLSAILSRSTELI

SAWEKIDKLHSEPSLDVKRMGE

RQDFDVPTSHLIGAHGYCTQ

NSRPKSGLIVRGMMSGPIASSP

ELVNLLLTGKAVSNVFNDVV

QDSFHRHYLRRSSPSSSSTQPQ

ELDSGDGNITLLRGIAARSD

EESRKVPELFVCTQQDILASSN

IGFLSLFEHYNMCQVGCFLK

SSPSRTSLGQLSELTVERQKTT

TPRFPIWVVCSESHFSILFS

ASSPPHLPSKRLPP

LQPGLLRDWRTERLFDLYYY

WDRARPRDPSEDTPAVDGSTDT

DGLANQQEQIRLTIDTTQTI

DRMPLKLYLPGGNSRMTQERLE

SEDTDNDLVPPLELCIRTKW

RAFKRQGSQPAPVRKNQLLPSD

KGASVNWNGSDPIL

KVDGELGALRLEDVEDELIREE

VILSPVPSVLKLQTASKPIDLS

VAKEIKTLLFGSSFCCFNEEWK

LQSFSFSNTASLKYGIVQNKGG

PCGVLAAVQGCVLQKLLFEGDS

KADCAQGLQPSDAHRTRCLVLA

LADIVWRAGGRERAVVALASRT

QQFSPTGKYKADGVLETLTLHS

LTCYEDLVTFLQQSIHQFEVGP

YGCILLTLSAILSRSTELIRQD

FDVPTSHLIGAHGY

CTQELVNLLLTGKAVSNVFNDV

VELDSGDGNITLLRGIAARSDI

GFLSLFEHYNMCQVGCFLKTPR

FPIWVVCSESHFSILFSLQPGL

LRDWRTERLFDLYYYDGLANQQ

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

DLEKPSLDVFPTLTVSSIQPSD

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

GAGVLSIYYLGKKFLGDLQPDG

PHSPALPSLQDIDAQMDYQL

RIMWQETGQTFNSPSAWATHCK

RLQGSSNGFQPCLALLCSPY

KLVNPAKKSGCGWASVKYKGQK

YSGNPGPESKISPFWVMPPP

LDKYKATWLRLHQLHTPATAAD

EMLLVEFYKGSPDLVRLQEP

ESPASEGEEEELLMEEEEEDVL

WSQEHTYLDKLKISLASRTP

AGVSAEDKSRRPLGKSPSEPAH

KDQSLCHVLEQVCGVLKQGS

PEATTPGKRVDSKIRVPVRYCM

LGSRDLARNPHTLVEVTSFAAI

NKFQPENVAVSSNVLFLLDFHS

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

ESRQMVGALLEDRAHQHLVDFD

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

VLMTSNIVQCLAAMLDTVVF

FK

K

MYSM1_HUMAN
100
MAAEEADVDIEGDVVAAAGAQP
208
QVKVASEALLIMDLHAHVSM

Histone

GSGENTASVLQKDHYLDSSWRT

AEVIGLLGGRYSEVDKVVEV

H2A

ENGLIPWTLDNTISEENRAVIE

CAAEPCNSLSTGLQCEMDPV

deubiquitinase

KMLLEEEYYLSKKSQPEKVWLD

SQTQASETLAVRGFSVIGWY

MYSM1

QKEDDKKYMKSLQKTAKIMVHS

HSHPAFDPNPSLRDIDTQAK

PTKPASYSVKWTIEEKELFEQG

YQSYFSRGGAKFIGMIVSPY

LAKFGRRWTKISKLIGSRTVLQ

NRNNPLPYSQITCLVISEEI

VKSYARQYFKNKVKCGLDKETP

SPDGSYRLPYKFEVQQMLEE

NQKTGHNLQVKNEDKGTKAWTP

PQWGLVFEKTRWIIEKYRLS

SCLRGRADPNLNAVKIEKLSDD

HSSVPMDKIFRRDSDLTCLQ

EEVDITDEVDELSSQTPQKNSS

KLLECMRKTLSKVTNCFMAE

SDLLLDFPNSKMHETNQGEFIT

EFLTEIENLFLSNYKSNQEN

SDSQEALFSKSSRGCLQNEKQD

GVTEENCTKELLM

ETLSSSEITLWTEK

QSNGDKKSIELNDQKFNELIKN

CNKHDGRGIIVDARQLPSPEPC

EIQKNLNDNEMLFHSCQMVEES

HEEEELKPPEQEIEIDRNIIQE

EEKQAIPEFFEGRQAKTPERYL

KIRNYILDQWEICKPKYLNKTS

VRPGLKNCGDVNCIGRIHTYLE

LIGAINFGCEQAVYNRPQTVDK

VRIRDRKDAVEAYQLAQRLQSM

RTRRRRVRDPWGNWCDAKDLEG

QTFEHLSAEELAKRREEEKGRP

VKSLKVPRPTKSSFDPFQLIPC

NFFSEEKQEPFQVKVASEALLI

MDLHAHVSMAEVIG

LLGGRYSEVDKVVEVCAAEPCN

SLSTGLQCEMDPVSQTQASETL

AVRGFSVIGWYHSHPAFDPNPS

LRDIDTQAKYQSYFSRGGAKFI

GMIVSPYNRNNPLPYSQITCLV

ISEEISPDGSYRLPYKFEVQQM

LEEPQWGLVFEKTRWIIEKYRL

SHSSVPMDKIFRRDSDLTCLQK

LLECMRKTLSKVINCFMAEEFL

TEIENLFLSNYKSNQENGVTEE

NCTKELLM

ABRX2_HUMAN
101
MAASISGYTFSAVCFHSANSNA
209
AVCFHSANSNADHEGFLLGE

BRISC

DHEGFLLGEVRQEETFSISDSQ

VRQEETFSISDSQISNTEFL

complex

ISNTEFLQVIEIHNHQPCSKLF

QVIEIHNHQPCSKLESFYDY

subunit

SFYDYASKVNEESLDRILKDRR

ASKVNEESLDRILKDRRKKV

Abraxas 2

KKVIGWYRFRRNTQQQMSYREQ

IGWYRFRRNTQQQMSYREQV

VLHKQLTRILGVPDLVFLLESF

LHKQLTRIL

ISTANNSTHALEYVLFRPNRRY

GVPDLVFLLFSFISTANNST

NQRISLAIPNLGNTSQQEYKVS

HALEYVLFRPNRRYNQRISL

SVPNTSQSYAKVIKEHGTDFFD

AIPNLGNTSQQEYKVSSVPN

KDGVMKDIRAIYQVYNALQEKV

TSQSYAKVIKEHGTDFFDKD

QAVCADVEKSERVVESCQAEVN

GVMKDIRAIYQVYNALQEKV

KLRRQITQRKNEKEQERRLQQA

QAVCADVEKSERVVESCQAE

VLSRQMPSESLDPAFSPRMPSS

VNKLRRQITQRKNEKEQERR

GFAAEGRSTLGDAE

LQQAVLSRQMPSESLDPAFS

ASDPPPPYSDFHPNNQESTLSH

PRMPSSGFAAEGRSTLGDAE

SRMERSVFMPRPQAVGSSNYAS

ASDPPPPYSDFHPNNQESTL

TSAGLKYPGSGADLPPPQRAAG

SHSRMERSVFMPRPQAVGSS

DSGEDSDDSDYENLIDPTEPSN

NYASTSAGLKYPGSGADLPP

SEYSHSKDSRPMAHPDEDPRNT

PQRAAGDSGEDSDDSDYENL

QTSQI

IDPTEPSNSEYSHSKDSRPM

AHPDEDPRNTQTSQI

PRP8_HUMAN
102
MAGVFPYRGPGNPVPGPLAPLP
210
FNPRTGQLELKIIHTSVWAG

Pre-mRNA-

DYMSEEKLQEKARKWQQLQAKR

QKRLGQLAKWKTAEEVAALI

processing-

YAEKRKFGFVDAQKEDMPPEHV

RSLPVEEQPKQIIVTRKGML

splicing

RKIIRDHGDMTNRKFRHDKRVY

DPLEVHLLDFPNIVIKGSEL

factor 8

LGALKYMPHAVLKLLENMPMPW

QLPFQACLKVEKFGDLILKA

EQIRDVPVLYHITGAISFVNEI

TEPQMVLFNLYDDWLKTISS

PWVIEPVYISQWGSMWIMMRRE

YTAFSRLILILRALHVNNDR

KRDRRHFKRMRFPPFDDEEPPL

AKVILKPDKTTITEPHHIWP

DYADNILDVEPLEAIQLELDPE

TLTDEEWIKVEVQLKDLILA

EDAPVLDWFYDHQPLRDSRKYV

DYGKKNNVNVASLTQSEIRD

NGSTYQRWQFTLPMMSTLYRLA

IILGMEISAPSQQRQQIAEI

NQLLTDLVDDNYFYLFDLKAFF

EKQTKEQSQLTATQTRTVNK

TSKALNMAIPGGPKFEPLVRDI

HGDEIITSTTSNYETQTFSS

NLQDEDWNEFNDIN

KTEWRVRAISAANLHLRTNH

KIIIRQPIRTEYKIAFPYLYNN

IYVSSDDIKETGYTYILPKN

LPHHVHLTWYHTPNVVFIKTED

VLKKFICISDLRAQIAGYLY

PDLPAFYFDPLINPISHRHSVK

GVSPPDNPQVKEIRCIVMVP

SQEPLPDDDEEFELPEFVEPFL

QWGTHQTVHLPGQLPQHEYL

KDTPLYTDNTANGIALLWAPRP

KEMEPLGWIHTQPNESPQLS

FNLRSGRTRRALDIPLVKNWYR

PQDVTTHAKIMADNPSWDGE

EHCPAGQPVKVRVSYQKLLKYY

KTIIITCSFTPGSCTLTAYK

VLNALKHRPPKAQKKRYLFRSF

LTPSGYEWGRQNTDKGNNPK

KATKFFQSTKLDWVEVGLQVCR

GYLPSHYERVQMLLSDRFLG

QGYNMLNLLIHRKNLNYLHLDY

FFMVPAQSSWNYNFMGVRHD

NFNLKPVKTLTTKERKKSRFGN

PNMKYELQLANPKEFYHEVH

AFHLCREVLRLTKLVVDSHVQY

RPSHFLNFALLQEGEVYSAD

RLGNVDAFQLADGLQYIFAHVG

REDLYA

QLTGMYRYKYKLMR

QIRMCKDLKHLIYYRFNTGPVG

KGPGCGFWAAGWRVWLFFMRGI

TPLLERWLGNLLARQFEGRHSK

GVAKTVTKQRVESHFDLELRAA

VMHDILDMMPEGIKQNKARTIL

QHLSEAWRCWKANIPWKVPGLP

TPIENMILRYVKAKADWWTNTA

HYNRERIRRGATVDKTVCKKNL

GRLTRLYLKAEQERQHNYLKDG

PYITAEEAVAVYTTTVHWLESR

RFSPIPFPPLSYKHDTKLLILA

LERLKEAYSVKSRLNQSQREEL

GLIEQAYDNPHEALSRIKRHLL

TQRAFKEVGIEFMD

LYSHLVPVYDVEPLEKITDAYL

DQYLWYEADKRRLFPPWIKPAD

TEPPPLLVYKWCQGINNLQDVW

ETSEGECNVMLESRFEKMYEKI

DLTLLNRLLRLIVDHNIADYMT

AKNNVVINYKDMNHTNSYGIIR

GLQFASFIVQYYGLVMDLLVLG

LHRASEMAGPPQMPNDFLSFQD

IATEAAHPIRLFCRYIDRIHIF

FRFTADEARDLIQRYLTEHPDP

NNENIVGYNNKKCWPRDARMRL

MKHDVNLGRAVFWDIKNRLPRS

VTTVQWENSFVSVYSKDNPNLL

FNMCGFECRILPKC

RTSYEEFTHKDGVWNLQNEVTK

ERTAQCFLRVDDESMQRFHNRV

RQILMASGSTTFTKIVNKWNTA

LIGLMTYFREAVVNTQELLDLL

VKCENKIQTRIKIGLNSKMPSR

FPPVVFYTPKELGGLGMLSMGH

VLIPQSDLRWSKQTDVGITHFR

SGMSHEEDQLIPNLYRYIQPWE

SEFIDSQRVWAEYALKRQEAIA

QNRRLTLEDLEDSWDRGIPRIN

TLFQKDRHTLAYDKGWRVRTDF

KQYQVLKQNPFWWTHQRHDGKL

WNLNNYRTDMIQALGGVEGILE

HTLFKGTYFPTWEG

LFWEKASGFEESMKWKKLTNAQ

RSGLNQIPNRRFTLWWSPTINR

ANVYVGFQVQLDLTGIFMHGKI

PTLKISLIQIFRAHLWQKIHES

IVMDLCQVFDQELDALEIETVQ

KETIHPRKSYKMNSSCADILLF

ASYKWNVSRPSLLADSKDVMDS

TTTQKYWIDIQLRWGDYDSHDI

ERYARAKFLDYTTDNMSIYPSP

TGVLIAIDLAYNLHSAYGNWFP

GSKPLIQQAMAKIMKANPALYV

LRERIRKGLQLYSSEPTEPYLS

SQNYGELFSNQIIWFVDDTNVY

RVTIHKTFEGNLTT

KPINGAIFIFNPRTGQLFLKII

HTSVWAGQKRLGQLAKWKTAEE

VAALIRSLPVEEQPKQIIVTRK

GMLDPLEVHLLDEPNIVIKGSE

LQLPFQACLKVEKFGDLILKAT

EPQMVLFNLYDDWLKTISSYTA

FSRLILILRALHVNNDRAKVIL

KPDKTTITEPHHIWPTLTDEEW

IKVEVQLKDLILADYGKKNNVN

VASLTQSEIRDIILGMEISAPS

QQRQQIAEIEKQTKEQSQLTAT

QTRTVNKHGDEIITSTTSNYET

QTFSSKTEWRVRAISAANLHLR

TNHIYVSSDDIKET

GYTYILPKNVLKKFICISDLRA

QIAGYLYGVSPPDNPQVKEIRC

IVMVPQWGTHQTVHLPGQLPQH

EYLKEMEPLGWIHTQPNESPQL

SPQDVTTHAKIMADNPSWDGEK

TIIITCSFTPGSCTLTAYKLTP

SGYEWGRQNTDKGNNPKGYLPS

HYERVQMLLSDRFLGFFMVPAQ

SSWNYNFMGVRHDPNMKYELQL

ANPKEFYHEVHRPSHFLNFALL

QEGEVYSADREDLYA

NPL4_HUMAN
103
MAESIIIRVQSPDGVKRITATK
211
QPSAITLNRQKYRHVDNIME

Mitochondrial

RETAATFLKKVAKEFGFQNNGF

ENHTVADRFLDFWRKTGNQH

protein

SVYINRNKTGEITASSNKSLNL

FGYLYGRYTEHKDIPLGIRA

localization

LKIKHGDLLFLFPSSLAGPSSE

EVAAIYEPPQIGTQNSLELL

protein 4

METSVPPGFKVFGAPNVVEDEI

EDPKAEVVDEIAAKLGLRKV

homolog

DQYLSKQDGKIYRSRDPQLCRH

GWIFTDLVSEDTRKGTVRYS

GPLGKCVHCVPLEPFDEDYLNH

RNKDTYFLSSEECITAGDFQ

LEPPVKHMSFHAYIRKLTGGAD

NKHPNMCRLSPDGHFGSKFV

KGKFVALENISCKIKSGCEGHL

TAVATGGPDNQVHFEGYQVS

PWPNGICTKCQPSAITLNRQKY

NQCMALVRDECLLPCKDAPE

RHVDNIMFENHTVADRFLDEWR

LGYAKESSSEQYVPDVFYKD

KTGNQHFGYLYGRYTEHKDIPL

VDKFGNEITQLARPLPVEYL

GIRAEVAAIYEPPQIGTQNSLE

IIDITTTFPKDPVYTFSISQ

LLEDPKAEVVDEIA

NPFPIENRDVLGETQDFHSL

AKLGLRKVGWIFTDLVSEDTRK

ATYLSQNTSSVELDTISDFH

GTVRYSRNKDTYFLSSEECITA

LLLFLVTNEVMPLQDSISLL

GDFQNKHPNMCRLSPDGHFGSK

LEAVRTRNEELAQTWKRSEQ

FVTAVATGGPDNQVHFEGYQVS

WATIEQLCSTVGGQLPGLHE

NQCMALVRDECLLPCKDAPELG

YGAVGGSTHTATAAMWACQH

YAKESSSEQYVPDVFYKDVDKF

CTFMNQPGTGHCEMCSLPRT

GNEITQLARPLPVEYLIIDITT

TFPKDPVYTFSISQNPFPIENR

DVLGETQDFHSLATYLSQNTSS

VFLDTISDFHLLLFLVTNEVMP

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

AEKVASRIAEGESDTALIMV

TMDCVAPTIHVYEHHENRWRCR

DNTKFTMDCVAPTIHVYEHH

DPHHDYCEDWPEAQRISASLLD

ENRWRCRDPHHDYCEDWPEA

SRSYETLVDFDNHLDDIRNDWT

QRISASLLDSRSYETLVDFD

NPEINKAVLHLC

NHLDDIRNDWTNPEINKAVL

HLC

ABRX1_HUMAN
105
MEGESTSAVLSGFVLGALAFQH
213
GFVLGALAFQHLNTDSDTEG

BRCA1-A

LNTDSDTEGFLLGEVKGEAKNS

FLLGEVKGEAKNSITDSQMD

complex

ITDSQMDDVEVVYTIDIQKYIP

DVEVVYTIDIQKYIPCYQLF

subunit

CYQLFSFYNSSGEVNEQALKKI

SFYNSSGEVNEQALKKILSN

Abraxas 1

LSNVKKNVVGWYKFRRHSDQIM

VKKNVVGWYKFRRHSDQIMT

TFRERLLHKNLQEHFSNQDLVF

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
VVLPEDLCHKFLQLAESNTV

AMSH-

SLSPEERVRALSKLGCNITISE

RGIETCGILCGKLTHNEFTI

like protease

DITPRRYFRSGVEMERMASVYL

THVIVPKQSAGPDYCDMENV

EEGNLENAFVLYNKFITLFVEK

EELFNVQDQHDLLTLGWIHT

LPNHRDYQQCAVPEKQDIMKKL

HPTQTAFLSSVDLHTHCSYQ

KEIAFPRTDELKNDLLKKYNVE

LMLPEAIAIVCSPKHKDTGI

YQEYLQSKNKYKAEILKKLEHQ

FRLTNAGMLEVSACKKKGFH

RLIEAERKRIAQMRQQQLESEQ

PHTKEPRLFSICKHVLVKDI

FLFFEDQLKKQELARGQMRSQQ

KIIVLDLR

TSGLSEQIDGSALSCFSTHQNN

SLLNVFADQPNKSDATNYASHS

PPVNRALTPAATLSAVQNLVVE

GLRCVVLPEDLCHKFLQLAESN

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

PSDIHVHKQVCEIIESPLFLKL

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

LQYAEDVLSGKVSADNTVGRFL

EKLVNL

MSLVNQVPKIVPDDFETMLNSN

INDLLMVTYLANLTQSQIALNE

KLVNL

PSMD7_HUMAN
109
MPELAVQKVVVHPLVLLSVVDH
217
VVVHPLVLLSVVDHFNRIGK

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

PINHQIIYQLQDVFNLLPDVSL

RSYLEKVATGKLPINHQIIY

QEFVKAFYLKTNDQMVVVYLAS

QLQDVFNLLPDVSLQEFVKA

LIRSVVALHNLINNKIANRDAE

FYLKTNDQMVVVYLASLIRS

KKEGQEKEESKKDRKEDKEKDK

VVALHNLINNKIANRDAEKK

DKEKSDVKKEEKKEKK

EGQEKEESKKDRKEDKEKDK

DKEKSDVKKEEKKEKK

EIF3H_HUMAN
110
MASRKEGTGSTATSSSSTAGAA
218
VQIDGLVVLKIIKHYQEEGQ

Eukaryotic

GKGKGKGGSGDSAVKQVQIDGL

GTEVVQGVLLGLVVEDRLEI

translation

VVLKIIKHYQEEGQGTEVVQGV

TNCFPFPQHTEDDADFDEVQ

initiation

LLGLVVEDRLEITNCFPFPQHT

YQMEMMRSLRHVNIDHLHVG

factor 3

EDDADFDEVQYQMEMMRSLRHV

WYQSTYYGSFVTRALLDSQF

subunit H

NIDHLHVGWYQSTYYGSFVTRA

SYQHAIEESVVLIYDPIKTA

LLDSQFSYQHAIEESVVLIYDP

QGSLSLKAYRLTPKLMEVCK

IKTAQGSLSLKAYRLTPKLMEV

EKDFSPEALKKANITFEYMF

CKEKDFSPEALKKANITFEYMF

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

SLLTNADYTTGQVFDLSEKL

NKYWVNTLSSSSLLTNADYTTG

EQSEAQLGRGSFMLGLETHD

QVEDLSEKLEQSEAQLGRGSFM

RKSEDKLAKATRDSCKTTIE

LGLETHDRKSEDKLAKATRDSC

AIHGLMSQVIKDKLFNQINI

KTTIEAIHGLMSQVIKDKLFNQ

S

INIS

BRCC3_HUMAN
112
MAVQVVQAVQAVHLESDAFLVC
220
VHLESDAFLVCLNHALSTEK

Lys-63-

LNHALSTEKEEVMGLCIGELND

EEVMGLCIGELNDDTRSDSK

specific

DTRSDSKFAYTGTEMRTVAEKV

FAYTGTEMRTVAEKVDAVRI

deubiquitinase

DAVRIVHIHSVIILRRSDKRKD

VHIHSVIILRRSDKRKDRVE

BRCC36

RVEISPEQLSAASTEAERLAEL

ISPEQLSAASTEAERLAELT

TGRPMRVVGWYHSHPHITVWPS

GRPMRVVGWYHSHPHITVWP

HVDVRTQAMYQMMDQGFVGLIF

SHVDVRTQAMYQMMDQGFVG

SCFIEDKNTKTGRVLYTCFQSI

LIFSCFIEDKNTKTGRVLYT

QAQKSSESLHGPRDFWSSSQHI

CFQSIQAQKSSESLHGPRDF

SIEGQKEEERYERIEIPIHIVP

WSSSQHISIEGQKEEERYER

HVTIGKVCLESAVELPKILCQE

IEIPIHIVPHVTIGKVCLES

EQDAYRRIHSLTHLDSVIKIHN

AVELPKILCQEEQDAYRRIH

GSVFTKNLCSQMSAVSGPLLQW

SLTHLDSVIKIHNGSVFTKN

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 mitochondrial 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 mitochondrial protein. In some embodiments, the targeting moiety specifically binds to a wild type target mitochondrial protein, but does not specifically binds to a variant of the target mitochondrial protein associated with a genetic disease. In some embodiments, the targeting moiety specifically binds to a naturally occurring variant of a target mitochondrial protein. In some embodiments, the targeting moiety specifically binds to a naturally occurring variant of a target mitochondrial 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 mitochondrial 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 mitochondrial protein that is a loss of a function variant. In some embodiments, the targeting moiety specifically binds a naturally occurring variant of a target mitochondrial 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 mitochondrial 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 Mitochondrial Proteins

In some embodiments, targeting moiety specifically binds a target mitochondrial protein (e.g., a mitochondrial protein described herein). Exemplary target mitochondrial proteins include, but are not limited to, dynamin-like 120 kDa protein (OPA1), protoporphyrinogen oxidase (PPOX), frataxin (FXN), DNA polymerase subunit gamma-1 (POLG), cytochrome c oxidase subunit 6A2, mitochondrial (COX6A2), ubiquinol-cytochrome-c reductase complex assembly factor 2 (UQCC2), and complex III assembly factor LYRM7 (LYRM7). In some embodiments, the target mitochondrial protein is OPA1. In some embodiments, the target mitochondrial protein is PPOX. In some embodiments, the target mitochondrial protein is FXN. In some embodiments, the target mitochondrial protein is POLG. In some embodiments, the target mitochondrial protein is cytochrome c oxidase subunit 6A2 mitochondrial (COX6A2). In some embodiments, the target mitochondrial protein is ubiquinol-cytochrome-c reductase complex assembly factor 2 (UQCC2). In some embodiments, the target mitochondrial protein is complex III assembly factor LYRM7 (LYRM7).

In some embodiments, the target mitochondrial 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 mitochondrial 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 mitochondrial 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 mitochondrial 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 mitochondrial 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: 271. In some embodiments, the target mitochondrial 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: 272. In some embodiments, the target mitochondrial 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: 273.

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 mitochondrial proteins to

target for deubiquitination utilizing the fusion proteins described

herein and exemplary disease associations

Disease
SEQ ID

Description
Associations
NO
WT Amino Acid Sequence

Dynamin-like
Optic atrophy 1
221

MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHL

120 kDa

VSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPL

protein (OPA1)

RKLKFSPIKYGYQPRRNFWPARLATRLLKLRYLIL

Signal

GSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIV

Sequence

WEIDEYIDFEKIRKALPSSEDLVKLAPDEDKIVES

Underlined

LSLLKDFFTSGSPEETAFRATDRGSESDKHERKVS

DKEKIDQLQEELLHTQLKYQRILERLEKENKELRK

LVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDA

SYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFP

RGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDL

TKEEDLAALRHEIELRMRKNVKEGCTVSPETISLN

VKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFS

ISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQM

DPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKL

FPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQN

SKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESV

EQQADSFKATRENLETEWKNNYPRLRELDRNELFE

KAKNEILDEVISLSQVTPKHWEEILQQSLWERVST

HVIENIYLPAAQTMNSGTENTTVDIKLKQWTDKQL

PNKAVEVAWETLQEEFSREMTEPKGKEHDDIEDKL

KEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSI

SDKQQWDAAIYEMEEALQARLKDTENAIENMVGPD

WKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEH

PAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQV

YRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECN

DVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNV

KEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVREI

QEKLDAFIEALHQEK

Protoporphy-
Porphyria
222
MGRTVVVLGGGISGLAASYHLSRAPCPPKVVLVES

rinogen oxidase
variegata

SERLGGWIRSVRGPNGAIFELGPRGIRPAGALGAR

(PPOX)

TLLLVSELGLDSEVLPVRGDHPAAQNRFLYVGGAL

HALPTGLRGLLRPSPPFSKPLFWAGLRELTKPRGK

EPDETVHSFAQRRLGPEVASLAMDSLCRGVFAGNS

RELSIRSCFPSLFQAEQTHRSILLGLLLGAGRTPQ

PDSALIRQALAERWSQWSLRGGLEMLPQALETHLT

SRGVSVLRGQPVCGLSLQAEGRWKVSLRDSSLEAD

HVISAIPASVLSELLPAEAAPLARALSAITAVSVA

VVNLQYQGAHLPVQGFGHLVPSSEDPGVLGIVYDS

VAFPEQDGSPPGLRVTVMLGGSWLQTLEASGCVLS

QELFQQRAQEAAATQLGLKEMPSHCLVHLHKNCIP

QYTLGHWQKLESARQFLTAHRLPLTLAGASYEGVA

VNDCIESGRQAAVSVLGTEPNS

Frataxin
Friedreic's
223

MWTLGRRAVAGLLASPSPAQAQTLTRVPRPAELAP

(FXN)
Ataxia

LCGRRGLRTDIDATCTPRRASSNQRGLNQIWNVKK

QSVYLMNLRKSGTLGHPGSLDETTYERLAEETLDS

LAEFFEDLADKPYTFEDYDVSFGSGVLTVKLGGDL

GTYVINKQTPNKQIWLSSPSSGPKRYDWTGKNWVY

SHDGVSLHELLAAELTKALKTKLDLSSLAYSGKDA

DNA
Alpers
224
MSRLLWRKVAGATVGPGPVPAPGRWVSSSVPASDP

polymerase
Syndrome

SDGQRRRQQQQQQQQQQQQQPQQPQVLSSEGGQLR

subunit

HNPLDIQMLSRGLHEQIFGQGGEMPGEAAVRRSVE

gamma-1

HLQKHGLWGQPAVPLPDVELRLPPLYGDNLDQHER

(POLG)

LLAQKQSLPYLEAANLLLQAQLPPKPPAWAWAEGW

TRYGPEGEAVPVAIPEERALVEDVEVCLAEGTCPT

LAVAISPSAWYSWCSQRLVEERYSWTSQLSPADLI

PLEVPTGASSPTQRDWQEQLVVGHNVSEDRAHIRE

QYLIQGSRMRFLDTMSMHMAISGLSSFQRSLWIAA

KOGKHKVQPPTKQGQKSQRKARRGPAISSWDWLDI

SSVNSLAEVHRLYVGGPPLEKEPRELFVKGTMKDI

RENFQDLMQYCAQDVWATHEVFQQQLPLFLERCPH

PVTLAGMLEMGVSYLPVNQNWERYLAEAQGTYEEL

QREMKKSLMDLANDACQLLSGERYKEDPWLWDLEW

DLQEFKQKKAKKVKKEPATASKLPIEGAGAPGDPM

DQEDLGPCSEEEEFQQDVMARACLQKLKGTTELLP

KRPQHLPGHPGWYRKLCPRLDDPAWTPGPSLLSLQ

MRVTPKLMALTWDGEPLHYSERHGWGYLVPGRRDN

LAKLPTGTTLESAGVVCPYRAIESLYRKHCLEQGK

QQLMPQEAGLAEEFLLTDNSAIWQTVEELDYLEVE

AEAKMENLRAAVPGQPLALTARGGPKDTQPSYHHG

NGPYNDVDIPGCWFFKLPHKDGNSCNVGSPFAKDE

LPKMEDGTLQAGPGGASGPRALEINKMISFWRNAH

KRISSQMVVWLPRSALPRAVIRHPDYDEEGLYGAI

LPQVVTAGTITRRAVEPTWLTASNARPDRVGSELK

AMVQAPPGYTLVGADVDSQELWIAAVLGDAHFAGM

HGCTAFGWMTLQGRKSRGTDLHSKTATTVGISREH

AKIFNYGRIYGAGQPFAERLLMQFNHRLTQQEAAE

KAQQMYAATKGLRWYRLSDEGEWLVRELNLPVDRT

EGGWISLQDLRKVQRETARKSQWKKWEVVAERAWK

GGTESEMENKLESIATSDIPRTPVLGCCISRALEP

SAVQEEFMTSRVNWVVQSSAVDYLHLMLVAMKWLF

EEFAIDGRFCISIHDEVRYLVREEDRYRAALALQI

TNLLTRCMFAYKLGLNDLPQSVAFFSAVDIDRCLR

KEVTMDCKTPSNPTGMERRYGIPQGEALDIYQIIE

LTKGSLEKRSQPGP

Cytochrome c
Mitochondrial
271

MALPLRPLTRGLASAAKGGHGGAGARTWRLLTFVL

oxidase
complex IV

ALPSVALCTENSYLHSGHRPRPEFRPYQHLRIRTK

subunit 6A2,
deficiency,

PYPWGDGNHTLFHNSHVNPLPTGYEHP

mitochondrial
nuclear type 18

(COX6A2)
(MC4DN18)

Signal

sequence

underlined

Ubiquinol-
Mitochondrial
272

MAASRYRRFLKLCEEWPVDETKRGRDLGAYLRQRV

cytochrome-c
complex III

AQAFREGENTQVAEPEACDQMYESLARLHSNYYKH

reductase
deficiency,

KYPRPRDTSFSGLSLEEYKLILSTDTLEELKEIDK

complex
nuclear 7

GMWKKLQEKFAPKGPEEDHKA

assembly
(MC3DN7)

factor 2

(UQCC2)

Signal

sequence

underlined

Complex III
Mitochondrial
273
MGRAVKVLQLFKTLHRTRQQVEKNDARALEAARIK

assembly factor
complex III

INEEFKNNKSETSSKKIEELMKIGSDVELLLRTSV

LYRM7
deficiency,

IQGIHTDHNTLKLVPRKDLLVENVPYCDAPTOKQ

(LYRM7)
nuclear 8

(MC3DN8)

5.3.3 Mitochondrial Localization Signals

In some embodiments, the fusion protein comprises a mitochondrial localization signal (MLS) at the N terminus of the fusion protein. Exemplary MLSs are provided in Table 3. In some embodiments, the MLS comprises an amino acid sequence at least 95%, 96%, 97%, 98%, 99%, or 100% identical to one of SEQ ID NO: 275-278.

TABLE 3

The amino acid sequence of exemplary MLSs

SEQ

ID

Amino Acid Sequence
NO

MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSH
275

HPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQPRRN

MWTLGRRAVAGLLASPSPAQAQTLTRVPRPAELAPLCGRRG
276

MALPLRPLTRGLA
277

MAASRYRRELKLC
278

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: 297-406, or the amino acid sequence of any one of SEQ ID NOS: 279-406 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: 297-406, or the amino acid sequence of any one of SEQ ID NOS: 297-406 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: 297-288, or the amino acid sequence of any one of SEQ ID NOS: 297-288 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: 297-288, or the amino acid sequence of any one of SEQ ID NOS: 297-288 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

Amino Acid Sequence
SEQ ID NO

GGGGSGGGGSGGGGSGGGGSGGGGS
279

GGGGSGGGGSGGGGSGGGGS
280

GGGGSGGGGSGGGGS
28

GGGGSGGGGS
282

GGGGS
283

SGGGGSGGGGSGGGGS
284

SGGGGSGGGGSGGGG
285

SGGGGSGGGG
286

SGGGG
287

GGSGG
288

AHFKISGEKRPSTDPGKKAKNPKKKKKKDP
289

AHRAKKMSKTHA
290

ASPEYVNLPINGNG
291

CTKRPRW
292

DKAKRVSRNKSEKKRR
293

EELRLKEELLKGIYA
294

EEQLRRRKNSRLNNTG
295

EVLKVIRTGKRKKKAWKRMVTKVC
296

HHHHHHHHHHHHQPH
297

HKKKHPDASVNESEFSK
298

HKRTKKNLS
299

IINGRKLKLKKSRRRSSQTSNNSFTSRRS
300

KAEQERRK
301

KEKRKRREELFIEQKKRK
302

KKGKDEWFSRGKKP
303

KKGPSVQKRKKTNLS
304

KKKTVINDLLHYKKEK
305

KKNGGKGKNKPSAKIKK
306

KKPKWDDFKKKKK
307

KKRKKDNLS
308

KKRRKRRRK
309

KKRRRRARK
310

KKSKRGR
311

KKSRKRGS
312

KKSTALSRELGKIMRRR
313

KKSYQDPEIIAHSRPRK
314

KKTGKNRKLKSKRVKTR
315

KKVSIAGQSGKLWRWKR
316

KKYENVVIKRSPRKRGRPRK
317

KNKKRK
318

KPKKKR
319

KRAMKDDSHGNSTSPKRRK
320

KRANSNLVAAYEKAKKK
321

KRASEDTTSGSPPKKSSAGPKR
322

KRFKRRWMVRKMKTKK
323

KRGLNSSFETSPKKVK
324

KRGNSSIGPNDLSKRKQRKK
325

KRIHSVSLSQSQIDPSKKVKRAK
326

KRKGKLKNKGSKRKK
327

KRRRRRRREKRKR
328

KRSNDRTYSPEEEKQRRA
329

KRTVATNGDASGAHRAKKMSK
330

KRVYNKGEDEQEHLPKGKKR
331

KSGKAPRRRAVSMDNSNK
332

KVNFLDMSLDDIIIYKELE
333

KVQHRIAKKTTRRRR
334

LSPSLSPL
335

MDSLLMNRRKFLYQFKNVRWAKGRRETYLC
336

MPQNEYIELHRKRYGYRLDYHEKKRKKESREAHERSKK
337

AKKMIGLKAKLYHK

MVQLRPRASR
338

NNKLLAKRRKGGASPKDDPMDDIK
339

NYKRPMDGTYGPPAKRHEGE
340

PDTKRAKLDSSETTMVKKK
341

PEKRTKI
342

PGGRGKKK
343

PGKMDKGEHRQERRDRPY
344

PKKGDKYDKTD
245

PKKKSRK
246

PKKNKPE
347

PKKRAKV
348

PKPKKLKVE
349

PKRGRGR
350

PKRRLVDDA
351

PKRRRTY
352

PLEKRR
353

PLRKAKR
354

PPAKRKCIF
355

PPARRRRL
356

PPKKKRKV
357

PPNKRMKVKH
358

PPRIYPQLPSAPT
359

PQRSPFPKSSVKR
360

PRPRKVPR
361

PRRRVQRKR
362

PRRVRLK
363

PSRKRPR
364

PSSKKRKV
365

PTKKRVK
366

QRPGPYDRP
367

RGKGGKGLGKGGAKRHRK
368

RKAGKGGGGHKTTKKRSAKDEKVP
369

RKIKLKRAK
370

RKIKRKRAK
371

RKKEAPGPREELRSRGR
372

RKKRKGK
373

RKKRRQRRR
374

RKKSIPLSIKNLKRKHKRKKNKITR
375

RKLVKPKNTKMKTKLRTNPY
376

RKRLILSDKGQLDWKK
377

RKRLKSK
378

RKRRVRDNM
379

RKRSPKDKKEKDLDGAGKRRKT
380

RKRTPRVDGQTGENDMNKRRRK
381

RLPVRRRRRR
382

RLRFRKPKSK
383

RQQRKR
384

RRDLNSSFETSPKKVK
385

RRDRAKLR
386

RRGDGRRR
387

RRGRKRKAEKQ
388

RRKKRR
389

RRKRSKSEDMDSVESKRRR
390

RRKRSR
391

RRPKGKTLQKRKPK
392

RRRGFERFGPDNMGRKRK
393

RRRGKNKVAAQNCRK
394

RRRKRRNLS
395

RRRQKQKGGASRRR
396

RRRREGPRARRRR
397

RRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSV
398

GMSHNAIRFGRMPRSEKAKLKAE

RRVPQRKEVSRCRKCRK
399

RVGGRRQAVECIEDLLNEPGQPLDLSCKRPRP
400

RVVKLRIAP
401

RVVRRR
402

SKRKTKISRKTR
403

SYVKTVPNRTRTYIKL
404

TGKNEAKKRKIA
405

TLSPASSPSSVSCPVIPASTDESPGSALNI
406

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, os LYRM7.

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 270; and a targeting domain comprising a targeting moiety that specifically binds a mitochondrial protein, wherein the mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, or LYRM7.

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 mitochondrial protein, wherein the mitochondrial 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: 221-224 or 271-273.

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 270; and a targeting domain comprising a targeting moiety that specifically binds a mitochondrial protein, wherein the mitochondrial 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: 221-224 or 271-273.

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 mitochondrial 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 270, and a targeting moiety comprising a VHH, (VHH)₂, or scFv that specifically binds to a mitochondrial 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: 270, and a targeting moiety comprising a VHH, (VHH)₂, or scFv that specifically binds to a mitochondrial 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 mitochondrial protein is OPA1, PPOX, FXN, POLG, COX6A2, UQCC2, and LYRM7.
- Embodiment 6. The fusion protein of any one of Embodiments 1-5, wherein said mitochondrial protein is OPA1, PPOX, FXN, or POLG.
- Embodiment 7. The fusion protein of any one of Embodiments 1-6, wherein said mitochondrial protein is COX6A2, UQCC2, or LYRM7.

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; or sodium 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 mitochondrial protein. In some embodiments, the genetic disease is associated with decreased stability of a functional target mitochondrial protein. In some embodiments, the genetic disease is associated with increased ubiquitination of a target mitochondrial protein. In some embodiments, the genetic disease is associated with increased ubiquitination and degradation of a target mitochondrial protein. In some embodiments, the genetic disease is a haploinsufficiency disease.

In some embodiments, the disease is selected from the group consisting of optic atrophy 1, Porphyria variegata, Friedreich's Ataxia, and Alpers Syndrome. In some embodiments, the target mitochondrial protein is OPA1, and the disease is Optic atrophy 1. In some embodiments, the target mitochondrial protein is PPOX, and the disease is Porphyria variegata. In some embodiments, the target mitochondrial protein is FXN, and the disease is Friedreich's Ataxia. In some embodiments, the target mitochondrial protein is POLG, and the disease is Alpers Syndrome. In some embodiments, the target mitochondrial protein is COX6A2, and the disease is mitochondrial complex IV deficiency nuclear type 18 (MC4DN18). In some embodiments, the target mitochondrial protein is UQCC2, and the disease is mitochondrial complex III deficiency nuclear 7 (MC3DN7). In some embodiments, the target mitochondrial protein is LYRM7, and the disease is mitochondrial complex III deficiency nuclear 8 (MC3DN8).

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

SEQ

Description
ID NO
Amino Acid Sequence

Target Proteins

Elongation
225
MAAATLLRATPHESGLAAGRTELLQGLLRLLKAPALPLLCRGLAVE

factor TU

AKKTYVRDKPHVNVGTIGHVDHGKTTLTAAITKILAEGGGAKFKKY

EEIDNAPEERARGITINAAHVEYSTAARHYAHTDCPGHADYVKNMI

TGTAPLDGCILVVAANDGPMPQTREHLLLARQIGVEHVVVYVNKAD

AVQDSEMVELVELEIRELLTEFGYKGEETPVIVGSALCALEGRDPE

LGLKSVQKLLDAVDTYIPVPARDLEKPFLLPVEAVYSVPGRGTVVT

GTLERGILKKGDECELLGHSKNIRTVVTGIEMFHKSLERAEAGDNL

GALVRGLKREDLRRGLVMVKPGSIKPHQKVEAQVYILSKEEGGRHK

PFVSHFMPVMFSLTWDMACRIILPPEKELAMPGEDLKENLILRQPM

ILEKGQRFTLRDGNRTIGTGLVTNTLAMTEEEKNIKWG

BAX
226
MDGSGEQPRGGGPTSSEQIMKTGALLLQGFIQDRAGRMGGEAPELA

LDPVPQDASTKKLSECLKRIGDELDSNMELQRMIAAVDTDSPREVE

FRVAADMESDGNENWGRVVALFYFASKLVLKALCTKVPELIRTIMG

WTLDFLRERLLGWIQDQGGWDGLLSYFGTPTWQTVTIFVAGVLTAS

LTIWKKMG

Fluorescent Proteins

YFP
227
VSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKF

ICTTGKLPVPWPTLVTTFGYGLQCFARYPDHMKQHDFFKSAMPEGY

VQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILG

HKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQ

NTPIGDGPVLLPDNHYLSYQSALSKDPNEKRDHMVLLEFVTAAGIT

LGMDELYK

mCherry
228
MVSKGEEDNMAIIKEFMRFKVHMEGSVNGHEFEIEGEGEGRPYEGT

QTAKLKVTKGGPLPFAWDILSPQFMYGSKAYVKHPADIPDYLKLSF

PEGFKWERVMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNFPSDG

PVMQKKTMGWEASSERMYPEDGALKGEIKQRLKLKDGGHYDAEVKT

TYKAKKPVQLPGAYNVNIKLDITSHNEDYTIVEQYERAEGRHSTGG

MDELYK

CFP
229
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYK

A2 Peptides

P2A
230
GSGATNFSLLKQAGDVEENPGP

T2A
231
GSGEGRGSLLTCGDVEENPGP

E2A
232
GSGQCTNYALLKLAGDVESNPGP

Target Binders

YFP targeting
233
QVQLVESGGALVQPGGSLRLSCAASGFPVNRYSMRWYRQAPGKERE

nanobody

WVAGMSSAGDRSSYEDSVKGRFTISRDDARNTVYLQMNSLKPEDTA

VYYCNVNVGFEYWGQGTQVTVSS

Elongation
234
QVQLQESGGGLAQAGGSLRLSCAASGRMFSINNMGWYRQAPGKORE

factor TU binder

LVAFITRGGTTTYADSMKGRVTISRDNAKNTVYLQMNSLKPEDTAV

(monobody)

YYCAADDINNPRRTTTYWGQGTQVTISS

BAX binder
235
DVQLQASGGGLVQAGGSLRLSCAASGRTESSYAMGWERRAPGKERE

1(monobody)

FVAAISWSGTNTNYADSVKGRFTISRDNAKNTMYLQMNRLAPEDTA

VYYCAATSTRTYYYTTSRSNEYVYWGQGTQVTVSS

BAX binder
236
DVQLQASGGGLVQAGGSLRLSCAASGRTNSWYSMGWFRQAPGKERE

2(monobody)

FVAAISWNGDAIYYTDSVKGRFTISRDNTKNTVYLQMNSLKPEDTA

VYICAAHAAAFTEAAHIPGYEYWGQGTQVTVSS

EnDUBS

Cezanne
237
PPSFSEGSGGSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRG

ISHASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYN

EDERSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTG

DGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWRW

QQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANCGG

VESSEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAP

IPFGGIYLPLEVPASQCHRSPLVLAYDQAHFSALVSMEQKENTKEQ

AVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVILSLEV

KLHLLHSYMNVKWIPLSSDAQAPLAQ

OTUD1
238
DEKLALYLAEVEKQDKYLRQRNKYRFHIIPDGNCLYRAVSKTVYGD

QSLHRELREQTVHYIADHLDHFSPLIEGDVGEFIIAAAQDGAWAGY

PELLAMGQMLNVNIHLTTGGRLESPTVSTMIHYLGPEDSLRPSIWL

SWLSNGHYDAVEDHSYPNPEYDNWCKQTQVQRKRDEELAKSMAISL

SKMYIEQNACS

TRABID
239
LEVDFKKLKQIKNRMKKTDWLFLNACVGVVEGDLAAIEAYKSSGGD

IARQLTADEVRLLNRPSAFDVGYTLVHLAIRFQRQDMLAILLTEVS

QQAAKCIPAMVCPELTEQIRREIAASLHQRKGDFACYFLTDLVTFT

LPADIEDLPPTVQEKLFDEVLDRDVQKELEEESPIINWSLELATRL

DSRLYALWNRTAGDCLLDSVLQATWGIYDKDSVLRKALHDSLHDCS

HWFYTRWKDWESWYSQSFGLHESLREEQWQEDWAFILSLASQPGAS

LEQTHIFVLAHILRRPIIVYGVKYYKSFRGETLGYTRFQGVYLPLL

WEQSFCWKSPIALGYTRGHESALVAMENDGYGNRGAGANLNTDDDV

TITFLPLVDSERKLLHVHELSAQELGNEEQQEKLLREWLDCCVTEG

GVLVAMQKSSRRRNHPLVTQMVEKWLDRYRQIRPCTSLS

USP21
240
SDDKMAHHTLLLGSGHVGLRNLGNTCELNAVLQCLSSTRPLRDECL

RRDFRQEVPGGGRAQELTEAFADVIGALWHPDSCEAVNPTRFRAVE

QKYVPSFSGYSQQDAQEFLKLLMERLHLEINRRGRRAPPILANGPV

PSPPRRGGALLEEPELSDDDRANLMWKRYLEREDSKIVDLFVGQLK

SCLKCQACGYRSTTFEVFCDLSLPIPKKGFAGGKVSLRDCENLETK

EEELESENAPVCDRCRQKTRSTKKLTVQRFPRILVLHLNRESASRG

SIKKSSVGVDFPLQRLSLGDFASDKAGSPVYQLYALCNHSGSVHYG

HYTALCRCQTGWHVYNDSRVSPVSENQVASSEGYVLFYQLMQEPPR

CL

OTUD4
241
ATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQSRHVEVRMA

CIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMY

RKDFIIYREPNVSPSQVTENNFPEKVLLCESNGNHYDIVYPIKYKE

SSAMCQSLLYELLYEKVFKTDVSKIVMELDTLEVADE

Human USP3
242
MECPHLSSSVCIAPDSAKFPNGSPSSWCCSVCRSNKSPWVCLTCSS

(full length)

VHCGRYVNGHAKKHYEDAQVPLTNHKKSEKQDKVQHTVCMDCSSYS

nuclear located

TYCYRCDDFVVNDTKLGLVQKVREHLQNLENSAFTADRHKKRKLLE

NSTLNSKLLKVNGSTTAICATGLRNLGNTCEMNAILQSLSNIEQFC

CYFKELPAVELRNGKTAGRRTYHTRSQGDNNVSLVEEFRKTLCALW

QGSQTAFSPESLFYVVWKIMPNERGYQQQDAHEFMRYLLDHLHLEL

QGGFNGVSRSAILQENSTLSASNKCCINGASTVVTAIFGGILQNEV

NCLICGTESRKFDPFLDLSLDIPSQFRSKRSKNQENGPVCSLRDCL

RSFTDLEELDETELYMCHKCKKKQKSTKKFWIQKLPKVLCLHLKRF

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

SEQ

ID

Description
NO
Amino Acid Sequence

Elongation
243
MAAATLLRATPHESGLAAGRTELLQGLLRLLKAPALPLLCRGLAVE

factor TU

AKKTYVRDKPHVNVGTIGHVDHGKTTLTAAITKILAEGGGAKFKKY

Target-YFP-

EEIDNAPEERARGITINAAHVEYSTAARHYAHTDCPGHADYVKNMI

P2A-mCherrry

TGTAPLDGCILVVAANDGPMPQTREHLLLARQIGVEHVVVYV

NKADAVQDSEMVELVELEIRELLTEFGYKGEETPVIVGSALCALEG

RDPELGLKSVQKLLDAVDTYIPVPARDLEKPELLPVEAVYSVPGRG

TVVTGTLERGILKKGDECELLGHSKNIRTVVTGIEMFHKSLERAEA

GDNLGALVRGLKREDLRRGLVMVKPGSIKPHQKVEAQVYILS

KEEGGRHKPFVSHEMPVMESLTWDMACRIILPPEKELAMPGEDLKF

NLILRQPMILEKGQRFTLRDGNRTIGTGLVTNTLAMTEEEKNIKWG

VSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLKF

ICTTGKLPVPWPTLVTTFGYGLQCFARYPDHMKQHDFFKSAMPEGY

VQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILG

HKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQ

NTPIGDGPVLLPDNHYLSYQSALSKDPNEKRDHMVLLEFVTAAGIT

LGMDELYKGSGATNFSLLKQAGDVEENPGPMVSKGEEDNMAIIKEF

MRFKVHMEGSVNGHEFEIEGEGEGRPYEGTQTAKLKVTKGGPLPFA

WDILSPQFMYGSKAYVKHPADIPDYLKLSFPEGFKWERVMNFEDGG

VVTVTQDSSLQDGEFIYKVKLRGTNFPSDGPVMQKKTMGWEASSER

MYPEDGALKGEIKQRLKLKDGGHYDAEVKTTYKAKKPVQLPGAYNV

NIKLDITSHNEDYTIVEQYERAEGRHSTGGMDELYK

BAX Target-
244
MDGSGEQPRGGGPTSSEQIMKTGALLLQGFIQDRAGRMGGEAPELA

YFP-P2A-

LDPVPQDASTKKLSECLKRIGDELDSNMELORMIAAVDTDSPREVE

mCherrry

FRVAADMESDGNENWGRVVALFYFASKLVLKALCTKVPELIRTIMG

WTLDELRERLLGWIQDQGGWDGLLSYFGTPTWQTVTIFVAGV

LTASLTIWKKMGVSKGEELFTGVVPILVELDGDVNGHKESVSGEGE

GDATYGKLTLKFICTTGKLPVPWPTLVTTFGYGLQCFARYPDHMKQ

HDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELK

GIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIE

DGSVQLADHYQQNTPIGDGPVLLPDNHYLSYQSALSKDPNEKRDHM

VLLEFVTAAGITLGMDELYKGSGATNFSLLKQAGDVEENPGPMVSK

GEEDNMAIIKEFMRFKVHMEGSVNGHEFEIEGEGEGRPYEGTQTAK

LKVTKGGPLPFAWDILSPQFMYGSKAYVKHPADIPDYLKLSFPEGE

KWERVMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNFPSDGPVMQ

KKTMGWEASSERMYPEDGALKGEIKQRLKLKDGGHYDAEVKTTYKA

KKPVQLPGAYNVNIKLDITSHNEDYTIVEQYERAEGRHSTGGMDEL

YK

CFP-P2A-
245
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Cezanne enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPPPSESEGSGGSRTPE

KGFSDREPTRPPRPILQRODDIVQEKRLSRGISHASSSIVSLARSH

VSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSFIERDLIEQS

MLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCLLHAASLGMWG

FHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQQNKESGLVYTE

DEWQKEWNELIKLASSEPRMHLGTNGANCGGVESSEEPVYESLEEF

HVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIPEGGIYLPLEVPAS

QCHRSPLVLAYDQAHESALVSMEQKENTKEQAVIPLTDSEYKLLPL

HFAVDPGKGWEWGKDDSDNVRLASVILSLEVKLHLLHSYMNVKWIP

LSSDAQAPLAQ

CFP-P2A-
246
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

OTUD1 enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDEKLALYLAEVEKQD

KYLRORNKYRFHIIPDGNCLYRAVSKTVYGDQSLHRELREQTVHYI

ADHLDHFSPLIEGDVGEFIIAAAQDGAWAGYPELLAMGQMLNVNIH

LTTGGRLESPTVSTMIHYLGPEDSLRPSIWLSWLSNGHYDAVEDHS

YPNPEYDNWCKQTQVQRKRDEELAKSMAISLSKMYIEQNACS

CFP-P2A-
247
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

TRABID

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKOKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPLEVDEKKLKQIKNRM

KKTDWLFLNACVGVVEGDLAAIEAYKSSGGDIARQLTADEVRLLNR

PSAFDVGYTLVHLAIRFQRQDMLAILLTEVSQQAAKCIPAMVCPEL

TEQIRREIAASLHQRKGDFACYFLTDLVTFTLPADIEDLPPTVQEK

LFDEVLDRDVQKELEEESPIINWSLELATRLDSRLYALWNRTAGDC

LLDSVLQATWGIYDKDSVLRKALHDSLHDCSHWFYTRWKDWESWYS

QSFGLHESLREEQWQEDWAFILSLASQPGASLEQTHIFVLAHILRR

PIIVYGVKYYKSFRGETLGYTRFQGVYLPLLWEQSFCWKSPIALGY

TRGHFSALVAMENDGYGNRGAGANLNTDDDVTITFLPLVDSERKLL

HVHELSAQELGNEEQQEKLLREWLDCCVTEGGVLVAMQKSSRRRNH

PLVTQMVEKWLDRYRQIRPCTSLS

CFP-P2A-
248
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

USP21 enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPSDDKMAHHTLLLGSG

HVGLRNLGNTCFLNAVLQCLSSTRPLRDFCLRRDERQEVPGGGRAQ

ELTEAFADVIGALWHPDSCEAVNPTRFRAVFQKYVPSFSGYSQQDA

QEFLKLLMERLHLEINRRGRRAPPILANGPVPSPPRRGGALLEEPE

LSDDDRANLMWKRYLEREDSKIVDLFVGQLKSCLKCQACGYRSTTE

EVFCDLSLPIPKKGFAGGKVSLRDCENLFTKEEELESENAPVCDRC

ROKTRSTKKLTVQRFPRILVLHLNRFSASRGSIKKSSVGVDFPLQR

LSLGDFASDKAGSPVYQLYALCNHSGSVHYGHYTALCRCQTGWHVY

NDSRVSPVSENQVASSEGYVLFYQLMQEPPRCL

CFP-P2A-
249
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

OTUD4 enDUB

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPATPMDAYLRKLGLYR

KLVAKDGSCLFRAVAEQVLHSQSRHVEVRMACIHYLRENREKFEAF

IEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNVSPS

QVTENNFPEKVLLCFSNGNHYDIVYPIKYKESSAMCQSLLYELLYE

KVFKTDVSKIVMELDTLEVADE

CFP-P2A-a-
250
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

Cezanne enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSPPSFSEGSGGSRTPEKGESDREPTRPPRPILQRQDDIV

QEKRLSRGISHASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQ

LPDLTVYNEDERSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQR

LLPLATTGDGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKE

ALKRRWRWQQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLG

TNGANCGGVESSEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRD

SGGEAFAPIPFGGIYLPLEVPASQCHRSPLVLAYDQAHESALVSME

QKENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLA

SVILSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

CFP-P2A-a-
251
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

OTUD1 enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPQVQLVESGGALVOPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSDEKLALYLAEVEKQDKYLRQRNKYRFHIIPDGNCLYRA

VSKTVYGDQSLHRELREQTVHYIADHLDHFSPLIEGDVGEFIIAAA

QDGAWAGYPELLAMGQMLNVNIHLTTGGRLESPTVSTMIHYLGPED

SLRPSIWLSWLSNGHYDAVEDHSYPNPEYDNWCKQTQVQRKRDEEL

AKSMAISLSKMYIEQNACS

CFP-P2A-a-
252
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

TRABID

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

enDUB

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSLEVDFKKLKQIKNRMKKTDWLELNACVGVVEGDLAAIE

AYKSSGGDIARQLTADEVRLLNRPSAFDVGYTLVHLAIRFQRQDML

AILLTEVSQQAAKCIPAMVCPELTEQIRREIAASLHQRKGDFACYF

LTDLVTFTLPADIEDLPPTVQEKLFDEVLDRDVQKELEEESPIINW

SLELATRLDSRLYALWNRTAGDCLLDSVLQATWGIYDKDSVLRKAL

HDSLHDCSHWFYTRWKDWESWYSQSFGLHESLREEQWQEDWAFILS

LASQPGASLEQTHIFVLAHILRRPIIVYGVKYYKSFRGETLGYTRE

QGVYLPLLWEQSFCWKSPIALGYTRGHFSALVAMENDGYGNRGAGA

NLNTDDDVTITFLPLVDSERKLLHVHELSAQELGNEEQQEKLLREW

LDCCVTEGGVLVAMQKSSRRRNHPLVTQMVEKWLDRYRQIRPCTSL

CFP-P2A-a-
253
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

USP21 enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSSDDKMAHHTLLLGSGHVGLRNLGNTCELNAVLQCLSST

RPLRDFCLRRDFRQEVPGGGRAQELTEAFADVIGALWHPDSCEAVN

PTRFRAVFQKYVPSFSGYSQQDAQEFLKLLMERLHLEINRRGRRAP

PILANGPVPSPPRRGGALLEEPELSDDDRANLMWKRYLEREDSKIV

DLFVGQLKSCLKCQACGYRSTTFEVFCDLSLPIPKKGFAGGKVSLR

DCFNLFTKEEELESENAPVCDRCRQKTRSTKKLTVQRFPRILVLHL

NRFSASRGSIKKSSVGVDFPLQRLSLGDFASDKAGSPVYQLYALCN

HSGSVHYGHYTALCRCQTGWHVYNDSRVSPVSENQVASSEGYVLFY

QLMQEPPRCL

CFP-P2A-a-
254
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

YFPnanobody-

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

OTUD4 enDUB

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLVESGGALVQPG

GSLRLSCAASGFPVNRYSMRWYRQAPGKEREWVAGMSSAGDRSSYE

DSVKGRFTISRDDARNTVYLQMNSLKPEDTAVYYCNVNVGFEYWGQ

GTQVTVSSATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQS

RHVEVRMACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVE

ISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCFSNGNHYDI

VYPIKYKESSAMCQSLLYELLYEKVEKTDVSKIVMELDTLEVADE

CFP-P2A-anti-
255
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Elongation

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

factor TU

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

targeting

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

binder-Cezanne

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

enDUB

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLQESGGGLAQAG

GSLRLSCAASGRMESINNMGWYRQAPGKQRELVAFITRGGTTTYAD

SMKGRVTISRDNAKNTVYLQMNSLKPEDTAVYYCAADDINNPRRTT

TYWGQGTQVTISSPPSFSEGSGGSRTPEKGESDREPTRPPRPILQR

QDDIVQEKRLSRGISHASSSIVSLARSHVSSNGGGGGSNEHPLEMP

ICAFQLPDLTVYNEDERSFIERDLIEQSMLVALEQAGRLNWWVSVD

PTSQRLLPLATTGDGNCLLHAASLGMWGFHDRDLMLRKALYALMEK

GVEKEALKRRWRWQQTQQNKESGLVYTEDEWQKEWNELIKLASSEP

RMHLGTNGANCGGVESSEEPVYESLEEFHVFVLAHVLRRPIVVVAD

TMLRDSGGEAFAPIPEGGIYLPLEVPASQCHRSPLVLAYDQAHFSA

LVSMEQKENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSD

NVRLASVILSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

CFP-P2A-anti-
256
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

Elongation

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

factor TU

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

targeting

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

binder-OTUD1

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

enDUB

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLQESGGGLAQAG

GSLRLSCAASGRMESINNMGWYRQAPGKQRELVAFITRGGTTTYAD

SMKGRVTISRDNAKNTVYLQMNSLKPEDTAVYYCAADDINNPRRTT

TYWGQGTQVTISSDEKLALYLAEVEKODKYLRQRNKYRFHIIPDGN

CLYRAVSKTVYGDQSLHRELREQTVHYIADHLDHFSPLIEGDVGEF

IIAAAQDGAWAGYPELLAMGQMLNVNIHLTTGGRLESPTVSTMIHY

LGPEDSLRPSIWLSWLSNGHYDAVEDHSYPNPEYDNWCKQTQVQRK

RDEELAKSMAISLSKMYIEQNACS

CFP-P2A-anti-
257
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

Elongation

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

factor TU

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

targeting

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

binder-TRABID

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

enDUB

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVQLQESGGGLAQAG

GSLRLSCAASGRMFSINNMGWYRQAPGKQRELVAFITRGGTTTYAD

SMKGRVTISRDNAKNTVYLQMNSLKPEDTAVYYCAADDINNPRRTT

TYWGQGTQVTISSLEVDFKKLKQIKNRMKKTDWLFLNACVGVVEGD

LAAIEAYKSSGGDIARQLTADEVRLLNRPSAFDVGYTLVHLAIRFQ

RQDMLAILLTEVSQQAAKCIPAMVCPELTEQIRREIAASLHQRKGD

FACYFLTDLVTFTLPADIEDLPPTVQEKLEDEVLDRDVQKELEEES

PIINWSLELATRLDSRLYALWNRTAGDCLLDSVLQATWGIYDKDSV

LRKALHDSLHDCSHWFYTRWKDWESWYSQSFGLHESLREEQWQEDW

AFILSLASQPGASLEQTHIFVLAHILRRPIIVYGVKYYKSERGETL

GYTRFQGVYLPLLWEQSFCWKSPIALGYTRGHFSALVAMENDGYGN

RGAGANLNTDDDVTITFLPLVDSERKLLHVHELSAQELGNEEQQEK

LLREWLDCCVTEGGVLVAMQKSSRRRNHPLVTQMVEKWLDRYRQIR

PCTSLS

CFP-P2A-anti-
258
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Elongation

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

factor TU

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

targeting

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

binder-USP21

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

enDUB

TLGMDELYKGSGATNF

QVQLQESGGGLAQAGGSLRLSCAASGRMESINNMGWYRQAPGKORE

LVAFITRGGTTTYADSMKGRVTISRDNAKNTVYLQMNSLKPEDTAV

YYCAADDINNPRRTTTYWGQGTQVTISSSDDKMAHHTLLLGSGHVG

LRNLGNTCFLNAVLQCLSSTRPLRDFCLRRDFRQEVPGGGRAQELT

EAFADVIGALWHPDSCEAVNPTRFRAVFQKYVPSFSGYSQQDAQEF

LKLLMERLHLEINRRGRRAPPILANGPVPSPPRRGGALLEEPELSD

DDRANLMWKRYLEREDSKIVDLFVGQLKSCLKCQACGYRSTTFEVE

CDLSLPIPKKGFAGGKVSLRDCFNLFTKEEELESENAPVCDRCRQK

TRSTKKLTVQRFPRILVLHLNRFSASRGSIKKSSVGVDFPLQRLSL

GDFASDKAGSPVYQLYALCNHSGSVHYGHYTALCRCQTGWHVYNDS

RVSPVSENQVASSEGYVLFYQLMQEPPRCL

CFP-P2A-anti-
259
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

Elongation

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

factor TU

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

targeting

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

binder-OTUD4

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

enDUB

TLGMDELYKGSGATNFSLLKQAGDVEENPGPQVOLQESGGGLAQAG

GSLRLSCAASGRMESINNMGWYRQAPGKQRELVAFITRGGTTTYAD

SMKGRVTISRDNAKNTVYLQMNSLKPEDTAVYYCAADDINNPRRTT

TYWGQGTQVTISSATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQV

LHSQSRHVEVRMACIHYLRENREKFEAFIEGSFEEYLKRLENPQEW

VGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCESNG

NHYDIVYPIKYKESSAMCQSLLYELLYEKVEKTDVSKIVMELDTLE

VADE

CFP-P2A-anti-
260
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

BAX A

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-Cezanne

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTESSYAMGWFRRAPGKEREFVAAISWSGTNTNYA

DSVKGRFTISRDNAKNTMYLQMNRLAPEDTAVYYCAATSTRTYYYT

TSRSNEYVYWGQGTQVTVSSPPSFSEGSGGSRTPEKGFSDREPTRP

PRPILQRQDDIVQEKRLSRGISHASSSIVSLARSHVSSNGGGGGSN

EHPLEMPICAFQLPDLTVYNEDERSFIERDLIEQSMLVALEQAGRL

NWWVSVDPTSQRLLPLATTGDGNCLLHAASLGMWGFHDRDLMLRKA

LYALMEKGVEKEALKRRWRWQQTQQNKESGLVYTEDEWQKEWNELI

KLASSEPRMHLGTNGANCGGVESSEEPVYESLEEFHVFVLAHVLRR

PIVVVADTMLRDSGGEAFAPIPEGGIYLPLEVPASQCHRSPLVLAY

DQAHFSALVSMEQKENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWE

WGKDDSDNVRLASVILSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

CFP-P2A-anti-
261
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

BAX A

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-OTUD1

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTFSSYAMGWFRRAPGKEREFVAAISWSGTNTNYA

DSVKGRFTISRDNAKNTMYLQMNRLAPEDTAVYYCAATSTRTYYYT

TSRSNEYVYWGQGTQVTVSSDEKLALYLAEVEKQDKYLRQRNKYRF

HIIPDGNCLYRAVSKTVYGDQSLHRELREQTVHYIADHLDHESPLI

EGDVGEFIIAAAQDGAWAGYPELLAMGQMLNVNIHLTTGGRLESPT

VSTMIHYLGPEDSLRPSIWLSWLSNGHYDAVEDHSYPNPEYDNWCK

QTQVQRKRDEELAKSMAISLSKMYIEQNACS

CFP-P2A-anti-
262
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX A

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDEFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-TRABID

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTFSSYAMGWFRRAPGKEREFVAAISWSGTNTNYA

DSVKGRFTISRDNAKNTMYLQMNRLAPEDTAVYYCAATSTRTYYYT

TSRSNEYVYWGQGTQVTVSSLEVDFKKLKQIKNRMKKTDWLFLNAC

VGVVEGDLAAIEAYKSSGGDIARQLTADEVRLLNRPSAFDVGYTLV

HLAIRFQRQDMLAILLTEVSQQAAKCIPAMVCPELTEQIRREIAAS

LHQRKGDFACYFLTDLVTFTLPADIEDLPPTVQEKLFDEVLDRDVQ

KELEEESPIINWSLELATRLDSRLYALWNRTAGDCLLDSVLQATWG

IYDKDSVLRKALHDSLHDCSHWFYTRWKDWESWYSQSFGLHESLRE

EQWQEDWAFILSLASQPGASLEQTHIFVLAHILRRPIIVYGVKYYK

SFRGETLGYTRFQGVYLPLLWEQSFCWKSPIALGYTRGHFSALVAM

ENDGYGNRGAGANLNTDDDVTITFLPLVDSERKLLHVHELSAQELG

NEEQQEKLLREWLDCCVTEGGVLVAMQKSSRRRNHPLVTQMVEKWL

DRYRQIRPCTSLS

CFP-P2A-anti-
263
MVSKGEELFTGVVPILVELDGDVNGHKESVSGEGEGDATYGKLTLK

BAX A

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-USP21

GHKLEYNYISHNVYITADKOKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTESSYAMGWFRRAPGKEREFVAAISWSGTNTNYA

DSVKGRFTISRDNAKNTMYLQMNRLAPEDTAVYYCAATSTRTYYYT

TSRSNEYVYWGQGTQVTVSSSDDKMAHHTLLLGSGHVGLRNLGNTC

FLNAVLQCLSSTRPLRDFCLRRDERQEVPGGGRAQELTEAFADVIG

ALWHPDSCEAVNPTRFRAVFQKYVPSFSGYSQQDAQEFLKLLMERL

HLEINRRGRRAPPILANGPVPSPPRRGGALLEEPELSDDDRANLMW

KRYLEREDSKIVDLFVGQLKSCLKCQACGYRSTTFEVECDLSLPIP

KKGFAGGKVSLRDCFNLFTKEEELESENAPVCDRCRQKTRSTKKLT

VQRFPRILVLHLNRFSASRGSIKKSSVGVDFPLQRLSLGDFASDKA

GSPVYQLYALCNHSGSVHYGHYTALCRCQTGWHVYNDSRVSPVSEN

QVASSEGYVLFYQLMQEPPRCL

CFP-P2A-anti-
264
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX A

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-OTUD4

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTESSYAMGWERRAPGKEREFVAAISWSGTNTNYA

DSVKGRFTISRDNAKNTMYLQMNRLAPEDTAVYYCAATSTRTYYYT

TSRSNEYVYWGQGTQVTVSSATPMDAYLRKLGLYRKLVAKDGSCLF

RAVAEQVLHSQSRHVEVRMACIHYLRENREKFEAFIEGSFEEYLKR

LENPQEWVGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKV

LLCFSNGNHYDIVYPIKYKESSAMCQSLLYELLYEKVEKTDVSKIV

MELDTLEVADE

CFP-P2A-anti-
265
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX B

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-Cezanne

GHKLEYNYISHNVYITADKOKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTNSWYSMGWFRQAPGKEREFVAAISWNGDAIYYT

DSVKGRFTISRDNTKNTVYLQMNSLKPEDTAVYICAAHAAAFTEAA

HIPGYEYWGQGTQVTVSSPPSFSEGSGGSRTPEKGFSDREPTRPPR

PILQRQDDIVQEKRLSRGISHASSSIVSLARSHVSSNGGGGGSNEH

PLEMPICAFQLPDLTVYNEDERSFIERDLIEQSMLVALEQAGRLNW

WVSVDPTSQRLLPLATTGDGNCLLHAASLGMWGFHDRDLMLRKALY

ALMEKGVEKEALKRRWRWQQTQQNKESGLVYTEDEWQKEWNELIKL

ASSEPRMHLGTNGANCGGVESSEEPVYESLEEFHVFVLAHVLRRPI

VVVADTMLRDSGGEAFAPIPEGGIYLPLEVPASQCHRSPLVLAYDQ

AHFSALVSMEQKENTKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWG

KDDSDNVRLASVILSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

CFP-P2A-anti-
266
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX B

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-OTUD1

GHKLEYNYSHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTNSWYSMGWFRQAPGKEREFVAAISWNGDAIYYT

DSVKGRFTISRDNTKNTVYLQMNSLKPEDTAVYICAAHAAAFTEAA

HIPGYEYWGQGTQVTVSSDEKLALYLAEVEKODKYLRQRNKYRFHI

IPDGNCLYRAVSKTVYGDQSLHRELREQTVHYIADHLDHFSPLIEG

DVGEFIIAAAQDGAWAGYPELLAMGQMLNVNIHLTTGGRLESPTVS

TMIHYLGPEDSLRPSIWLSWLSNGHYDAVEDHSYPNPEYDNWCKQT

QVQRKRDEELAKSMAISLSKMYIEQNACS

CFP-P2A-anti-
267
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX B

FICTTGKLPVPWPTLVTTLTWGVQCESRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-TRABID

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRINSWYSMGWFRQAPGKEREFVAAISWNGDAIYYT

DSVKGRFTISRDNTKNTVYLQMNSLKPEDTAVYICAAHAAAFTEAA

HIPGYEYWGQGTQVTVSSLEVDFKKLKQIKNRMKKTDWLFLNACVG

VVEGDLAAIEAYKSSGGDIARQLTADEVRLLNRPSAFDVGYTLVHL

AIRFQRQDMLAILLTEVSQQAAKCIPAMVCPELTEQIRREIAASLH

QRKGDFACYFLTDLVTFTLPADIEDLPPTVQEKLEDEVLDRDVQKE

LEEESPIINWSLELATRLDSRLYALWNRTAGDCLLDSVLQATWGIY

DKDSVLRKALHDSLHDCSHWFYTRWKDWESWYSQSFGLHESLREEQ

WQEDWAFILSLASQPGASLEQTHIFVLAHILRRPIIVYGVKYYKSF

RGETLGYTRFQGVYLPLLWEQSFCWKSPIALGYTRGHESALVAMEN

DGYGNRGAGANLNTDDDVTITELPLVDSERKLLHVHELSAQELGNE

EQQEKLLREWLDCCVTEGGVLVAMQKSSRRRNHPLVTQMVEKWLDR

YRQIRPCTSLS

CFP-P2A-anti-
268
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX B

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-USP21

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNESLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRTNSWYSMGWFRQAPGKEREFVAAISWNGDAIYYT

DSVKGRFTISRDNTKNTVYLQMNSLKPEDTAVYICAAHAAAFTEAA

HIPGYEYWGQGTQVTVSSSDDKMAHHTLLLGSGHVGLRNLGNTCEL

NAVLQCLSSTRPLRDFCLRRDFRQEVPGGGRAQELTEAFADVIGAL

WHPDSCEAVNPTRFRAVFQKYVPSFSGYSQQDAQEFLKLLMERLHL

EINRRGRRAPPILANGPVPSPPRRGGALLEEPELSDDDRANLMWKR

YLEREDSKIVDLFVGQLKSCLKCQACGYRSTTFEVFCDLSLPIPKK

GFAGGKVSLRDCFNLFTKEEELESENAPVCDRCRQKTRSTKKLTVQ

RFPRILVLHLNRESASRGSIKKSSVGVDFPLQRLSLGDFASDKAGS

PVYQLYALCNHSGSVHYGHYTALCRCQTGWHVYNDSRVSPVSENQV

ASSEGYVLFYQLMQEPPRCL

CFP-P2A-anti-
269
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLK

BAX B

FICTTGKLPVPWPTLVTTLTWGVQCFSRYPDHMKQHDFFKSAMPEG

targeting

YVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNIL

binder-OTUD4

GHKLEYNYISHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQ

enDUB

QNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGI

TLGMDELYKGSGATNFSLLKQAGDVEENPGPDVQLQASGGGLVQAG

GSLRLSCAASGRINSWYSMGWFRQAPGKEREFVAAISWNGDAIYYT

DSVKGRFTISRDNTKNTVYLQMNSLKPEDTAVYICAAHAAAFTEAA

HIPGYEYWGQGTQVTVSSATPMDAYLRKLGLYRKLVAKDGSCLFRA

VAEQVLHSQSRHVEVRMACIHYLRENREKFEAFIEGSFEEYLKRLE

NPQEWVGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLL

CFSNGNHYDIVYPIKYKESSAMCQSLLYELLYEKVEKTDVSKIVME

LDTLEVADE

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 (α-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≢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 μg 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 & G® 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

SEQ

Description

ID NO
Amino Acid Sequence

Fluorescent
NanoLuc
407
VFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQ

Protein

NLGVSVTPIQRIVLSGENGLKIDIHVIIPYEGL

SGDQMGQIEKIFKVVYPVDDHHFKVILHYGTLV

IDGVTPNMIDYFGRPYEGIAVEDGKKITVTGTL

WNGNKIIDERLINPDGSLLFRVTINGVTGWRLC

ERILA

Firefly
408
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRY

Luciferase

ALVPGTIAFTDAHIEVDITYAEYFEMSVRLAEA

MKRYGLNTNHRIVVCSENSLQFFMPVLGALFIG

VAVAPANDIYNERELLNSMGISQPTVVFVSKKG

LQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMY

TFVTSHLPPGENEYDFVPESEDRDKTIALIMNS

SGSTGLPKGVALPHRTACVRFSHARDPIFGNQI

IPDTAILSVVPFHHGFGMFTTLGYLICGFRVVL

MYRFEEELFLRSLQDYKIQSALLVPTLESFFAK

STLIDKYDLSNLHEIASGGAPLSKEVGEAVAKR

FHLPGIRQGYGLTETTSAILITPEGDDKPGAVG

KVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPM

IMSGYVNNPEATNALIDKDGWLHSGDIAYWDED

EHFFIVDRLKSLIKYKGYQVAPAELESILLQHP

NIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTG

KLDARKIREILIKAKKGGKIAVTRLK

Alfa Tag

409
PSRLEEELRRRLTEP

P2A

410
GSGATNFSLLKQAGDVEENPGP

Cezanne (Exemplary

411
PPSFSEGSGGSRTPEKGFSDREPTRPPRPILQR

Catalytic Domain)

QDDIVQEKRLSRGISHASSSIVSLARSHVSSNG

GGGGSNEHPLEMPICAFQLPDLTVYNEDERSFI

ERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLL

PLATTGDGNCLLHAASLGMWGFHDRDLMLRKAL

YALMEKGVEKEALKRRWRWQQTQQNKESGLVYT

EDEWQKEWNELIKLASSEPRMHLGTNGANCGGV

ESSEEPVYESLEEFHVFVLAHVLRRPIVVVADT

MLRDSGGEAFAPIPFGGIYLPLEVPASQCHRSP

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

SEQ

Test Protein
ID NO
Amino Acid Sequence

COX6A2-nanoluc-
412
MALPLRPLTRGLASAAKGGHGGAGARTWRLLTFVLALPSVALCTF

alfa-tag-fusion

NSYLHSGHRPRPEFRPYQHLRIRTKPYPWGDGNHTLFHNSHVNPL

PTGYEHPKVPVFTLEDFVGDWRQTAGYNLDOVLEQGGVSSLFQNL

GVSVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQIEKIFKV

VYPVDDHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVEDGKK

ITVTGTLWNGNKIIDERLINPDGSLLFRVTINGVTGWRLCERILA

GGGGSPSRLEEELRRRLTEP

UQCC2-nanoluc-
413
MAASRYRRELKLCEEWPVDETKRGRDLGAYLRQRVAQAFREGENT

alfa-tag-fusion

QYPRPRDTSFSGLSLEEYKLILSTDTLEELKEIDKGMWKKLQEKE

APKGPEEDHKAKVPVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSL

FQNLGVSVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQIEK

IFKVVYPVDDHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVE

DGKKITVTGTLWNGNKIIDERLINPDGSLLERVTINGVTGWRLCE

RILAGGGGSPSRLEEELRRRLTEP

LYRM7-nanoluc-
414
MGRAVKVLQLFKTLHRTRQQVEKNDARALEAARIKINEEFKNNKS

alfa-tag-fusion

ETSSKKIEELMKIGSDVELLLRTSVIQGIHTDHNTLKLVPRKDLL

VENVPYCDAPTQKQKVPVFTLEDFVGDWRQTAGYNLDOVLEQGGV

SSLFQNLGVSVTPIQRIVLSGENGLKIDIHVIIPYEGLSGDQMGQ

IEKIFKVVYPVDDHHFKVILHYGTLVIDGVTPNMIDYEGRPYEGI

AVFDGKKITVTGTLWNGNKIIDERLINPDGSLLFRVTINGVTGWR

LCERILAGGGGSPSRLEEELRRRLTEP

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-
415
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDA

P2A-nano

HIEVDITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFM

(Control)

PVLGALFIGVAVAPANDIYNERELLNSMGISQPTVVFVSKKGLQK

ILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGENEYD

FVPESEDRDKTIALIMNSSGSTGLPKGVALPHRTACVRESHARDP

IFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEE

ELFLRSLQDYKIQSALLVPTLESFFAKSTLIDKYDLSNLHEIASG

GAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPG

AVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNP

EATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVA

PAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILI

KAKKGGKIAVTRLKGSGATNFSLLKQAGDVEENPGPRSGTGSSGE

VQLQESGGGLVQPGGSLRLSCTASGVTISALNAMAMGWYRQAPGE

RRVMVAAVSERGNAMYRESVQGRFTVTRDFTNKMVSLQMDNLKPE

DTAVYYCHVLEDRVDSFHDYWGQGTQVTVSS

FireflyLuciferase-
416
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDA

P2A-Cezanne

HIEVDITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFM

(Control)

PVLGALFIGVAVAPANDIYNERELLNSMGISQPTVVFVSKKGLQK

ILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGENEYD

FVPESFDRDKTIALIMNSSGSTGLPKGVALPHRTACVRESHARDP

IFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEE

ELFLRSLQDYKIQSALLVPTLESFFAKSTLIDKYDLSNLHEIASG

GAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPG

AVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNP

EATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVA

PAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILI

KAKKGGKIAVTRLKGSGATNFSLLKQAGDVEENPGPRSGTGSPPS

FSEGSGGSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGIS

HASSSIVSLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNE

DERSFIERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTG

DGNCLLHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWR

WQQTQQNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANC

GGVESSEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRDSGGEA

FAPIPFGGIYLPLEVPASQCHRSPLVLAYDQAHFSALVSMEQKEN

TKEQAVIPLTDSEYKLLPLHFAVDPGKGWEWGKDDSDNVRLASVI

LSLEVKLHLLHSYMNVKWIPLSSDAQAPLAQ

FireflyLuciferase-
417
MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDA

P2A-

HIEVDITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFM

a_alfatag_nano-

PVLGALFIGVAVAPANDIYNERELLNSMGISQPTVVFVSKKGLQK

Cezanne

ILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGENEYD

FVPESEDRDKTIALIMNSSGSTGLPKGVALPHRTACVRESHARDP

IFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEE

ELFLRSLQDYKIQSALLVPTLESFFAKSTLIDKYDLSNLHEIASG

GAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPG

AVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNP

EATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVA

PAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTE

KEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILI

KAKKGGKIAVTRLKGSGATNFSLLKQAGDVEENPGPRSGTGSSGE

VQLQESGGGLVQPGGSLRLSCTASGVTISALNAMAMGWYRQAPGE

RRVMVAAVSERGNAMYRESVQGRFTVTRDFTNKMVSLQMDNLKPE

DTAVYYCHVLEDRVDSFHDYWGQGTQVTVSSGAPGSGPPSFSEGS

GGSRTPEKGFSDREPTRPPRPILQRQDDIVQEKRLSRGISHASSS

IVSLARSHVSSNGGGGGSNEHPLEMPICAFQLPDLTVYNEDERSE

IERDLIEQSMLVALEQAGRLNWWVSVDPTSQRLLPLATTGDGNCL

LHAASLGMWGFHDRDLMLRKALYALMEKGVEKEALKRRWRWQQTQ

QNKESGLVYTEDEWQKEWNELIKLASSEPRMHLGTNGANCGGVES

SEEPVYESLEEFHVFVLAHVLRRPIVVVADTMLRDSGGEAFAPIP

FGGIYLPLEVPASQCHRSPLVLAYDQAHESALVSMEQKENTKEQA

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 COX6A2 targeting are shown in FIG. 3, showing a 1.48-fold increase in COX6A2 protein expression. The results of the UQCC2 targeting are shown in FIG. 4, showing a 2.87-fold increase in UQCC2 protein expression. The results of the LYRM7 targeting are shown in FIG. 5, showing a 1.386-fold increase in LYRM7 protein expression. The control used for the COX6A, UQCC2, and LYRM7 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.

MITOCHONDRIAL PROTEIN TARGETING ENGINEERED DEUBIQUITINASES AND METHODS OF USE THEREOF

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