Human thrombospondin repeat proteins and polynucleotides encoding the same

Abstract

Novel human polynucleotide and polypeptide sequences are disclosed that can be used in therapeutic, diagnostic, and pharmacogenomic applications.

Description

1. INTRODUCTION

The present invention relates to the discovery, identification, and characterization of novel human polynucleotides encoding proteins that share sequence similarity with animal proteins having thrombospondin repeats. The invention encompasses the described polynucleotides, host cell expression systems, the encoded proteins, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that either lack or over express the disclosed polynucleotide sequences, antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed polynucleotide sequences that can be used for diagnosis, drug screening, clinical trial monitoring, the treatment of diseases and disorders, or cosmetic or nutriceutical applications.

2. BACKGROUND OF THE INVENTION

Thrombospondins have been implicated in, inter alia, mediating angiogensis, cancer, and development. Proteins having thrombospondin repeats can act as receptors, secreted extracellular matrix proteins, and proteases.

3. SUMMARY OF THE INVENTION

The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human proteins, and the corresponding amino acid sequences of these proteins. The novel human proteins (NHPs) described for the first time herein share structural similarity with proteins having thrombospondin repeats.

The novel human nucleic acid sequences described herein, encode alternative proteins/open reading frames (ORFs) of 1,691, 446, 372, 724, 650, 845, 771, and 1,617 amino acids in length (see SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, and 16 respectively).

The invention also encompasses agonists and antagonists of the described NHPs, including small molecules, large molecules, mutant NHPs, or portions thereof that compete with native NHP, peptides, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NHPs (e.g., antisense and ribozyme molecules, and gene or regulatory sequence replacement constructs) or to enhance the expression of the described NHP polynucleotide sequences (e.g., expression constructs that place the described polynucleotide sequence under the control of a strong promoter system), and transgenic animals that express a NHP transgene, or “knockouts” (which can be conditional) that do not express a functional NHP.

Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP activity that utilize purified preparations of the described NHPs and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES

The Sequence Listing provides the sequences of the described NHP ORFs that encode the described NHP amino acid sequences. SEQ ID NO:17 describes a NHP ORF and flanking regions.

5. DETAILED DESCRIPTION OF THE INVENTION

The NHPs, described for the first time herein, are novel proteins that are expressed in, inter alia, human cell lines, human pituitary, lymph node, prostate, testis, adrenal gland, uterus, fetal kidney, fetal lung, and gene trapped human cells.

The present invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described polynucleotide sequences, including the specifically described NHPs, and the NHP products; (b) nucleotides that encode one or more portions of the NHPs that correspond to functional domains, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of any active domain(s); (c) isolated nucleotides that encode mutant versions, engineered or naturally occurring, of the described NHPs in which all or a part of at least one domain is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble proteins and peptides in which all or a portion of the signal sequence is deleted; (d) nucleotides that encode chimeric fusion proteins containing all or a portion of a coding region of a NHP, or one of its domains (e.g., a receptor or ligand binding domain, accessory protein/self-association domain, etc.) fused to another peptide or polypeptide; or (e) therapeutic or diagnostic derivatives of the described polynucleotides such as oligonucleotides, antisense polynucleotides, ribozymes, dsRNA, or gene therapy constructs comprising a sequence first disclosed in the Sequence Listing.

As discussed above, the present invention includes:

(a) the human DNA sequences presented in the Sequence Listing (and vectors comprising the same) and additionally contemplates any nucleotide sequence encoding a contiguous NHP open reading frame (ORF) that hybridizes to a complement of a DNA sequence presented in the Sequence Listing under highly stringent conditions, e.g., hybridization to filter-bound DNA in 0.5 M NaHPO 4 , 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1×SSC/0.1% SDS at 68° C. (Ausubel F. M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc., and John Wiley & sons, Inc., New York, at p. 2.10.3) and encodes a functionally equivalent gene product. Additionally contemplated are any nucleotide sequences that hybridize to the complement of a DNA sequence that encodes and expresses an amino acid sequence presented in the Sequence Listing under moderately stringent conditions, e.g., washing in 0.2×SSC/0.1% SDS at 42° C. (Ausubel et al., 1989, supra), yet still encodes a functionally equivalent NHP product. Functional equivalents of a NHP include naturally occurring NHPs present in other species and mutant NHPs whether naturally occurring or engineered (by site directed mutagenesis, gene shuffling, directed evolution as described in, for example, U.S. Pat. No. 5,837,458). The invention also includes degenerate nucleic acid variants of the disclosed NHP polynucleotide sequences.

Additionally contemplated are polynucleotides encoding NHP ORFs, or their functional equivalents, encoded by polynucleotide sequences that are about 99, 95, 90, or about 85 percent similar or identical to corresponding regions of the nucleotide sequences of the Sequence Listing (as measured by BLAST sequence comparison analysis using, for example, the GCG sequence analysis package (Madison, Wis.) using standard default settings).

The invention also includes nucleic acid molecules, preferably DNA molecules, that hybridize to, and are therefore the complements of, the described NHP nucleotide sequences. Such hybridization conditions may be highly stringent or less highly stringent, as described above. In instances where the nucleic acid molecules are deoxyoligonucleotides (“DNA oligos”), such molecules are generally about 16 to about 100 bases long, or about 20 to about 80, or about 34 to about 45 bases long, or any variation or combination of sizes represented therein that incorporate a contiguous region of sequence first disclosed in the Sequence Listing. Such oligonucleotides can be used in conjunction with the polymerase chain reaction (PCR) to screen libraries, isolate clones, and prepare cloning and sequencing templates, etc.

Alternatively, such NHP oligonucleotides can be used as hybridization probes for screening libraries, and assessing gene expression patterns (particularly using a micro array or high-throughput “chip” format). Additionally, a series of the described NHP oligonucleotide sequences, or the complements thereof, can be used to represent all or a portion of the described NHP sequences. An oligonucleotide or polynucleotide sequence first disclosed in at least a portion of one or more of the sequences of SEQ ID NOS: 1-17 can be used as a hybridization probe in conjunction with a solid support matrix/substrate (resins, beads, membranes, plastics, polymers, metal or metallized substrates, crystalline or polycrystalline substrates, etc.). Of particular note are spatially addressable arrays (i.e., gene chips, microtiter plates, etc.) of oligonucleotides and polynucleotides, or corresponding oligopeptides and polypeptides, wherein at least one of the biopolymers present on the spatially addressable array comprises an oligonucleotide or polynucleotide sequence first disclosed in at least one of the sequences of SEQ ID NOS: 1-17, or an amino acid sequence encoded thereby. Methods for attaching biopolymers to, or synthesizing biopolymers on, solid support matrices, and conducting binding studies thereon are disclosed in, inter alia, U.S. Pat. Nos. 5,700,637, 5,556,752, 5,744,305, 4,631,211, 5,445,934, 5,252,743, 4,713,326, 5,424,186, and 4,689,405 the disclosures of which are herein incorporated by reference in their entirety.

Addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-17 can be used to identify and characterize the temporal and tissue specific expression of a gene. These addressable arrays incorporate oligonucleotide sequences of sufficient length to confer the required specificity, yet be within the limitations of the production technology. The length of these probes is within a range of between about 8 to about 2000 nucleotides. Preferably the probes consist of 60 nucleotides and more preferably 25 nucleotides from the sequences first disclosed in SEQ ID NOS:1-17.

For example, a series of the described oligonucleotide sequences, or the complements thereof, can be used in chip format to represent all or a portion of the described sequences. The oligonucleotides, typically between about 16 to about 40 (or any whole number within the stated range) nucleotides in length can partially overlap each other and/or the sequence may be represented using oligonucleotides that do not overlap. Accordingly, the described polynucleotide sequences shall typically comprise at least about two or three distinct oligonucleotide sequences of at least about 8 nucleotides in length that are each first disclosed in the described Sequence Listing. Such oligonucleotide sequences can begin at any nucleotide present within a sequence in the Sequence Listing and proceed in either a sense (5′-to-3′) orientation vis-a-vis the described sequence or in an antisense orientation.

Microarray-based analysis allows the discovery of broad patterns of genetic activity, providing new understanding of gene functions and generating novel and unexpected insight into transcriptional processes and biological mechanisms. The use of addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-17 provides detailed information about transcriptional changes involved in a specific pathway, potentially leading to the identification of novel components or gene functions that manifest themselves as novel phenotypes.

Probes consisting of sequences first disclosed in SEQ ID NOS:1-17 can also be used in the identification, selection and validation of novel molecular targets for drug discovery. The use of these unique sequences permits the direct confirmation of drug targets and recognition of drug dependent changes in gene expression that are modulated through pathways distinct from the drugs intended target. These unique sequences therefore also have utility in defining and monitoring both drug action and toxicity.

As an example of utility, the sequences first disclosed in SEQ ID NOS:1-17 can be utilized in microarrays or other assay formats, to screen collections of genetic material from patients who have a particular medical condition. These investigations can also be carried out using the sequences first disclosed in SEQ ID NOS:1-17 in silico and by comparing previously collected genetic databases and the disclosed sequences using computer software known to those in the art.

Thus the sequences first disclosed in SEQ ID NOS:1-17 can be used to identify mutations associated with a particular disease and also as a diagnostic or prognostic assay.

Although the presently described sequences have been specifically described using nucleotide sequence, it should be appreciated that each of the sequences can uniquely be described using any of a wide variety of additional structural attributes, or combinations thereof. For example, a given sequence can be described by the net composition of the nucleotides present within a given region of the sequence in conjunction with the presence of one or more specific oligonucleotide sequence(s) first disclosed in the SEQ ID NOS: 1-17. Alternatively, a restriction map specifying the relative positions of restriction endonuclease digestion sites, or various palindromic or other specific oligonucleotide sequences can be used to structurally describe a given sequence. Such restriction maps, which are typically generated by widely available computer programs (e.g., the University of Wisconsin GCG sequence analysis package, SEQUENCHER 3.0, Gene Codes Corp., Ann Arbor, Mich., etc.), can optionally be used in conjunction with one or more discrete nucleotide sequence(s) present in the sequence that can be described by the relative position of the sequence relatve to one or more additional sequence(s) or one or more restriction sites present in the disclosed sequence.

For oligonucleotide probes, highly stringent conditions may refer, e.g., to washing in 6× SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligos), 48° C. (for 17-base oligos), 55° C. (for 20-base oligos), and 60° C. (for 23-base oligos). These nucleic acid molecules may encode or act as NHP gene antisense molecules, useful, for example, in NHP gene regulation (for and/or as antisense primers in amplification reactions of NHP nucleic acid sequences). With respect to NHP gene regulation, such techniques can be used to regulate biological functions. Further, such sequences may be used as part of ribozyme and/or triple helix sequences that are also useful for NHP gene regulation.

Inhibitory antisense or double stranded oligonucleotides can additionally comprise at least one modified base moiety which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.

The antisense oligonucleotide can also comprise at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-fluoroarabinose, xylulose, and hexose.

In yet another embodiment, the antisense oligonucleotide will comprise at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

In yet another embodiment, the antisense oligonucleotide is an α-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330). Alternatively, double stranded RNA can be used to disrupt the expression and function of a targeted NHP.

Oligonucleotides of the invention can be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), and methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.

Low stringency conditions are well known to those of skill in the art, and will vary predictably depending on the specific organisms from which the library and the labeled sequences are derived. For guidance regarding such conditions see, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual (and periodic updates thereof), Cold Springs Harbor Press, N.Y.; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y.

Alternatively, suitably labeled NHP nucleotide probes can be used to screen a human genomic library using appropriately stringent conditions or by PCR. The identification and characterization of human genomic clones is helpful for identifying polymorphisms (including, but not limited to, nucleotide repeats, microsatellite alleles, single nucleotide polymorphisms, or coding single nucleotide polymorphisms), determining the genomic structure of a given locus/allele, and designing diagnostic tests. For example, sequences derived from regions adjacent to the intron/exon boundaries of the human gene can be used to design primers for use in amplification assays to detect mutations within the exons, introns, splice sites (e.g., splice acceptor and/or donor sites), etc., that can be used in diagnostics and pharmacogenomics.

Further, a NHP gene homolog can be isolated from nucleic acid from an organism of interest by performing PCR using two degenerate or “wobble” oligonucleotide primer pools designed on the basis of amino acid sequences within the NHP products disclosed herein. The template for the reaction may be total RNA, mRNA, and/or cDNA obtained by reverse transcription of mRNA prepared from human or non-human cell lines or tissue known or suspected to express an allele of a NHP gene.

The PCR product can be subcloned and sequenced to ensure that the amplified sequences represent the sequence of the desired NHP gene. The PCR fragment can then be used to isolate a full length cDNA clone by a variety of methods. For example, the amplified fragment can be labeled and used to screen a cDNA library, such as a bacteriophage cDNA library. Alternatively, the labeled fragment can be used to isolate genomic clones via the screening of a genomic library.

PCR technology can also be used to isolate full length cDNA sequences. For example, RNA can be isolated, following standard procedures, from an appropriate cellular or tissue source (i.e., one known, or suspected, to express a NHP gene). A reverse transcription (RT) reaction can be performed on the RNA using an oligonucleotide primer specific for the most 5′ end of the amplified fragment for the priming of first strand synthesis. The resulting RNA/DNA hybrid may then be “tailed” using a standard terminal transferase reaction, the hybrid may be digested with RNase H, and second strand synthesis may then be primed with a complementary primer. Thus, cDNA sequences upstream of the amplified fragment can be isolated. For a review of cloning strategies that can be used, see e.g., Sambrook et al., 1989, supra.

A cDNA encoding a mutant NHP gene can be isolated, for example, by using PCR. In this case, the first cDNA strand may be synthesized by hybridizing an oligo-dT oligonucleotide to mRNA isolated from tissue known or suspected to be expressed in an individual putatively carrying a mutant NHP allele, and by extending the new strand with reverse transcriptase. The second strand of the cDNA is then synthesized using an oligonucleotide that hybridizes specifically to the 5′ end of the normal gene. Using these two primers, the product is then amplified via PCR, optionally cloned into a suitable vector, and subjected to DNA sequence analysis through methods well known to those of skill in the art. By comparing the DNA sequence of the mutant NHP allele to that of a corresponding normal NHP allele, the mutation(s) responsible for the loss or alteration of function of the mutant NHP gene product can be ascertained.

Alternatively, a genomic library can be constructed using DNA obtained from an individual suspected of or known to carry a mutant NHP allele (e.g., a person manifesting a NHP-associated phenotype such as, for example, obesity, vision disorders, high blood pressure, depression, infertility, etc.), or a cDNA library can be constructed using RNA from a tissue known, or suspected, to express a mutant NHP allele. A normal NHP gene, or any suitable fragment thereof, can then be labeled and used as a probe to identify the corresponding mutant NHP allele in such libraries. Clones containing mutant NHP gene sequences can then be purified and subjected to sequence analysis according to methods well known to those skilled in the art.

Additionally, an expression library can be constructed utilizing cDNA synthesized from, for example, RNA isolated from a tissue known, or suspected, to express a mutant NHP allele in an individual suspected of or known to carry such a mutant allele. In this manner, gene products made by the putatively mutant tissue can be expressed and screened using standard antibody screening techniques in conjunction with antibodies raised against a normal NHP product, as described below. (For screening techniques, see, for example, Harlow, E. and Lane, eds., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Press, Cold Spring Harbor.) Additionally, screening can be accomplished by screening with labeled NHP fusion proteins, such as, for example, alkaline phosphatase-NHP or NHP-alkaline phosphatase fusion proteins. In cases where a NHP mutation results in an expressed gene product with altered function (e.g., as a result of a missense or a frameshift mutation), polyclonal antibodies to a NHP are likely to cross-react with a corresponding mutant NHP gene product. Library clones detected via their reaction with such labeled antibodies can be purified and subjected to sequence analysis according to methods well known in the art.

The invention also encompasses (a) DNA vectors that contain any of the foregoing NHP coding sequences and/or their complements (i.e., antisense); (b) DNA expression vectors that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences (for example, baculo virus as described in U.S. Pat. No. 5,869,336 herein incorporated by reference); (c) genetically engineered host cells that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences in the host cell; and (d) genetically engineered host cells that express an endogenous NHP gene under the control of an exogenously introduced regulatory element (i.e., gene activation). As used herein, regulatory elements include, but are not limited to, inducible and non-inducible promoters, enhancers, operators and other elements known to those skilled in the art that drive and regulate expression. Such regulatory elements include but are not limited to the cytomegalovirus (hCMV) immediate early gene, regulatable, viral elements (particularly retroviral LTR promoters), the early or late promoters of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase (PGK), the promoters of acid phosphatase, and the promoters of the yeast a-mating factors.

The present invention also encompasses antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists and agonists of the NHP, as well as compounds or nucleotide constructs that inhibit expression of a NHP gene (transcription factor inhibitors, antisense and ribozyme molecules, or gene or regulatory sequence replacement constructs), or promote the expression of a NHP (e.g., expression constructs in which NHP coding sequences are operatively associated with expression control elements such as promoters, promoter/enhancers, etc.).

The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotide sequences, antibodies, antagonists and agonists can be useful for the detection of mutant NHPs or inappropriately expressed NHPs for the diagnosis of disease. The NHP proteins or peptides, NHP fusion proteins, NHP nucleotide sequences, host cell expression systems, antibodies, antagonists, agonists and genetically engineered cells and animals can be used for screening for drugs (or high throughput screening of combinatorial libraries) effective in the treatment of the symptomatic or phenotypic manifestations of perturbing the normal function of NHP in the body. The use of engineered host cells and/or animals may offer an advantage in that such systems allow not only for the identification of compounds that bind to the endogenous receptor for an NHP, but can also identify compounds that trigger NHP-mediated activities or pathways.

Finally, the NHP products can be used as therapeutics. For example, soluble derivatives such as NHP peptides/domains corresponding to the NHPs, NHP fusion protein products (especially NHP-Ig fusion proteins, i.e., fusions of a NHP, or a domain of a NHP, to an IgFc), NHP antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists or agonists (including compounds that modulate or act on downstream targets in a NHP-mediated pathway) can be used to directly treat diseases or disorders. For instance, the administration of an effective amount of soluble NHP, or a NHP-IgFc fusion protein or an anti-idiotypic antibody (or its Fab) that mimics the NHP could activate or effectively antagonize the endogenous NHP receptor. Nucleotide constructs encoding such NHP products can be used to genetically engineer host cells to express such products in vivo; these genetically engineered cells function as “bioreactors” in the body delivering a continuous supply of a NHP, a NHP peptide, or a NHP fusion protein to the body. Nucleotide constructs encoding functional NHPs, mutant NHPs, as well as antisense and ribozyme molecules can also be used in “gene therapy” approaches for the modulation of NHP expression. Thus, the invention also encompasses pharmaceutical formulations and methods for treating biological disorders.

Various aspects of the invention are described in greater detail in the subsections below.

5.1 The NHP Sequences

The cDNA sequences and the corresponding deduced amino acid sequences of the described NHPs are presented in the Sequence Listing. The NHP nucleotides were obtained from clustered human gene trapped sequences, ESTs, and cDNA isolated from human lymph node, pituitary, placenta, trachea and mammary gland cDNA cell libraries (Edge Biosystems, Gaithersburg, Md.). The described sequences share limited structural similarity with a variety of proteins, including, but not limited to, proteinases, thrombospondin-1, F-spondin, ADAMTS metalloproteases, Tango-71, and distintegrins.

5.2 NHPs and NHP Polypeptides

NHPs, polypeptides, peptide fragments, mutated, truncated, or deleted forms of the NHPs, and/or NHP fusion proteins can be prepared for a variety of uses. These uses include but are not limited to the generation of antibodies, as reagents in diagnostic assays, the identification of other cellular gene products related to a NHP, as reagents in assays for screening for compounds that can be as pharmaceutical reagents useful in the therapeutic treatment of mental, biological, or medical disorders and diseases. Given the similarity information and expression data, the described NHPs can be targeted (by drugs, oligos, antibodies, etc,) in order to treat disease, or to therapeutically augment the efficacy of therapeutic agents.

The Sequence Listing discloses the amino acid sequences encoded by the described NHP polynucleotide sequences. The NHPs typically display initiator methionines in DNA sequence contexts consistent with a translation initiation site, and a signal sequence characteristic of membrane or secreted proteins.

The NHP amino acid sequences of the invention include the amino acid sequences presented in the Sequence Listing as well as analogues and derivatives thereof. Further, corresponding NHP homologues from other species are encompassed by the invention. In fact, any NHP protein encoded by the NHP nucleotide sequences described above are within the scope of the invention, as are any novel polynucleotide sequences encoding all or any novel portion of an amino acid sequence presented in the Sequence Listing. The degenerate nature of the genetic code is well known, and, accordingly, each amino acid presented in the Sequence Listing, is generically representative of the well known nucleic acid “triplet” codon, or in many cases codons, that can encode the amino acid. As such, as contemplated herein, the amino acid sequences presented in the Sequence Listing, when taken together with the genetic code (see, for example, Table 4-1 at page 109 of “Molecular Cell Biology”, 1986, J. Darnell et al. eds., Scientific American Books, New York, N.Y., herein incorporated by reference) are generically representative of all the various permutations and combinations of nucleic acid sequences that can encode such amino acid sequences.

The invention also encompasses proteins that are functionally equivalent to the NHPs encoded by the presently described nucleotide sequences as judged by any of a number of criteria, including, but not limited to, the ability to bind and cleave a substrate of a NHP, or the ability to effect an identical or complementary downstream pathway, or a change in cellular metabolism (e.g., proteolytic activity, ion flux, tyrosine phosphorylation, transport, etc.). Such functionally equivalent NHP proteins include, but are not limited to, additions or substitutions of amino acid residues within the amino acid sequence encoded by the NHP nucleotide sequences described above, but which result in a silent change, thus producing a functionally equivalent gene product. Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.

A variety of host-expression vector systems can be used to express the NHP nucleotide sequences of the invention. Where, as in the present instance, the NHP peptide or polypeptide is thought to be membrane protein, the hydrophobic regions of the protein can be excised and the resulting soluble peptide or polypeptide can be recovered from the culture media. Such expression systems also encompass engineered host cells that express a NHP, or functional equivalent, in situ. Purification or enrichment of a NHP from such expression systems can be accomplished using appropriate detergents and lipid micelles and methods well known to those skilled in the art. However, such engineered host cells themselves may be used in situations where it is important not only to retain the structural and functional characteristics of the NHP, but to assess biological activity, e.g., in drug screening assays.

The expression systems that can be used for purposes of the invention include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis ) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing NHP nucleotide sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing NHP nucleotide sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing NHP sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing NHP nucleotide sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter).

In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the NHP product being expressed. For example, when a large quantity of such a protein is to be produced for the generation of pharmaceutical compositions of or containing NHP, or for raising antibodies to a NHP, vectors that direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO J. 2:1791), in which a NHP coding sequence may be ligated individually into the vector in frame with the lacZ coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster, 1989, J. Biol. Chem. 264:5503-5509); and the like. pGEX vectors (Pharmacia or American Type Culture Collection) can also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption to glutathione-agarose beads followed by elution in the presence of free glutathione. The PGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

In an insect system, Autographa califormica nuclear polyhidrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. A NHP coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter). Successful insertion of NHP coding sequence will result in inactivation of the polyhedrin gene and production of non-occluded recombinant virus (i.e., virus lacking the proteinaceous coat coded for by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted gene is expressed (e.g., see Smith et al., 1983, J. Virol. 46:584; Smith, U.S. Pat. No. 4,215,051).

In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the NHP nucleotide sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing a NHP product in infected hosts (e.g., See Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA 81:3655-3659). Specific initiation signals may also be required for efficient translation of inserted NHP nucleotide sequences. These signals include the ATG initiation codon and adjacent sequences. In cases where an entire NHP gene or cDNA, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. However, in cases where only a portion of a NHP coding sequence is inserted, exogenous translational control signals, including, perhaps, the ATG initiation codon, must be provided. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (See Bittner et al., 1987, Methods in Enzymol. 153:516-544).

In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, WI38, and in particular, human cell lines.

For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the NHP sequences described above can be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the NHP product. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that affect the endogenous activity of the NHP product.

A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler, et al., 1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), and adenine phosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817) genes can be employed in tk, hgprt or aprt cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler, et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc. Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Colberre-Garapin, et al., 1981, J. Mol. Biol. 150:1); and hygro, which confers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).

Alternatively, any fusion protein can be readily purified by utilizing an antibody specific for the fusion protein being expressed. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-8976). In this system, the polynucleotide sequence of interest is subcloned into a vaccinia recombination plasmid such that the gene's open reading frame is translationally fused to an amino-terminal tag consisting of six histidine residues. Extracts from cells infected with recombinant vaccinia virus are loaded onto Ni 2+ .nitriloacetic acid-agarose columns and histidine-tagged proteins are selectively eluted with imidazole-containing buffers.

Also encompassed by the present invention are fusion proteins that direct the NHP to a target organ and/or facilitate transport across the membrane into the cytosol. Conjugation of NHPs to antibody molecules or their Fab fragments could be used to target cells bearing a particular epitope. Attaching the appropriate signal sequence to the NHP would also transport the NHP to the desired location within the cell. Alternatively targeting of NHP or its nucleic acid sequence might be achieved using liposome or lipid complex based delivery systems. Such technologies are described in Liposomes: A Practical Approach , New, RRC ed., Oxford University Press, New York and in U.S. Pat. Nos. 4,594,595, 5,459,127, 5,948,767 and 6,110,490 and their respective disclosures which are herein incorporated by reference in their entirety. Additionally embodied are novel protein constructs engineered in such a way that they facilitate transport of the NHP to the target site or desired organ, where they cross the cell membrane and/or the nucleus where the NHP can exert its functional activity. This goal may be achieved by coupling of the NHP to a cytokine or other ligand that provides targeting specificity, and/or to a protein transducing domain (see generally U.S. applications Ser. No. 60/111,701 and 60/056,713, both of which are herein incorporated by reference, for examples of such transducing sequences) to facilitate passage across cellular membranes and can optionally be engineered to include nuclear localization sequences.

5.3 Antibodies To NHP Products

Antibodies that specifically recognize one or more epitopes of a NHP, or epitopes of conserved variants of a NHP, or peptide fragments of a NHP are also encompassed by the invention. Such antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′) 2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.

The antibodies of the invention may be used, for example, in the detection of NHP in a biological sample and may, therefore, be utilized as part of a diagnostic or prognostic technique whereby patients may be tested for abnormal amounts of NHP. Such antibodies may also be utilized in conjunction with, for example, compound screening schemes for the evaluation of the effect of test compounds on expression and/or activity of a NHP gene product. Additionally, such antibodies can be used in conjunction gene therapy to, for example, evaluate the normal and/or engineered NHP-expressing cells prior to their introduction into the patient. Such antibodies may additionally be used as a method for the inhibition of abnormal NHP activity. Thus, such antibodies may, therefore, be utilized as part of treatment methods.

For the production of antibodies, various host animals may be immunized by injection with the NHP, an NHP peptide (e.g., one corresponding to a functional domain of an NHP), truncated NHP polypeptides (NHP in which one or more domains have been deleted), functional equivalents of the NHP or mutated variant of the NHP. Such host animals may include but are not limited to pigs, rabbits, mice, goats, and rats, to name but a few. Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's adjuvant (complete and incomplete), mineral salts such as aluminum hydroxide or aluminum phosphate, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium parvum . Alternatively, the immune response could be enhanced by combination and or coupling with molecules such as keyhole limpet hemocyanin, tetanus toxoid, diptheria toxoid, ovalbumin, cholera toxin or fragments thereof. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.

Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, can be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, (1975, Nature 256:495-497; and U.S. Pat. No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cole et al., 1983, Proc. Natl. Acad. Sci. USA 80:2026-2030), and the EBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this the presently preferred method of production.

In addition, techniques developed for the production of “chimeric antibodies” (Morrison et al., 1984, Proc. Natl. Acad. Sci., 81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda et al., 1985, Nature, 314:452-454) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region. Such technologies are described in U.S. Pat. Nos. 6,075,181 and 5,877,397 and their respective disclosures which are herein incorporated by reference in their entirety. Also encompassed by the present invention is the use of fully humanized monoclonal antibodies as described in U.S. Pat. No. 6,150,584 and respective disclosures which are herein incorporated by reference in their entirety.

Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 334:544-546) can be adapted to produce single chain antibodies against NHP gene products. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.

Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, such fragments include, but are not limited to: the F(ab′) 2 fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab′) 2 fragments. Alternatively, Fab expression libraries may be constructed (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.

Antibodies to a NHP can, in turn, be utilized to generate anti-idiotype antibodies that “mimic” a given NHP, using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, 1993, FASEB J 7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). For example antibodies which bind to a NHP domain and competitively inhibit the binding of NHP to its cognate receptor can be used to generate anti-idiotypes that “mimic” the NHP and, therefore, bind and activate or neutralize a receptor. Such anti-idiotypic antibodies or Fab fragments of such anti-idiotypes can be used in therapeutic regimens involving a NHP mediated pathway.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. All cited publications, patents, and patent applications are herein incorporated by reference in their entirety.

#             SEQUENCE LISTING
<160> NUMBER OF SEQ ID NOS: 17
<210> SEQ ID NO 1
<211> LENGTH: 5076
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 1
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggagcctatt tccttcccga gt
#ttgcactt    120
tctcctcagg gaagttttct ggaagacaca acaggggagc agttcctcac tt
#atcgctat    180
gatgaccaga cctcaagaaa cactcgttca gatgaagaca aagatggcaa ct
#gggatgct    240
tggggcgact ggagtgactg ctcccggacc tgtgggggag gagcatcata tt
#ctctgcgg    300
agatgtttga ctggaaggaa ttgtgaaggg cagaacattc ggtacaagac at
#gcagcaat    360
catgactgcc ctccagatgc agaagatttc agagcccagc agtgctcagc ct
#acaatgat    420
gtccagtatc aggggcatta ctatgaatgg cttccacgat ataatgatcc tg
#ctgccccg    480
tgtgcactca agtgtcatgc acaaggacaa aacttggtgg tggagctggc ac
#ctaaggta    540
ctggatggaa ctcgttgcaa cacggactcc ttggacatgt gtatcagtgg ca
#tctgtcag    600
gcagtgggct gcgatcggca actgggaagc aatgccaagg aggacaactg tg
#gagtctgt    660
gccggcgatg gctccacctg caggcttgta cggggacaat caaagtcaca cg
#tttctcct    720
gaaaaaagag aagaaaatgt aattgctgtt cctttgggaa gtcgaagtgt ga
#gaattaca    780
gtgaaaggac ctgcccacct ctttattgaa tcaaaaacac ttcaaggaag ca
#aaggagaa    840
cacagcttta acagccccgg cgtctttgtc gtagaaaaca caacagtgga at
#ttcagagg    900
ggctccgaga ggcaaacttt taagattcca ggacctctga tggctgattt ca
#tcttcaag    960
accaggtaca ctgcagccaa agacagcgtg gttcagttct tcttttacca gc
#ccatcagt   1020
catcagtgga gacaaactga cttctttccc tgcactgtga cgtgtggagg ag
#gttatcag   1080
ctcaattctg ctgaatgtgt ggatatccgc ttgaagaggg tagttcctga cc
#attattgt   1140
cactactacc ctgaaaatgt aaaaccaaaa ccaaaactga aggaatgcag ca
#tggatccc   1200
tgcccatcaa gtgatggatt taaagagata atgccctatg accacttcca ac
#ctcttcct   1260
cgctgggaac ataatccttg gactgcatgt tccgtgtcct gtggaggagg ga
#ttcagaga   1320
cggagctttg tgtgtgtaga ggaatccatg catggagaga tattgcaggt gg
#aagaatgg   1380
aagtgcatgt acgcacccaa acccaaggtt atgcaaactt gtaatctgtt tg
#attgcccc   1440
aagtggattg ccatggagtg gtctcagtgc acagtgactt gtggccgagg gt
#tacggtac   1500
cgggttgttc tgtgtattaa ccaccgcgga gagcatgttg ggggctgcaa tc
#cacaactg   1560
aagttacaca tcaaagaaga atgtgtcatt cccatcccgt gttataaacc aa
#aagaaaaa   1620
agtccagtgg aagcaaaatt gccttggctg aaacaagcac aagaactaga ag
#agaccaga   1680
atagcaacag aagaaccaac gttcattcca gaaccctggt cagcctgcag ta
#ccacgtgt   1740
gggccaggtg tgcaggtccg cgaggtgaag tgccgtgtgc tcctcacatt ca
#cgcagact   1800
gagactgagc tgcccgagga agagtgtgaa ggccccaagc tgcccaccga ac
#ggccctgc   1860
ctcctggaag catgtgatga gagcccggcc tcccgagagc tagacatccc tc
#tccctgag   1920
gacagtgaga cgacttacga ctgggagtac gctgggttca ccccttgcac ag
#caacatgc   1980
ttgggaggcc atcaagaagc catagcagtg tgcttacata tccagaccca gc
#agacagtc   2040
aatgacagct tgtgtgatat ggtccaccgt cctccagcca tgagccaggc ct
#gtaacaca   2100
gagccctgtc cccccaggtg gcatgtgggc tcttgggggc cctgctcagc ta
#cctgtgga   2160
gttggaattc agacccgaga tgtgtactgc ctgcacccag gggagacccc tg
#cccctcct   2220
gaggagtgcc gagatgaaaa gccccatgct ttacaagcat gcaatcagtt tg
#actgccct   2280
cctggctggc acattgaaga atggcagcag tgttccagga cttgtggcgg gg
#gaactcag   2340
aacagaagag tcacctgtcg gcagctgcta acggatggca gctttttgaa tc
#tctcagat   2400
gaattgtgcc aaggacccaa ggcatcgtct cacaagtcct gtgccaggac ag
#actgtcct   2460
ccacatttag ctgtgggaga ctggtcgaag tgttctgtca gttgtggtgt tg
#gaatccag   2520
agaagaaagc aggtgtgtca aaggctggca gccaaaggtc ggcgcatccc cc
#tcagtgag   2580
atgatgtgca gggatctacc agggttccct cttgtaagat cttgccagat gc
#ctgagtgc   2640
agtaaaatca aatcagagat gaagacaaaa cttggtgagc agggtccgca ga
#tcctcagt   2700
gtccagagag tctacattca gacaagggaa gagaagcgta ttaacctgac ca
#ttggtagc   2760
agagcctatt tgctgcccaa cacatccgtg attattaagt gccccgtgcg ac
#gattccag   2820
aaatctctga tccagtggga gaaggatggc cgttgcctgc agaactccaa ac
#ggcttggc   2880
atcaccaagt caggctcact aaaaatccac ggtcttgctg cccccgacat cg
#gcgtgtac   2940
cggtgcattg caggctctgc acaggaaaca gttgtgctca agctcattgg ta
#ctgacaac   3000
cggctcatcg cacgcccagc cctcagggag cctatgaggg aatatcctgg ga
#tggaccac   3060
agcgaagcca atagtttggg agtcacatgg cacaaaatga ggcaaatgtg ga
#ataacaaa   3120
aatgaccttt atctggatga tgaccacatt agtaaccagc ctttcttgag ag
#ctctgtta   3180
ggccactgca gcaattctgc aggaagcacc aactcctggg agttgaagaa ta
#agcagttt   3240
gaagcagcag ttaaacaagg agcatatagc atggatacag cccagtttga tg
#agctgata   3300
agaaacatga gtcagctcat ggaaaccgga gaggtcagcg atgatcttgc gt
#cccagctg   3360
atatatcagc tggtggccga attagccaag gcacagccaa cacacatgca gt
#ggcggggc   3420
atccaggaag agacacctcc tgctgctcag ctcagagggg aaacagggag tg
#tgtcccaa   3480
agctcgcatg caaaaaactc aggcaagctg acattcaagc cgaaaggacc tg
#ttctcatg   3540
aggcaaagcc aacctccctc aatttcattt aataaaacaa taaattccag ga
#ttggaaat   3600
acagtataca ttacaaaaag gacagaggtc atcaatatac tgtgtgacct ta
#ttaccccc   3660
agtgaggcca catatacatg gaccaaggat ggaaccttgt tacagccctc ag
#taaaaata   3720
attttggatg gaactgggaa gatacagata cagaatccta caaggaaaga ac
#aaggcata   3780
tatgaatgtt ctgtagctaa tcatcttggt tcagatgtgg aaagttcttc tg
#tgctgtat   3840
gcagaggcac ctgtcatctt gtctgttgaa agaaatatca ccaaaccaga gc
#acaaccat   3900
ctgtctgttg tggttggagg catcgtggag gcagcccttg gagcaaacgt ga
#caatccga   3960
tgtcctgtaa aaggtgtccc tcagcctaat ataacttggt tgaagagagg ag
#gatctctg   4020
agtggcaatg tttccttgct tttcaatgga tccctgttgt tgcagaatgt tt
#cccttgaa   4080
aatgaaggaa cctacgtctg catagccacc aatgctcttg gaaaggcagt gg
#caacatct   4140
gtactccact tgctggaacg aagatggcca gagagtagaa tcgtatttct gc
#aaggacat   4200
aaaaagtaca ttctccaggc aaccaacact agaaccaaca gcaatgaccc aa
#caggagaa   4260
cccccgcctc aagagccttt ttgggagcct ggtaactggt cacattgttc tg
#ccacctgt   4320
ggtcatttgg gagcccgcat tcagagaccc cagtgtgtga tggccaatgg gc
#aggaagtg   4380
agtgaggccc tgtgtgatca cctccagaag ccactggctg ggtttgagcc ct
#gtaacatc   4440
cgggactgcc cagcgaggtg gttcacaagt gtgtggtcac agtgctctgt gt
#cttgcggt   4500
gaaggatacc acagtcggca ggtgacgtgc aagcggacaa aagccaatgg aa
#ctgtgcag   4560
gtggtgtctc caagagcatg tgcccctaaa gaccggcctc tgggaagaaa ac
#catgtttt   4620
ggtcatccat gtgttcagtg ggaaccaggg aaccggtgtc ctggacgttg ca
#tgggccgt   4680
gctgtgagga tgcagcagcg tcacacagct tgtcaacaca acagctctga ct
#ccaactgt   4740
gatgacagaa agagacccac cttaagaagg aactgcacat caggggcctg tg
#atgtgtgt   4800
tggcacacag gcccttggaa gccctgtaca gcagcctgtg gcaggggttt cc
#agtctcgg   4860
aaagtcgact gtatccacac aaggagttgc aaacctgtgg ccaagagaca ct
#gtgtacag   4920
aaaaagaaac caatttcctg gcggcactgt cttgggccct cctgtgatag ag
#actgcaca   4980
gacacaactc actactgtat gtttgtaaaa catcttaatt tgtgttctct ag
#accgctac   5040
aaacaaaggt gctgccagtc atgtcaagag ggataa
#
#     5076
<210> SEQ ID NO 2
<211> LENGTH: 1691
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 2
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Ala
20
#            25
#            30
Tyr Phe Leu Pro Glu Phe Ala Leu Ser Pro Gl
#n Gly Ser Phe Leu Glu
35
#        40
#        45
Asp Thr Thr Gly Glu Gln Phe Leu Thr Tyr Ar
#g Tyr Asp Asp Gln Thr
50
#    55
#    60
Ser Arg Asn Thr Arg Ser Asp Glu Asp Lys As
#p Gly Asn Trp Asp Ala
65
#70
#75
#80
Trp Gly Asp Trp Ser Asp Cys Ser Arg Thr Cy
#s Gly Gly Gly Ala Ser
85
#                90
#                95
Tyr Ser Leu Arg Arg Cys Leu Thr Gly Arg As
#n Cys Glu Gly Gln Asn
100
#           105
#           110
Ile Arg Tyr Lys Thr Cys Ser Asn His Asp Cy
#s Pro Pro Asp Ala Glu
115
#       120
#       125
Asp Phe Arg Ala Gln Gln Cys Ser Ala Tyr As
#n Asp Val Gln Tyr Gln
130
#   135
#   140
Gly His Tyr Tyr Glu Trp Leu Pro Arg Tyr As
#n Asp Pro Ala Ala Pro
145                 1
#50                 1
#55                 1
#60
Cys Ala Leu Lys Cys His Ala Gln Gly Gln As
#n Leu Val Val Glu Leu
165
#               170
#               175
Ala Pro Lys Val Leu Asp Gly Thr Arg Cys As
#n Thr Asp Ser Leu Asp
180
#           185
#           190
Met Cys Ile Ser Gly Ile Cys Gln Ala Val Gl
#y Cys Asp Arg Gln Leu
195
#       200
#       205
Gly Ser Asn Ala Lys Glu Asp Asn Cys Gly Va
#l Cys Ala Gly Asp Gly
210
#   215
#   220
Ser Thr Cys Arg Leu Val Arg Gly Gln Ser Ly
#s Ser His Val Ser Pro
225                 2
#30                 2
#35                 2
#40
Glu Lys Arg Glu Glu Asn Val Ile Ala Val Pr
#o Leu Gly Ser Arg Ser
245
#               250
#               255
Val Arg Ile Thr Val Lys Gly Pro Ala His Le
#u Phe Ile Glu Ser Lys
260
#           265
#           270
Thr Leu Gln Gly Ser Lys Gly Glu His Ser Ph
#e Asn Ser Pro Gly Val
275
#       280
#       285
Phe Val Val Glu Asn Thr Thr Val Glu Phe Gl
#n Arg Gly Ser Glu Arg
290
#   295
#   300
Gln Thr Phe Lys Ile Pro Gly Pro Leu Met Al
#a Asp Phe Ile Phe Lys
305                 3
#10                 3
#15                 3
#20
Thr Arg Tyr Thr Ala Ala Lys Asp Ser Val Va
#l Gln Phe Phe Phe Tyr
325
#               330
#               335
Gln Pro Ile Ser His Gln Trp Arg Gln Thr As
#p Phe Phe Pro Cys Thr
340
#           345
#           350
Val Thr Cys Gly Gly Gly Tyr Gln Leu Asn Se
#r Ala Glu Cys Val Asp
355
#       360
#       365
Ile Arg Leu Lys Arg Val Val Pro Asp His Ty
#r Cys His Tyr Tyr Pro
370
#   375
#   380
Glu Asn Val Lys Pro Lys Pro Lys Leu Lys Gl
#u Cys Ser Met Asp Pro
385                 3
#90                 3
#95                 4
#00
Cys Pro Ser Ser Asp Gly Phe Lys Glu Ile Me
#t Pro Tyr Asp His Phe
405
#               410
#               415
Gln Pro Leu Pro Arg Trp Glu His Asn Pro Tr
#p Thr Ala Cys Ser Val
420
#           425
#           430
Ser Cys Gly Gly Gly Ile Gln Arg Arg Ser Ph
#e Val Cys Val Glu Glu
435
#       440
#       445
Ser Met His Gly Glu Ile Leu Gln Val Glu Gl
#u Trp Lys Cys Met Tyr
450
#   455
#   460
Ala Pro Lys Pro Lys Val Met Gln Thr Cys As
#n Leu Phe Asp Cys Pro
465                 4
#70                 4
#75                 4
#80
Lys Trp Ile Ala Met Glu Trp Ser Gln Cys Th
#r Val Thr Cys Gly Arg
485
#               490
#               495
Gly Leu Arg Tyr Arg Val Val Leu Cys Ile As
#n His Arg Gly Glu His
500
#           505
#           510
Val Gly Gly Cys Asn Pro Gln Leu Lys Leu Hi
#s Ile Lys Glu Glu Cys
515
#       520
#       525
Val Ile Pro Ile Pro Cys Tyr Lys Pro Lys Gl
#u Lys Ser Pro Val Glu
530
#   535
#   540
Ala Lys Leu Pro Trp Leu Lys Gln Ala Gln Gl
#u Leu Glu Glu Thr Arg
545                 5
#50                 5
#55                 5
#60
Ile Ala Thr Glu Glu Pro Thr Phe Ile Pro Gl
#u Pro Trp Ser Ala Cys
565
#               570
#               575
Ser Thr Thr Cys Gly Pro Gly Val Gln Val Ar
#g Glu Val Lys Cys Arg
580
#           585
#           590
Val Leu Leu Thr Phe Thr Gln Thr Glu Thr Gl
#u Leu Pro Glu Glu Glu
595
#       600
#       605
Cys Glu Gly Pro Lys Leu Pro Thr Glu Arg Pr
#o Cys Leu Leu Glu Ala
610
#   615
#   620
Cys Asp Glu Ser Pro Ala Ser Arg Glu Leu As
#p Ile Pro Leu Pro Glu
625                 6
#30                 6
#35                 6
#40
Asp Ser Glu Thr Thr Tyr Asp Trp Glu Tyr Al
#a Gly Phe Thr Pro Cys
645
#               650
#               655
Thr Ala Thr Cys Leu Gly Gly His Gln Glu Al
#a Ile Ala Val Cys Leu
660
#           665
#           670
His Ile Gln Thr Gln Gln Thr Val Asn Asp Se
#r Leu Cys Asp Met Val
675
#       680
#       685
His Arg Pro Pro Ala Met Ser Gln Ala Cys As
#n Thr Glu Pro Cys Pro
690
#   695
#   700
Pro Arg Trp His Val Gly Ser Trp Gly Pro Cy
#s Ser Ala Thr Cys Gly
705                 7
#10                 7
#15                 7
#20
Val Gly Ile Gln Thr Arg Asp Val Tyr Cys Le
#u His Pro Gly Glu Thr
725
#               730
#               735
Pro Ala Pro Pro Glu Glu Cys Arg Asp Glu Ly
#s Pro His Ala Leu Gln
740
#           745
#           750
Ala Cys Asn Gln Phe Asp Cys Pro Pro Gly Tr
#p His Ile Glu Glu Trp
755
#       760
#       765
Gln Gln Cys Ser Arg Thr Cys Gly Gly Gly Th
#r Gln Asn Arg Arg Val
770
#   775
#   780
Thr Cys Arg Gln Leu Leu Thr Asp Gly Ser Ph
#e Leu Asn Leu Ser Asp
785                 7
#90                 7
#95                 8
#00
Glu Leu Cys Gln Gly Pro Lys Ala Ser Ser Hi
#s Lys Ser Cys Ala Arg
805
#               810
#               815
Thr Asp Cys Pro Pro His Leu Ala Val Gly As
#p Trp Ser Lys Cys Ser
820
#           825
#           830
Val Ser Cys Gly Val Gly Ile Gln Arg Arg Ly
#s Gln Val Cys Gln Arg
835
#       840
#       845
Leu Ala Ala Lys Gly Arg Arg Ile Pro Leu Se
#r Glu Met Met Cys Arg
850
#   855
#   860
Asp Leu Pro Gly Phe Pro Leu Val Arg Ser Cy
#s Gln Met Pro Glu Cys
865                 8
#70                 8
#75                 8
#80
Ser Lys Ile Lys Ser Glu Met Lys Thr Lys Le
#u Gly Glu Gln Gly Pro
885
#               890
#               895
Gln Ile Leu Ser Val Gln Arg Val Tyr Ile Gl
#n Thr Arg Glu Glu Lys
900
#           905
#           910
Arg Ile Asn Leu Thr Ile Gly Ser Arg Ala Ty
#r Leu Leu Pro Asn Thr
915
#       920
#       925
Ser Val Ile Ile Lys Cys Pro Val Arg Arg Ph
#e Gln Lys Ser Leu Ile
930
#   935
#   940
Gln Trp Glu Lys Asp Gly Arg Cys Leu Gln As
#n Ser Lys Arg Leu Gly
945                 9
#50                 9
#55                 9
#60
Ile Thr Lys Ser Gly Ser Leu Lys Ile His Gl
#y Leu Ala Ala Pro Asp
965
#               970
#               975
Ile Gly Val Tyr Arg Cys Ile Ala Gly Ser Al
#a Gln Glu Thr Val Val
980
#           985
#           990
Leu Lys Leu Ile Gly Thr Asp Asn Arg Leu Il
#e Ala Arg Pro Ala Leu
995
#       1000
#      1005
Arg Glu Pro Met Arg Glu Tyr Pro Gly Met As
#p His Ser Glu Ala Asn
1010
#   1015
#  1020
Ser Leu Gly Val Thr Trp His Lys Met Arg Gl
#n Met Trp Asn Asn Lys
1025                1030
#                1035
#               1040
Asn Asp Leu Tyr Leu Asp Asp Asp His Ile Se
#r Asn Gln Pro Phe Leu
1045
#               1050
#              1055
Arg Ala Leu Leu Gly His Cys Ser Asn Ser Al
#a Gly Ser Thr Asn Ser
1060
#           1065
#          1070
Trp Glu Leu Lys Asn Lys Gln Phe Glu Ala Al
#a Val Lys Gln Gly Ala
1075
#       1080
#      1085
Tyr Ser Met Asp Thr Ala Gln Phe Asp Glu Le
#u Ile Arg Asn Met Ser
1090
#   1095
#  1100
Gln Leu Met Glu Thr Gly Glu Val Ser Asp As
#p Leu Ala Ser Gln Leu
1105                1110
#                1115
#               1120
Ile Tyr Gln Leu Val Ala Glu Leu Ala Lys Al
#a Gln Pro Thr His Met
1125
#               1130
#              1135
Gln Trp Arg Gly Ile Gln Glu Glu Thr Pro Pr
#o Ala Ala Gln Leu Arg
1140
#           1145
#          1150
Gly Glu Thr Gly Ser Val Ser Gln Ser Ser Hi
#s Ala Lys Asn Ser Gly
1155
#       1160
#      1165
Lys Leu Thr Phe Lys Pro Lys Gly Pro Val Le
#u Met Arg Gln Ser Gln
1170
#   1175
#  1180
Pro Pro Ser Ile Ser Phe Asn Lys Thr Ile As
#n Ser Arg Ile Gly Asn
1185                1190
#                1195
#               1200
Thr Val Tyr Ile Thr Lys Arg Thr Glu Val Il
#e Asn Ile Leu Cys Asp
1205
#               1210
#              1215
Leu Ile Thr Pro Ser Glu Ala Thr Tyr Thr Tr
#p Thr Lys Asp Gly Thr
1220
#           1225
#          1230
Leu Leu Gln Pro Ser Val Lys Ile Ile Leu As
#p Gly Thr Gly Lys Ile
1235
#       1240
#      1245
Gln Ile Gln Asn Pro Thr Arg Lys Glu Gln Gl
#y Ile Tyr Glu Cys Ser
1250
#   1255
#  1260
Val Ala Asn His Leu Gly Ser Asp Val Glu Se
#r Ser Ser Val Leu Tyr
1265                1270
#                1275
#               1280
Ala Glu Ala Pro Val Ile Leu Ser Val Glu Ar
#g Asn Ile Thr Lys Pro
1285
#               1290
#              1295
Glu His Asn His Leu Ser Val Val Val Gly Gl
#y Ile Val Glu Ala Ala
1300
#           1305
#          1310
Leu Gly Ala Asn Val Thr Ile Arg Cys Pro Va
#l Lys Gly Val Pro Gln
1315
#       1320
#      1325
Pro Asn Ile Thr Trp Leu Lys Arg Gly Gly Se
#r Leu Ser Gly Asn Val
1330
#   1335
#  1340
Ser Leu Leu Phe Asn Gly Ser Leu Leu Leu Gl
#n Asn Val Ser Leu Glu
1345                1350
#                1355
#               1360
Asn Glu Gly Thr Tyr Val Cys Ile Ala Thr As
#n Ala Leu Gly Lys Ala
1365
#               1370
#              1375
Val Ala Thr Ser Val Leu His Leu Leu Glu Ar
#g Arg Trp Pro Glu Ser
1380
#           1385
#          1390
Arg Ile Val Phe Leu Gln Gly His Lys Lys Ty
#r Ile Leu Gln Ala Thr
1395
#       1400
#      1405
Asn Thr Arg Thr Asn Ser Asn Asp Pro Thr Gl
#y Glu Pro Pro Pro Gln
1410
#   1415
#  1420
Glu Pro Phe Trp Glu Pro Gly Asn Trp Ser Hi
#s Cys Ser Ala Thr Cys
1425                1430
#                1435
#               1440
Gly His Leu Gly Ala Arg Ile Gln Arg Pro Gl
#n Cys Val Met Ala Asn
1445
#               1450
#              1455
Gly Gln Glu Val Ser Glu Ala Leu Cys Asp Hi
#s Leu Gln Lys Pro Leu
1460
#           1465
#          1470
Ala Gly Phe Glu Pro Cys Asn Ile Arg Asp Cy
#s Pro Ala Arg Trp Phe
1475
#       1480
#      1485
Thr Ser Val Trp Ser Gln Cys Ser Val Ser Cy
#s Gly Glu Gly Tyr His
1490
#   1495
#  1500
Ser Arg Gln Val Thr Cys Lys Arg Thr Lys Al
#a Asn Gly Thr Val Gln
1505                1510
#                1515
#               1520
Val Val Ser Pro Arg Ala Cys Ala Pro Lys As
#p Arg Pro Leu Gly Arg
1525
#               1530
#              1535
Lys Pro Cys Phe Gly His Pro Cys Val Gln Tr
#p Glu Pro Gly Asn Arg
1540
#           1545
#          1550
Cys Pro Gly Arg Cys Met Gly Arg Ala Val Ar
#g Met Gln Gln Arg His
1555
#       1560
#      1565
Thr Ala Cys Gln His Asn Ser Ser Asp Ser As
#n Cys Asp Asp Arg Lys
1570
#   1575
#  1580
Arg Pro Thr Leu Arg Arg Asn Cys Thr Ser Gl
#y Ala Cys Asp Val Cys
1585                1590
#                1595
#               1600
Trp His Thr Gly Pro Trp Lys Pro Cys Thr Al
#a Ala Cys Gly Arg Gly
1605
#               1610
#              1615
Phe Gln Ser Arg Lys Val Asp Cys Ile His Th
#r Arg Ser Cys Lys Pro
1620
#           1625
#          1630
Val Ala Lys Arg His Cys Val Gln Lys Lys Ly
#s Pro Ile Ser Trp Arg
1635
#       1640
#      1645
His Cys Leu Gly Pro Ser Cys Asp Arg Asp Cy
#s Thr Asp Thr Thr His
1650
#   1655
#  1660
Tyr Cys Met Phe Val Lys His Leu Asn Leu Cy
#s Ser Leu Asp Arg Tyr
1665                1670
#                1675
#               1680
Lys Gln Arg Cys Cys Gln Ser Cys Gln Glu Gl
#y
1685
#               1690
<210> SEQ ID NO 3
<211> LENGTH: 1341
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 3
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggagcctatt tccttcccga gt
#ttgcactt    120
tctcctcagg gaagttttct ggaagacaca acaggggagc agttcctcac tt
#atcgctat    180
gatgaccaga cctcaagaaa cactcgttca gatgaagaca aagatggcaa ct
#gggatgct    240
tggggcgact ggagtgactg ctcccggacc tgtgggggag gagcatcata tt
#ctctgcgg    300
agatgtttga ctggaaggaa ttgtgaaggg cagaacattc ggtacaagac at
#gcagcaat    360
catgactgcc ctccagatgc agaagatttc agagcccagc agtgctcagc ct
#acaatgat    420
gtccagtatc aggggcatta ctatgaatgg cttccacgat ataatgatcc tg
#ctgccccg    480
tgtgcactca agtgtcatgc acaaggacaa aacttggtgg tggagctggc ac
#ctaaggta    540
ctggatggaa ctcgttgcaa cacggactcc ttggacatgt gtatcagtgg ca
#tctgtcag    600
gcagtgggct gcgatcggca actgggaagc aatgccaagg aggacaactg tg
#gagtctgt    660
gccggcgatg gctccacctg caggcttgta cggggacaat caaagtcaca cg
#tttctcct    720
gaaaaaagag aagaaaatgt aattgctgtt cctttgggaa gtcgaagtgt ga
#gaattaca    780
gtgaaaggac ctgcccacct ctttattgaa tcaaaaacac ttcaaggaag ca
#aaggagaa    840
cacagcttta acagccccgg cgtctttgtc gtagaaaaca caacagtgga at
#ttcagagg    900
ggctccgaga ggcaaacttt taagattcca ggacctctga tggctgattt ca
#tcttcaag    960
accaggtaca ctgcagccaa agacagcgtg gttcagttct tcttttacca gc
#ccatcagt   1020
catcagtgga gacaaactga cttctttccc tgcactgtga cgtgtggagg ag
#gttatcag   1080
ctcaattctg ctgaatgtgt ggatatccgc ttgaagaggg tagttcctga cc
#attattgt   1140
cactactacc ctgaaaatgt aaaaccaaaa ccaaaactga aggaatgcag ca
#tggatccc   1200
tgcccatcaa gtgatggatt taaagagata atgccctatg accacttcca ac
#ctcttcct   1260
cgagctggga acataatcct tggactgcat gttccgtgtc ctgtggagga gg
#gattcaga   1320
gacggagctt tgtgtgtgta g
#
#                1341
<210> SEQ ID NO 4
<211> LENGTH: 446
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 4
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Ala
20
#            25
#            30
Tyr Phe Leu Pro Glu Phe Ala Leu Ser Pro Gl
#n Gly Ser Phe Leu Glu
35
#        40
#        45
Asp Thr Thr Gly Glu Gln Phe Leu Thr Tyr Ar
#g Tyr Asp Asp Gln Thr
50
#    55
#    60
Ser Arg Asn Thr Arg Ser Asp Glu Asp Lys As
#p Gly Asn Trp Asp Ala
65
#70
#75
#80
Trp Gly Asp Trp Ser Asp Cys Ser Arg Thr Cy
#s Gly Gly Gly Ala Ser
85
#                90
#                95
Tyr Ser Leu Arg Arg Cys Leu Thr Gly Arg As
#n Cys Glu Gly Gln Asn
100
#           105
#           110
Ile Arg Tyr Lys Thr Cys Ser Asn His Asp Cy
#s Pro Pro Asp Ala Glu
115
#       120
#       125
Asp Phe Arg Ala Gln Gln Cys Ser Ala Tyr As
#n Asp Val Gln Tyr Gln
130
#   135
#   140
Gly His Tyr Tyr Glu Trp Leu Pro Arg Tyr As
#n Asp Pro Ala Ala Pro
145                 1
#50                 1
#55                 1
#60
Cys Ala Leu Lys Cys His Ala Gln Gly Gln As
#n Leu Val Val Glu Leu
165
#               170
#               175
Ala Pro Lys Val Leu Asp Gly Thr Arg Cys As
#n Thr Asp Ser Leu Asp
180
#           185
#           190
Met Cys Ile Ser Gly Ile Cys Gln Ala Val Gl
#y Cys Asp Arg Gln Leu
195
#       200
#       205
Gly Ser Asn Ala Lys Glu Asp Asn Cys Gly Va
#l Cys Ala Gly Asp Gly
210
#   215
#   220
Ser Thr Cys Arg Leu Val Arg Gly Gln Ser Ly
#s Ser His Val Ser Pro
225                 2
#30                 2
#35                 2
#40
Glu Lys Arg Glu Glu Asn Val Ile Ala Val Pr
#o Leu Gly Ser Arg Ser
245
#               250
#               255
Val Arg Ile Thr Val Lys Gly Pro Ala His Le
#u Phe Ile Glu Ser Lys
260
#           265
#           270
Thr Leu Gln Gly Ser Lys Gly Glu His Ser Ph
#e Asn Ser Pro Gly Val
275
#       280
#       285
Phe Val Val Glu Asn Thr Thr Val Glu Phe Gl
#n Arg Gly Ser Glu Arg
290
#   295
#   300
Gln Thr Phe Lys Ile Pro Gly Pro Leu Met Al
#a Asp Phe Ile Phe Lys
305                 3
#10                 3
#15                 3
#20
Thr Arg Tyr Thr Ala Ala Lys Asp Ser Val Va
#l Gln Phe Phe Phe Tyr
325
#               330
#               335
Gln Pro Ile Ser His Gln Trp Arg Gln Thr As
#p Phe Phe Pro Cys Thr
340
#           345
#           350
Val Thr Cys Gly Gly Gly Tyr Gln Leu Asn Se
#r Ala Glu Cys Val Asp
355
#       360
#       365
Ile Arg Leu Lys Arg Val Val Pro Asp His Ty
#r Cys His Tyr Tyr Pro
370
#   375
#   380
Glu Asn Val Lys Pro Lys Pro Lys Leu Lys Gl
#u Cys Ser Met Asp Pro
385                 3
#90                 3
#95                 4
#00
Cys Pro Ser Ser Asp Gly Phe Lys Glu Ile Me
#t Pro Tyr Asp His Phe
405
#               410
#               415
Gln Pro Leu Pro Arg Ala Gly Asn Ile Ile Le
#u Gly Leu His Val Pro
420
#           425
#           430
Cys Pro Val Glu Glu Gly Phe Arg Asp Gly Al
#a Leu Cys Val
435
#       440
#       445
<210> SEQ ID NO 5
<211> LENGTH: 1119
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 5
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggaaggaatt gtgaagggca ga
#acattcgg    120
tacaagacat gcagcaatca tgactgccct ccagatgcag aagatttcag ag
#cccagcag    180
tgctcagcct acaatgatgt ccagtatcag gggcattact atgaatggct tc
#cacgatat    240
aatgatcctg ctgccccgtg tgcactcaag tgtcatgcac aaggacaaaa ct
#tggtggtg    300
gagctggcac ctaaggtact ggatggaact cgttgcaaca cggactcctt gg
#acatgtgt    360
atcagtggca tctgtcaggc agtgggctgc gatcggcaac tgggaagcaa tg
#ccaaggag    420
gacaactgtg gagtctgtgc cggcgatggc tccacctgca ggcttgtacg gg
#gacaatca    480
aagtcacacg tttctcctga aaaaagagaa gaaaatgtaa ttgctgttcc tt
#tgggaagt    540
cgaagtgtga gaattacagt gaaaggacct gcccacctct ttattgaatc aa
#aaacactt    600
caaggaagca aaggagaaca cagctttaac agccccggcg tctttgtcgt ag
#aaaacaca    660
acagtggaat ttcagagggg ctccgagagg caaactttta agattccagg ac
#ctctgatg    720
gctgatttca tcttcaagac caggtacact gcagccaaag acagcgtggt tc
#agttcttc    780
ttttaccagc ccatcagtca tcagtggaga caaactgact tctttccctg ca
#ctgtgacg    840
tgtggaggag gttatcagct caattctgct gaatgtgtgg atatccgctt ga
#agagggta    900
gttcctgacc attattgtca ctactaccct gaaaatgtaa aaccaaaacc aa
#aactgaag    960
gaatgcagca tggatccctg cccatcaagt gatggattta aagagataat gc
#cctatgac   1020
cacttccaac ctcttcctcg agctgggaac ataatccttg gactgcatgt tc
#cgtgtcct   1080
gtggaggagg gattcagaga cggagctttg tgtgtgtag
#
#  1119
<210> SEQ ID NO 6
<211> LENGTH: 372
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 6
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Arg
20
#            25
#            30
Asn Cys Glu Gly Gln Asn Ile Arg Tyr Lys Th
#r Cys Ser Asn His Asp
35
#        40
#        45
Cys Pro Pro Asp Ala Glu Asp Phe Arg Ala Gl
#n Gln Cys Ser Ala Tyr
50
#    55
#    60
Asn Asp Val Gln Tyr Gln Gly His Tyr Tyr Gl
#u Trp Leu Pro Arg Tyr
65
#70
#75
#80
Asn Asp Pro Ala Ala Pro Cys Ala Leu Lys Cy
#s His Ala Gln Gly Gln
85
#                90
#                95
Asn Leu Val Val Glu Leu Ala Pro Lys Val Le
#u Asp Gly Thr Arg Cys
100
#           105
#           110
Asn Thr Asp Ser Leu Asp Met Cys Ile Ser Gl
#y Ile Cys Gln Ala Val
115
#       120
#       125
Gly Cys Asp Arg Gln Leu Gly Ser Asn Ala Ly
#s Glu Asp Asn Cys Gly
130
#   135
#   140
Val Cys Ala Gly Asp Gly Ser Thr Cys Arg Le
#u Val Arg Gly Gln Ser
145                 1
#50                 1
#55                 1
#60
Lys Ser His Val Ser Pro Glu Lys Arg Glu Gl
#u Asn Val Ile Ala Val
165
#               170
#               175
Pro Leu Gly Ser Arg Ser Val Arg Ile Thr Va
#l Lys Gly Pro Ala His
180
#           185
#           190
Leu Phe Ile Glu Ser Lys Thr Leu Gln Gly Se
#r Lys Gly Glu His Ser
195
#       200
#       205
Phe Asn Ser Pro Gly Val Phe Val Val Glu As
#n Thr Thr Val Glu Phe
210
#   215
#   220
Gln Arg Gly Ser Glu Arg Gln Thr Phe Lys Il
#e Pro Gly Pro Leu Met
225                 2
#30                 2
#35                 2
#40
Ala Asp Phe Ile Phe Lys Thr Arg Tyr Thr Al
#a Ala Lys Asp Ser Val
245
#               250
#               255
Val Gln Phe Phe Phe Tyr Gln Pro Ile Ser Hi
#s Gln Trp Arg Gln Thr
260
#           265
#           270
Asp Phe Phe Pro Cys Thr Val Thr Cys Gly Gl
#y Gly Tyr Gln Leu Asn
275
#       280
#       285
Ser Ala Glu Cys Val Asp Ile Arg Leu Lys Ar
#g Val Val Pro Asp His
290
#   295
#   300
Tyr Cys His Tyr Tyr Pro Glu Asn Val Lys Pr
#o Lys Pro Lys Leu Lys
305                 3
#10                 3
#15                 3
#20
Glu Cys Ser Met Asp Pro Cys Pro Ser Ser As
#p Gly Phe Lys Glu Ile
325
#               330
#               335
Met Pro Tyr Asp His Phe Gln Pro Leu Pro Ar
#g Ala Gly Asn Ile Ile
340
#           345
#           350
Leu Gly Leu His Val Pro Cys Pro Val Glu Gl
#u Gly Phe Arg Asp Gly
355
#       360
#       365
Ala Leu Cys Val
370
<210> SEQ ID NO 7
<211> LENGTH: 2175
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 7
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggagcctatt tccttcccga gt
#ttgcactt    120
tctcctcagg gaagttttct ggaagacaca acaggggagc agttcctcac tt
#atcgctat    180
gatgaccaga cctcaagaaa cactcgttca gatgaagaca aagatggcaa ct
#gggatgct    240
tggggcgact ggagtgactg ctcccggacc tgtgggggag gagcatcata tt
#ctctgcgg    300
agatgtttga ctggaaggaa ttgtgaaggg cagaacattc ggtacaagac at
#gcagcaat    360
catgactgcc ctccagatgc agaagatttc agagcccagc agtgctcagc ct
#acaatgat    420
gtccagtatc aggggcatta ctatgaatgg cttccacgat ataatgatcc tg
#ctgccccg    480
tgtgcactca agtgtcatgc acaaggacaa aacttggtgg tggagctggc ac
#ctaaggta    540
ctggatggaa ctcgttgcaa cacggactcc ttggacatgt gtatcagtgg ca
#tctgtcag    600
gcagtgggct gcgatcggca actgggaagc aatgccaagg aggacaactg tg
#gagtctgt    660
gccggcgatg gctccacctg caggcttgta cggggacaat caaagtcaca cg
#tttctcct    720
gaaaaaagag aagaaaatgt aattgctgtt cctttgggaa gtcgaagtgt ga
#gaattaca    780
gtgaaaggac ctgcccacct ctttattgaa tcaaaaacac ttcaaggaag ca
#aaggagaa    840
cacagcttta acagccccgg cgtctttgtc gtagaaaaca caacagtgga at
#ttcagagg    900
ggctccgaga ggcaaacttt taagattcca ggacctctga tggctgattt ca
#tcttcaag    960
accaggtaca ctgcagccaa agacagcgtg gttcagttct tcttttacca gc
#ccatcagt   1020
catcagtgga gacaaactga cttctttccc tgcactgtga cgtgtggagg ag
#gttatcag   1080
ctcaattctg ctgaatgtgt ggatatccgc ttgaagaggg tagttcctga cc
#attattgt   1140
cactactacc ctgaaaatgt aaaaccaaaa ccaaaactga aggaatgcag ca
#tggatccc   1200
tgcccatcaa gtgatggatt taaagagata atgccctatg accacttcca ac
#ctcttcct   1260
cgctgggaac ataatccttg gactgcatgt tccgtgtcct gtggaggagg ga
#ttcagaga   1320
cggagctttg tgtgtgtaga ggaatccatg catggagaga tattgcaggt gg
#aagaatgg   1380
aagtgcatgt acgcacccaa acccaaggtt atgcaaactt gtaatctgtt tg
#attgcccc   1440
aagtggattg ccatggagtg gtctcagtgc acagtgactt gtggccgagg gt
#tacggtac   1500
cgggttgttc tgtgtattaa ccaccgcgga gagcatgttg ggggctgcaa tc
#cacaactg   1560
aagttacaca tcaaagaaga atgtgtcatt cccatcccgt gttataaacc aa
#aagaaaaa   1620
agtccagtgg aagcaaaatt gccttggctg aaacaagcac aagaactaga ag
#agaccaga   1680
atagcaacag aagaaccaac gttcattcca gaaccctggt cagcctgcag ta
#ccacgtgt   1740
gggccaggtg tgcaggtccg cgaggtgaag tgccgtgtgc tcctcacatt ca
#cgcagact   1800
gagactgagc tgcccgagga agagtgtgaa ggccccaagc tgcccaccga ac
#ggccctgc   1860
ctcctggaag catgtgatga gagcccggcc tcccgagagc tagacatccc tc
#tccctgag   1920
gacagtgaga cgacttacga ctgggagtac gctgggttca ccccttgcac ag
#caacatgc   1980
ttgggaggcc atcaagaagc catagcagtg tgcttacata tccagaccca gc
#agacagtc   2040
aatgacagct tgtgtgatat ggtccaccgt cctccagcca tgagccaggc ct
#gtaacaca   2100
gagccctgtc cccccaggag agagccagca gcttgtagaa gcatgccggg tt
#acataatg   2160
gtcctgctag tctga
#
#
#  2175
<210> SEQ ID NO 8
<211> LENGTH: 724
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 8
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Ala
20
#            25
#            30
Tyr Phe Leu Pro Glu Phe Ala Leu Ser Pro Gl
#n Gly Ser Phe Leu Glu
35
#        40
#        45
Asp Thr Thr Gly Glu Gln Phe Leu Thr Tyr Ar
#g Tyr Asp Asp Gln Thr
50
#    55
#    60
Ser Arg Asn Thr Arg Ser Asp Glu Asp Lys As
#p Gly Asn Trp Asp Ala
65
#70
#75
#80
Trp Gly Asp Trp Ser Asp Cys Ser Arg Thr Cy
#s Gly Gly Gly Ala Ser
85
#                90
#                95
Tyr Ser Leu Arg Arg Cys Leu Thr Gly Arg As
#n Cys Glu Gly Gln Asn
100
#           105
#           110
Ile Arg Tyr Lys Thr Cys Ser Asn His Asp Cy
#s Pro Pro Asp Ala Glu
115
#       120
#       125
Asp Phe Arg Ala Gln Gln Cys Ser Ala Tyr As
#n Asp Val Gln Tyr Gln
130
#   135
#   140
Gly His Tyr Tyr Glu Trp Leu Pro Arg Tyr As
#n Asp Pro Ala Ala Pro
145                 1
#50                 1
#55                 1
#60
Cys Ala Leu Lys Cys His Ala Gln Gly Gln As
#n Leu Val Val Glu Leu
165
#               170
#               175
Ala Pro Lys Val Leu Asp Gly Thr Arg Cys As
#n Thr Asp Ser Leu Asp
180
#           185
#           190
Met Cys Ile Ser Gly Ile Cys Gln Ala Val Gl
#y Cys Asp Arg Gln Leu
195
#       200
#       205
Gly Ser Asn Ala Lys Glu Asp Asn Cys Gly Va
#l Cys Ala Gly Asp Gly
210
#   215
#   220
Ser Thr Cys Arg Leu Val Arg Gly Gln Ser Ly
#s Ser His Val Ser Pro
225                 2
#30                 2
#35                 2
#40
Glu Lys Arg Glu Glu Asn Val Ile Ala Val Pr
#o Leu Gly Ser Arg Ser
245
#               250
#               255
Val Arg Ile Thr Val Lys Gly Pro Ala His Le
#u Phe Ile Glu Ser Lys
260
#           265
#           270
Thr Leu Gln Gly Ser Lys Gly Glu His Ser Ph
#e Asn Ser Pro Gly Val
275
#       280
#       285
Phe Val Val Glu Asn Thr Thr Val Glu Phe Gl
#n Arg Gly Ser Glu Arg
290
#   295
#   300
Gln Thr Phe Lys Ile Pro Gly Pro Leu Met Al
#a Asp Phe Ile Phe Lys
305                 3
#10                 3
#15                 3
#20
Thr Arg Tyr Thr Ala Ala Lys Asp Ser Val Va
#l Gln Phe Phe Phe Tyr
325
#               330
#               335
Gln Pro Ile Ser His Gln Trp Arg Gln Thr As
#p Phe Phe Pro Cys Thr
340
#           345
#           350
Val Thr Cys Gly Gly Gly Tyr Gln Leu Asn Se
#r Ala Glu Cys Val Asp
355
#       360
#       365
Ile Arg Leu Lys Arg Val Val Pro Asp His Ty
#r Cys His Tyr Tyr Pro
370
#   375
#   380
Glu Asn Val Lys Pro Lys Pro Lys Leu Lys Gl
#u Cys Ser Met Asp Pro
385                 3
#90                 3
#95                 4
#00
Cys Pro Ser Ser Asp Gly Phe Lys Glu Ile Me
#t Pro Tyr Asp His Phe
405
#               410
#               415
Gln Pro Leu Pro Arg Trp Glu His Asn Pro Tr
#p Thr Ala Cys Ser Val
420
#           425
#           430
Ser Cys Gly Gly Gly Ile Gln Arg Arg Ser Ph
#e Val Cys Val Glu Glu
435
#       440
#       445
Ser Met His Gly Glu Ile Leu Gln Val Glu Gl
#u Trp Lys Cys Met Tyr
450
#   455
#   460
Ala Pro Lys Pro Lys Val Met Gln Thr Cys As
#n Leu Phe Asp Cys Pro
465                 4
#70                 4
#75                 4
#80
Lys Trp Ile Ala Met Glu Trp Ser Gln Cys Th
#r Val Thr Cys Gly Arg
485
#               490
#               495
Gly Leu Arg Tyr Arg Val Val Leu Cys Ile As
#n His Arg Gly Glu His
500
#           505
#           510
Val Gly Gly Cys Asn Pro Gln Leu Lys Leu Hi
#s Ile Lys Glu Glu Cys
515
#       520
#       525
Val Ile Pro Ile Pro Cys Tyr Lys Pro Lys Gl
#u Lys Ser Pro Val Glu
530
#   535
#   540
Ala Lys Leu Pro Trp Leu Lys Gln Ala Gln Gl
#u Leu Glu Glu Thr Arg
545                 5
#50                 5
#55                 5
#60
Ile Ala Thr Glu Glu Pro Thr Phe Ile Pro Gl
#u Pro Trp Ser Ala Cys
565
#               570
#               575
Ser Thr Thr Cys Gly Pro Gly Val Gln Val Ar
#g Glu Val Lys Cys Arg
580
#           585
#           590
Val Leu Leu Thr Phe Thr Gln Thr Glu Thr Gl
#u Leu Pro Glu Glu Glu
595
#       600
#       605
Cys Glu Gly Pro Lys Leu Pro Thr Glu Arg Pr
#o Cys Leu Leu Glu Ala
610
#   615
#   620
Cys Asp Glu Ser Pro Ala Ser Arg Glu Leu As
#p Ile Pro Leu Pro Glu
625                 6
#30                 6
#35                 6
#40
Asp Ser Glu Thr Thr Tyr Asp Trp Glu Tyr Al
#a Gly Phe Thr Pro Cys
645
#               650
#               655
Thr Ala Thr Cys Leu Gly Gly His Gln Glu Al
#a Ile Ala Val Cys Leu
660
#           665
#           670
His Ile Gln Thr Gln Gln Thr Val Asn Asp Se
#r Leu Cys Asp Met Val
675
#       680
#       685
His Arg Pro Pro Ala Met Ser Gln Ala Cys As
#n Thr Glu Pro Cys Pro
690
#   695
#   700
Pro Arg Arg Glu Pro Ala Ala Cys Arg Ser Me
#t Pro Gly Tyr Ile Met
705                 7
#10                 7
#15                 7
#20
Val Leu Leu Val
<210> SEQ ID NO 9
<211> LENGTH: 1953
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 9
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggaaggaatt gtgaagggca ga
#acattcgg    120
tacaagacat gcagcaatca tgactgccct ccagatgcag aagatttcag ag
#cccagcag    180
tgctcagcct acaatgatgt ccagtatcag gggcattact atgaatggct tc
#cacgatat    240
aatgatcctg ctgccccgtg tgcactcaag tgtcatgcac aaggacaaaa ct
#tggtggtg    300
gagctggcac ctaaggtact ggatggaact cgttgcaaca cggactcctt gg
#acatgtgt    360
atcagtggca tctgtcaggc agtgggctgc gatcggcaac tgggaagcaa tg
#ccaaggag    420
gacaactgtg gagtctgtgc cggcgatggc tccacctgca ggcttgtacg gg
#gacaatca    480
aagtcacacg tttctcctga aaaaagagaa gaaaatgtaa ttgctgttcc tt
#tgggaagt    540
cgaagtgtga gaattacagt gaaaggacct gcccacctct ttattgaatc aa
#aaacactt    600
caaggaagca aaggagaaca cagctttaac agccccggcg tctttgtcgt ag
#aaaacaca    660
acagtggaat ttcagagggg ctccgagagg caaactttta agattccagg ac
#ctctgatg    720
gctgatttca tcttcaagac caggtacact gcagccaaag acagcgtggt tc
#agttcttc    780
ttttaccagc ccatcagtca tcagtggaga caaactgact tctttccctg ca
#ctgtgacg    840
tgtggaggag gttatcagct caattctgct gaatgtgtgg atatccgctt ga
#agagggta    900
gttcctgacc attattgtca ctactaccct gaaaatgtaa aaccaaaacc aa
#aactgaag    960
gaatgcagca tggatccctg cccatcaagt gatggattta aagagataat gc
#cctatgac   1020
cacttccaac ctcttcctcg ctgggaacat aatccttgga ctgcatgttc cg
#tgtcctgt   1080
ggaggaggga ttcagagacg gagctttgtg tgtgtagagg aatccatgca tg
#gagagata   1140
ttgcaggtgg aagaatggaa gtgcatgtac gcacccaaac ccaaggttat gc
#aaacttgt   1200
aatctgtttg attgccccaa gtggattgcc atggagtggt ctcagtgcac ag
#tgacttgt   1260
ggccgagggt tacggtaccg ggttgttctg tgtattaacc accgcggaga gc
#atgttggg   1320
ggctgcaatc cacaactgaa gttacacatc aaagaagaat gtgtcattcc ca
#tcccgtgt   1380
tataaaccaa aagaaaaaag tccagtggaa gcaaaattgc cttggctgaa ac
#aagcacaa   1440
gaactagaag agaccagaat agcaacagaa gaaccaacgt tcattccaga ac
#cctggtca   1500
gcctgcagta ccacgtgtgg gccaggtgtg caggtccgcg aggtgaagtg cc
#gtgtgctc   1560
ctcacattca cgcagactga gactgagctg cccgaggaag agtgtgaagg cc
#ccaagctg   1620
cccaccgaac ggccctgcct cctggaagca tgtgatgaga gcccggcctc cc
#gagagcta   1680
gacatccctc tccctgagga cagtgagacg acttacgact gggagtacgc tg
#ggttcacc   1740
ccttgcacag caacatgctt gggaggccat caagaagcca tagcagtgtg ct
#tacatatc   1800
cagacccagc agacagtcaa tgacagcttg tgtgatatgg tccaccgtcc tc
#cagccatg   1860
agccaggcct gtaacacaga gccctgtccc cccaggagag agccagcagc tt
#gtagaagc   1920
atgccgggtt acataatggt cctgctagtc tga
#
#       1953
<210> SEQ ID NO 10
<211> LENGTH: 650
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 10
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Arg
20
#            25
#            30
Asn Cys Glu Gly Gln Asn Ile Arg Tyr Lys Th
#r Cys Ser Asn His Asp
35
#        40
#        45
Cys Pro Pro Asp Ala Glu Asp Phe Arg Ala Gl
#n Gln Cys Ser Ala Tyr
50
#    55
#    60
Asn Asp Val Gln Tyr Gln Gly His Tyr Tyr Gl
#u Trp Leu Pro Arg Tyr
65
#70
#75
#80
Asn Asp Pro Ala Ala Pro Cys Ala Leu Lys Cy
#s His Ala Gln Gly Gln
85
#                90
#                95
Asn Leu Val Val Glu Leu Ala Pro Lys Val Le
#u Asp Gly Thr Arg Cys
100
#           105
#           110
Asn Thr Asp Ser Leu Asp Met Cys Ile Ser Gl
#y Ile Cys Gln Ala Val
115
#       120
#       125
Gly Cys Asp Arg Gln Leu Gly Ser Asn Ala Ly
#s Glu Asp Asn Cys Gly
130
#   135
#   140
Val Cys Ala Gly Asp Gly Ser Thr Cys Arg Le
#u Val Arg Gly Gln Ser
145                 1
#50                 1
#55                 1
#60
Lys Ser His Val Ser Pro Glu Lys Arg Glu Gl
#u Asn Val Ile Ala Val
165
#               170
#               175
Pro Leu Gly Ser Arg Ser Val Arg Ile Thr Va
#l Lys Gly Pro Ala His
180
#           185
#           190
Leu Phe Ile Glu Ser Lys Thr Leu Gln Gly Se
#r Lys Gly Glu His Ser
195
#       200
#       205
Phe Asn Ser Pro Gly Val Phe Val Val Glu As
#n Thr Thr Val Glu Phe
210
#   215
#   220
Gln Arg Gly Ser Glu Arg Gln Thr Phe Lys Il
#e Pro Gly Pro Leu Met
225                 2
#30                 2
#35                 2
#40
Ala Asp Phe Ile Phe Lys Thr Arg Tyr Thr Al
#a Ala Lys Asp Ser Val
245
#               250
#               255
Val Gln Phe Phe Phe Tyr Gln Pro Ile Ser Hi
#s Gln Trp Arg Gln Thr
260
#           265
#           270
Asp Phe Phe Pro Cys Thr Val Thr Cys Gly Gl
#y Gly Tyr Gln Leu Asn
275
#       280
#       285
Ser Ala Glu Cys Val Asp Ile Arg Leu Lys Ar
#g Val Val Pro Asp His
290
#   295
#   300
Tyr Cys His Tyr Tyr Pro Glu Asn Val Lys Pr
#o Lys Pro Lys Leu Lys
305                 3
#10                 3
#15                 3
#20
Glu Cys Ser Met Asp Pro Cys Pro Ser Ser As
#p Gly Phe Lys Glu Ile
325
#               330
#               335
Met Pro Tyr Asp His Phe Gln Pro Leu Pro Ar
#g Trp Glu His Asn Pro
340
#           345
#           350
Trp Thr Ala Cys Ser Val Ser Cys Gly Gly Gl
#y Ile Gln Arg Arg Ser
355
#       360
#       365
Phe Val Cys Val Glu Glu Ser Met His Gly Gl
#u Ile Leu Gln Val Glu
370
#   375
#   380
Glu Trp Lys Cys Met Tyr Ala Pro Lys Pro Ly
#s Val Met Gln Thr Cys
385                 3
#90                 3
#95                 4
#00
Asn Leu Phe Asp Cys Pro Lys Trp Ile Ala Me
#t Glu Trp Ser Gln Cys
405
#               410
#               415
Thr Val Thr Cys Gly Arg Gly Leu Arg Tyr Ar
#g Val Val Leu Cys Ile
420
#           425
#           430
Asn His Arg Gly Glu His Val Gly Gly Cys As
#n Pro Gln Leu Lys Leu
435
#       440
#       445
His Ile Lys Glu Glu Cys Val Ile Pro Ile Pr
#o Cys Tyr Lys Pro Lys
450
#   455
#   460
Glu Lys Ser Pro Val Glu Ala Lys Leu Pro Tr
#p Leu Lys Gln Ala Gln
465                 4
#70                 4
#75                 4
#80
Glu Leu Glu Glu Thr Arg Ile Ala Thr Glu Gl
#u Pro Thr Phe Ile Pro
485
#               490
#               495
Glu Pro Trp Ser Ala Cys Ser Thr Thr Cys Gl
#y Pro Gly Val Gln Val
500
#           505
#           510
Arg Glu Val Lys Cys Arg Val Leu Leu Thr Ph
#e Thr Gln Thr Glu Thr
515
#       520
#       525
Glu Leu Pro Glu Glu Glu Cys Glu Gly Pro Ly
#s Leu Pro Thr Glu Arg
530
#   535
#   540
Pro Cys Leu Leu Glu Ala Cys Asp Glu Ser Pr
#o Ala Ser Arg Glu Leu
545                 5
#50                 5
#55                 5
#60
Asp Ile Pro Leu Pro Glu Asp Ser Glu Thr Th
#r Tyr Asp Trp Glu Tyr
565
#               570
#               575
Ala Gly Phe Thr Pro Cys Thr Ala Thr Cys Le
#u Gly Gly His Gln Glu
580
#           585
#           590
Ala Ile Ala Val Cys Leu His Ile Gln Thr Gl
#n Gln Thr Val Asn Asp
595
#       600
#       605
Ser Leu Cys Asp Met Val His Arg Pro Pro Al
#a Met Ser Gln Ala Cys
610
#   615
#   620
Asn Thr Glu Pro Cys Pro Pro Arg Arg Glu Pr
#o Ala Ala Cys Arg Ser
625                 6
#30                 6
#35                 6
#40
Met Pro Gly Tyr Ile Met Val Leu Leu Val
645
#               650
<210> SEQ ID NO 11
<211> LENGTH: 2538
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 11
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggagcctatt tccttcccga gt
#ttgcactt    120
tctcctcagg gaagttttct ggaagacaca acaggggagc agttcctcac tt
#atcgctat    180
gatgaccaga cctcaagaaa cactcgttca gatgaagaca aagatggcaa ct
#gggatgct    240
tggggcgact ggagtgactg ctcccggacc tgtgggggag gagcatcata tt
#ctctgcgg    300
agatgtttga ctggaaggaa ttgtgaaggg cagaacattc ggtacaagac at
#gcagcaat    360
catgactgcc ctccagatgc agaagatttc agagcccagc agtgctcagc ct
#acaatgat    420
gtccagtatc aggggcatta ctatgaatgg cttccacgat ataatgatcc tg
#ctgccccg    480
tgtgcactca agtgtcatgc acaaggacaa aacttggtgg tggagctggc ac
#ctaaggta    540
ctggatggaa ctcgttgcaa cacggactcc ttggacatgt gtatcagtgg ca
#tctgtcag    600
gcagtgggct gcgatcggca actgggaagc aatgccaagg aggacaactg tg
#gagtctgt    660
gccggcgatg gctccacctg caggcttgta cggggacaat caaagtcaca cg
#tttctcct    720
gaaaaaagag aagaaaatgt aattgctgtt cctttgggaa gtcgaagtgt ga
#gaattaca    780
gtgaaaggac ctgcccacct ctttattgaa tcaaaaacac ttcaaggaag ca
#aaggagaa    840
cacagcttta acagccccgg cgtctttgtc gtagaaaaca caacagtgga at
#ttcagagg    900
ggctccgaga ggcaaacttt taagattcca ggacctctga tggctgattt ca
#tcttcaag    960
accaggtaca ctgcagccaa agacagcgtg gttcagttct tcttttacca gc
#ccatcagt   1020
catcagtgga gacaaactga cttctttccc tgcactgtga cgtgtggagg ag
#gttatcag   1080
ctcaattctg ctgaatgtgt ggatatccgc ttgaagaggg tagttcctga cc
#attattgt   1140
cactactacc ctgaaaatgt aaaaccaaaa ccaaaactga aggaatgcag ca
#tggatccc   1200
tgcccatcaa gtgatggatt taaagagata atgccctatg accacttcca ac
#ctcttcct   1260
cgctgggaac ataatccttg gactgcatgt tccgtgtcct gtggaggagg ga
#ttcagaga   1320
cggagctttg tgtgtgtaga ggaatccatg catggagaga tattgcaggt gg
#aagaatgg   1380
aagtgcatgt acgcacccaa acccaaggtt atgcaaactt gtaatctgtt tg
#attgcccc   1440
aagtggattg ccatggagtg gtctcagtgc acagtgactt gtggccgagg gt
#tacggtac   1500
cgggttgttc tgtgtattaa ccaccgcgga gagcatgttg ggggctgcaa tc
#cacaactg   1560
aagttacaca tcaaagaaga atgtgtcatt cccatcccgt gttataaacc aa
#aagaaaaa   1620
agtccagtgg aagcaaaatt gccttggctg aaacaagcac aagaactaga ag
#agaccaga   1680
atagcaacag aagaaccaac gttcattcca gaaccctggt cagcctgcag ta
#ccacgtgt   1740
gggccaggtg tgcaggtccg cgaggtgaag tgccgtgtgc tcctcacatt ca
#cgcagact   1800
gagactgagc tgcccgagga agagtgtgaa ggccccaagc tgcccaccga ac
#ggccctgc   1860
ctcctggaag catgtgatga gagcccggcc tcccgagagc tagacatccc tc
#tccctgag   1920
gacagtgaga cgacttacga ctgggagtac gctgggttca ccccttgcac ag
#caacatgc   1980
ttgggaggcc atcaagaagc catagcagtg tgcttacata tccagaccca gc
#agacagtc   2040
aatgacagct tgtgtgatat ggtccaccgt cctccagcca tgagccaggc ct
#gtaacaca   2100
gagccctgtc cccccaggtg gcatgtgggc tcttgggggc cctgctcagc ta
#cctgtgga   2160
gttggaattc agacccgaga tgtgtactgc ctgcacccag gggagacccc tg
#cccctcct   2220
gaggagtgcc gagatgaaaa gccccatgct ttacaagcat gcaatcagtt tg
#actgccct   2280
cctggctggc acattgaaga atggcagcag tgttccagga cttgtggcgg gg
#gaactcag   2340
aacagaagag tcacctgtcg gcagctgcta acggatggca gctttttgaa tc
#tctcagat   2400
gaattgtgcc aaggacccaa ggcatcgtct cacaagtcct gtgccaggac ag
#actgtcct   2460
ccacatttag ctgtgggaga ctggtcgaag gagcattcaa tgcaagagga ca
#atggagca   2520
ggatctacac aattctaa
#
#
#2538
<210> SEQ ID NO 12
<211> LENGTH: 845
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 12
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Ala
20
#            25
#            30
Tyr Phe Leu Pro Glu Phe Ala Leu Ser Pro Gl
#n Gly Ser Phe Leu Glu
35
#        40
#        45
Asp Thr Thr Gly Glu Gln Phe Leu Thr Tyr Ar
#g Tyr Asp Asp Gln Thr
50
#    55
#    60
Ser Arg Asn Thr Arg Ser Asp Glu Asp Lys As
#p Gly Asn Trp Asp Ala
65
#70
#75
#80
Trp Gly Asp Trp Ser Asp Cys Ser Arg Thr Cy
#s Gly Gly Gly Ala Ser
85
#                90
#                95
Tyr Ser Leu Arg Arg Cys Leu Thr Gly Arg As
#n Cys Glu Gly Gln Asn
100
#           105
#           110
Ile Arg Tyr Lys Thr Cys Ser Asn His Asp Cy
#s Pro Pro Asp Ala Glu
115
#       120
#       125
Asp Phe Arg Ala Gln Gln Cys Ser Ala Tyr As
#n Asp Val Gln Tyr Gln
130
#   135
#   140
Gly His Tyr Tyr Glu Trp Leu Pro Arg Tyr As
#n Asp Pro Ala Ala Pro
145                 1
#50                 1
#55                 1
#60
Cys Ala Leu Lys Cys His Ala Gln Gly Gln As
#n Leu Val Val Glu Leu
165
#               170
#               175
Ala Pro Lys Val Leu Asp Gly Thr Arg Cys As
#n Thr Asp Ser Leu Asp
180
#           185
#           190
Met Cys Ile Ser Gly Ile Cys Gln Ala Val Gl
#y Cys Asp Arg Gln Leu
195
#       200
#       205
Gly Ser Asn Ala Lys Glu Asp Asn Cys Gly Va
#l Cys Ala Gly Asp Gly
210
#   215
#   220
Ser Thr Cys Arg Leu Val Arg Gly Gln Ser Ly
#s Ser His Val Ser Pro
225                 2
#30                 2
#35                 2
#40
Glu Lys Arg Glu Glu Asn Val Ile Ala Val Pr
#o Leu Gly Ser Arg Ser
245
#               250
#               255
Val Arg Ile Thr Val Lys Gly Pro Ala His Le
#u Phe Ile Glu Ser Lys
260
#           265
#           270
Thr Leu Gln Gly Ser Lys Gly Glu His Ser Ph
#e Asn Ser Pro Gly Val
275
#       280
#       285
Phe Val Val Glu Asn Thr Thr Val Glu Phe Gl
#n Arg Gly Ser Glu Arg
290
#   295
#   300
Gln Thr Phe Lys Ile Pro Gly Pro Leu Met Al
#a Asp Phe Ile Phe Lys
305                 3
#10                 3
#15                 3
#20
Thr Arg Tyr Thr Ala Ala Lys Asp Ser Val Va
#l Gln Phe Phe Phe Tyr
325
#               330
#               335
Gln Pro Ile Ser His Gln Trp Arg Gln Thr As
#p Phe Phe Pro Cys Thr
340
#           345
#           350
Val Thr Cys Gly Gly Gly Tyr Gln Leu Asn Se
#r Ala Glu Cys Val Asp
355
#       360
#       365
Ile Arg Leu Lys Arg Val Val Pro Asp His Ty
#r Cys His Tyr Tyr Pro
370
#   375
#   380
Glu Asn Val Lys Pro Lys Pro Lys Leu Lys Gl
#u Cys Ser Met Asp Pro
385                 3
#90                 3
#95                 4
#00
Cys Pro Ser Ser Asp Gly Phe Lys Glu Ile Me
#t Pro Tyr Asp His Phe
405
#               410
#               415
Gln Pro Leu Pro Arg Trp Glu His Asn Pro Tr
#p Thr Ala Cys Ser Val
420
#           425
#           430
Ser Cys Gly Gly Gly Ile Gln Arg Arg Ser Ph
#e Val Cys Val Glu Glu
435
#       440
#       445
Ser Met His Gly Glu Ile Leu Gln Val Glu Gl
#u Trp Lys Cys Met Tyr
450
#   455
#   460
Ala Pro Lys Pro Lys Val Met Gln Thr Cys As
#n Leu Phe Asp Cys Pro
465                 4
#70                 4
#75                 4
#80
Lys Trp Ile Ala Met Glu Trp Ser Gln Cys Th
#r Val Thr Cys Gly Arg
485
#               490
#               495
Gly Leu Arg Tyr Arg Val Val Leu Cys Ile As
#n His Arg Gly Glu His
500
#           505
#           510
Val Gly Gly Cys Asn Pro Gln Leu Lys Leu Hi
#s Ile Lys Glu Glu Cys
515
#       520
#       525
Val Ile Pro Ile Pro Cys Tyr Lys Pro Lys Gl
#u Lys Ser Pro Val Glu
530
#   535
#   540
Ala Lys Leu Pro Trp Leu Lys Gln Ala Gln Gl
#u Leu Glu Glu Thr Arg
545                 5
#50                 5
#55                 5
#60
Ile Ala Thr Glu Glu Pro Thr Phe Ile Pro Gl
#u Pro Trp Ser Ala Cys
565
#               570
#               575
Ser Thr Thr Cys Gly Pro Gly Val Gln Val Ar
#g Glu Val Lys Cys Arg
580
#           585
#           590
Val Leu Leu Thr Phe Thr Gln Thr Glu Thr Gl
#u Leu Pro Glu Glu Glu
595
#       600
#       605
Cys Glu Gly Pro Lys Leu Pro Thr Glu Arg Pr
#o Cys Leu Leu Glu Ala
610
#   615
#   620
Cys Asp Glu Ser Pro Ala Ser Arg Glu Leu As
#p Ile Pro Leu Pro Glu
625                 6
#30                 6
#35                 6
#40
Asp Ser Glu Thr Thr Tyr Asp Trp Glu Tyr Al
#a Gly Phe Thr Pro Cys
645
#               650
#               655
Thr Ala Thr Cys Leu Gly Gly His Gln Glu Al
#a Ile Ala Val Cys Leu
660
#           665
#           670
His Ile Gln Thr Gln Gln Thr Val Asn Asp Se
#r Leu Cys Asp Met Val
675
#       680
#       685
His Arg Pro Pro Ala Met Ser Gln Ala Cys As
#n Thr Glu Pro Cys Pro
690
#   695
#   700
Pro Arg Trp His Val Gly Ser Trp Gly Pro Cy
#s Ser Ala Thr Cys Gly
705                 7
#10                 7
#15                 7
#20
Val Gly Ile Gln Thr Arg Asp Val Tyr Cys Le
#u His Pro Gly Glu Thr
725
#               730
#               735
Pro Ala Pro Pro Glu Glu Cys Arg Asp Glu Ly
#s Pro His Ala Leu Gln
740
#           745
#           750
Ala Cys Asn Gln Phe Asp Cys Pro Pro Gly Tr
#p His Ile Glu Glu Trp
755
#       760
#       765
Gln Gln Cys Ser Arg Thr Cys Gly Gly Gly Th
#r Gln Asn Arg Arg Val
770
#   775
#   780
Thr Cys Arg Gln Leu Leu Thr Asp Gly Ser Ph
#e Leu Asn Leu Ser Asp
785                 7
#90                 7
#95                 8
#00
Glu Leu Cys Gln Gly Pro Lys Ala Ser Ser Hi
#s Lys Ser Cys Ala Arg
805
#               810
#               815
Thr Asp Cys Pro Pro His Leu Ala Val Gly As
#p Trp Ser Lys Glu His
820
#           825
#           830
Ser Met Gln Glu Asp Asn Gly Ala Gly Ser Th
#r Gln Phe
835
#       840
#       845
<210> SEQ ID NO 13
<211> LENGTH: 2316
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 13
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggaaggaatt gtgaagggca ga
#acattcgg    120
tacaagacat gcagcaatca tgactgccct ccagatgcag aagatttcag ag
#cccagcag    180
tgctcagcct acaatgatgt ccagtatcag gggcattact atgaatggct tc
#cacgatat    240
aatgatcctg ctgccccgtg tgcactcaag tgtcatgcac aaggacaaaa ct
#tggtggtg    300
gagctggcac ctaaggtact ggatggaact cgttgcaaca cggactcctt gg
#acatgtgt    360
atcagtggca tctgtcaggc agtgggctgc gatcggcaac tgggaagcaa tg
#ccaaggag    420
gacaactgtg gagtctgtgc cggcgatggc tccacctgca ggcttgtacg gg
#gacaatca    480
aagtcacacg tttctcctga aaaaagagaa gaaaatgtaa ttgctgttcc tt
#tgggaagt    540
cgaagtgtga gaattacagt gaaaggacct gcccacctct ttattgaatc aa
#aaacactt    600
caaggaagca aaggagaaca cagctttaac agccccggcg tctttgtcgt ag
#aaaacaca    660
acagtggaat ttcagagggg ctccgagagg caaactttta agattccagg ac
#ctctgatg    720
gctgatttca tcttcaagac caggtacact gcagccaaag acagcgtggt tc
#agttcttc    780
ttttaccagc ccatcagtca tcagtggaga caaactgact tctttccctg ca
#ctgtgacg    840
tgtggaggag gttatcagct caattctgct gaatgtgtgg atatccgctt ga
#agagggta    900
gttcctgacc attattgtca ctactaccct gaaaatgtaa aaccaaaacc aa
#aactgaag    960
gaatgcagca tggatccctg cccatcaagt gatggattta aagagataat gc
#cctatgac   1020
cacttccaac ctcttcctcg ctgggaacat aatccttgga ctgcatgttc cg
#tgtcctgt   1080
ggaggaggga ttcagagacg gagctttgtg tgtgtagagg aatccatgca tg
#gagagata   1140
ttgcaggtgg aagaatggaa gtgcatgtac gcacccaaac ccaaggttat gc
#aaacttgt   1200
aatctgtttg attgccccaa gtggattgcc atggagtggt ctcagtgcac ag
#tgacttgt   1260
ggccgagggt tacggtaccg ggttgttctg tgtattaacc accgcggaga gc
#atgttggg   1320
ggctgcaatc cacaactgaa gttacacatc aaagaagaat gtgtcattcc ca
#tcccgtgt   1380
tataaaccaa aagaaaaaag tccagtggaa gcaaaattgc cttggctgaa ac
#aagcacaa   1440
gaactagaag agaccagaat agcaacagaa gaaccaacgt tcattccaga ac
#cctggtca   1500
gcctgcagta ccacgtgtgg gccaggtgtg caggtccgcg aggtgaagtg cc
#gtgtgctc   1560
ctcacattca cgcagactga gactgagctg cccgaggaag agtgtgaagg cc
#ccaagctg   1620
cccaccgaac ggccctgcct cctggaagca tgtgatgaga gcccggcctc cc
#gagagcta   1680
gacatccctc tccctgagga cagtgagacg acttacgact gggagtacgc tg
#ggttcacc   1740
ccttgcacag caacatgctt gggaggccat caagaagcca tagcagtgtg ct
#tacatatc   1800
cagacccagc agacagtcaa tgacagcttg tgtgatatgg tccaccgtcc tc
#cagccatg   1860
agccaggcct gtaacacaga gccctgtccc cccaggtggc atgtgggctc tt
#gggggccc   1920
tgctcagcta cctgtggagt tggaattcag acccgagatg tgtactgcct gc
#acccaggg   1980
gagacccctg cccctcctga ggagtgccga gatgaaaagc cccatgcttt ac
#aagcatgc   2040
aatcagtttg actgccctcc tggctggcac attgaagaat ggcagcagtg tt
#ccaggact   2100
tgtggcgggg gaactcagaa cagaagagtc acctgtcggc agctgctaac gg
#atggcagc   2160
tttttgaatc tctcagatga attgtgccaa ggacccaagg catcgtctca ca
#agtcctgt   2220
gccaggacag actgtcctcc acatttagct gtgggagact ggtcgaagga gc
#attcaatg   2280
caagaggaca atggagcagg atctacacaa ttctaa
#
#     2316
<210> SEQ ID NO 14
<211> LENGTH: 771
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 14
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Arg
20
#            25
#            30
Asn Cys Glu Gly Gln Asn Ile Arg Tyr Lys Th
#r Cys Ser Asn His Asp
35
#        40
#        45
Cys Pro Pro Asp Ala Glu Asp Phe Arg Ala Gl
#n Gln Cys Ser Ala Tyr
50
#    55
#    60
Asn Asp Val Gln Tyr Gln Gly His Tyr Tyr Gl
#u Trp Leu Pro Arg Tyr
65
#70
#75
#80
Asn Asp Pro Ala Ala Pro Cys Ala Leu Lys Cy
#s His Ala Gln Gly Gln
85
#                90
#                95
Asn Leu Val Val Glu Leu Ala Pro Lys Val Le
#u Asp Gly Thr Arg Cys
100
#           105
#           110
Asn Thr Asp Ser Leu Asp Met Cys Ile Ser Gl
#y Ile Cys Gln Ala Val
115
#       120
#       125
Gly Cys Asp Arg Gln Leu Gly Ser Asn Ala Ly
#s Glu Asp Asn Cys Gly
130
#   135
#   140
Val Cys Ala Gly Asp Gly Ser Thr Cys Arg Le
#u Val Arg Gly Gln Ser
145                 1
#50                 1
#55                 1
#60
Lys Ser His Val Ser Pro Glu Lys Arg Glu Gl
#u Asn Val Ile Ala Val
165
#               170
#               175
Pro Leu Gly Ser Arg Ser Val Arg Ile Thr Va
#l Lys Gly Pro Ala His
180
#           185
#           190
Leu Phe Ile Glu Ser Lys Thr Leu Gln Gly Se
#r Lys Gly Glu His Ser
195
#       200
#       205
Phe Asn Ser Pro Gly Val Phe Val Val Glu As
#n Thr Thr Val Glu Phe
210
#   215
#   220
Gln Arg Gly Ser Glu Arg Gln Thr Phe Lys Il
#e Pro Gly Pro Leu Met
225                 2
#30                 2
#35                 2
#40
Ala Asp Phe Ile Phe Lys Thr Arg Tyr Thr Al
#a Ala Lys Asp Ser Val
245
#               250
#               255
Val Gln Phe Phe Phe Tyr Gln Pro Ile Ser Hi
#s Gln Trp Arg Gln Thr
260
#           265
#           270
Asp Phe Phe Pro Cys Thr Val Thr Cys Gly Gl
#y Gly Tyr Gln Leu Asn
275
#       280
#       285
Ser Ala Glu Cys Val Asp Ile Arg Leu Lys Ar
#g Val Val Pro Asp His
290
#   295
#   300
Tyr Cys His Tyr Tyr Pro Glu Asn Val Lys Pr
#o Lys Pro Lys Leu Lys
305                 3
#10                 3
#15                 3
#20
Glu Cys Ser Met Asp Pro Cys Pro Ser Ser As
#p Gly Phe Lys Glu Ile
325
#               330
#               335
Met Pro Tyr Asp His Phe Gln Pro Leu Pro Ar
#g Trp Glu His Asn Pro
340
#           345
#           350
Trp Thr Ala Cys Ser Val Ser Cys Gly Gly Gl
#y Ile Gln Arg Arg Ser
355
#       360
#       365
Phe Val Cys Val Glu Glu Ser Met His Gly Gl
#u Ile Leu Gln Val Glu
370
#   375
#   380
Glu Trp Lys Cys Met Tyr Ala Pro Lys Pro Ly
#s Val Met Gln Thr Cys
385                 3
#90                 3
#95                 4
#00
Asn Leu Phe Asp Cys Pro Lys Trp Ile Ala Me
#t Glu Trp Ser Gln Cys
405
#               410
#               415
Thr Val Thr Cys Gly Arg Gly Leu Arg Tyr Ar
#g Val Val Leu Cys Ile
420
#           425
#           430
Asn His Arg Gly Glu His Val Gly Gly Cys As
#n Pro Gln Leu Lys Leu
435
#       440
#       445
His Ile Lys Glu Glu Cys Val Ile Pro Ile Pr
#o Cys Tyr Lys Pro Lys
450
#   455
#   460
Glu Lys Ser Pro Val Glu Ala Lys Leu Pro Tr
#p Leu Lys Gln Ala Gln
465                 4
#70                 4
#75                 4
#80
Glu Leu Glu Glu Thr Arg Ile Ala Thr Glu Gl
#u Pro Thr Phe Ile Pro
485
#               490
#               495
Glu Pro Trp Ser Ala Cys Ser Thr Thr Cys Gl
#y Pro Gly Val Gln Val
500
#           505
#           510
Arg Glu Val Lys Cys Arg Val Leu Leu Thr Ph
#e Thr Gln Thr Glu Thr
515
#       520
#       525
Glu Leu Pro Glu Glu Glu Cys Glu Gly Pro Ly
#s Leu Pro Thr Glu Arg
530
#   535
#   540
Pro Cys Leu Leu Glu Ala Cys Asp Glu Ser Pr
#o Ala Ser Arg Glu Leu
545                 5
#50                 5
#55                 5
#60
Asp Ile Pro Leu Pro Glu Asp Ser Glu Thr Th
#r Tyr Asp Trp Glu Tyr
565
#               570
#               575
Ala Gly Phe Thr Pro Cys Thr Ala Thr Cys Le
#u Gly Gly His Gln Glu
580
#           585
#           590
Ala Ile Ala Val Cys Leu His Ile Gln Thr Gl
#n Gln Thr Val Asn Asp
595
#       600
#       605
Ser Leu Cys Asp Met Val His Arg Pro Pro Al
#a Met Ser Gln Ala Cys
610
#   615
#   620
Asn Thr Glu Pro Cys Pro Pro Arg Trp His Va
#l Gly Ser Trp Gly Pro
625                 6
#30                 6
#35                 6
#40
Cys Ser Ala Thr Cys Gly Val Gly Ile Gln Th
#r Arg Asp Val Tyr Cys
645
#               650
#               655
Leu His Pro Gly Glu Thr Pro Ala Pro Pro Gl
#u Glu Cys Arg Asp Glu
660
#           665
#           670
Lys Pro His Ala Leu Gln Ala Cys Asn Gln Ph
#e Asp Cys Pro Pro Gly
675
#       680
#       685
Trp His Ile Glu Glu Trp Gln Gln Cys Ser Ar
#g Thr Cys Gly Gly Gly
690
#   695
#   700
Thr Gln Asn Arg Arg Val Thr Cys Arg Gln Le
#u Leu Thr Asp Gly Ser
705                 7
#10                 7
#15                 7
#20
Phe Leu Asn Leu Ser Asp Glu Leu Cys Gln Gl
#y Pro Lys Ala Ser Ser
725
#               730
#               735
His Lys Ser Cys Ala Arg Thr Asp Cys Pro Pr
#o His Leu Ala Val Gly
740
#           745
#           750
Asp Trp Ser Lys Glu His Ser Met Gln Glu As
#p Asn Gly Ala Gly Ser
755
#       760
#       765
Thr Gln Phe
770
<210> SEQ ID NO 15
<211> LENGTH: 4854
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 15
atggcttcct ggacgagccc ctggtgggtg ctgataggga tggtcttcat gc
#actctccc     60
ctcccgcaga ccacagctga gaaatctcct ggaaggaatt gtgaagggca ga
#acattcgg    120
tacaagacat gcagcaatca tgactgccct ccagatgcag aagatttcag ag
#cccagcag    180
tgctcagcct acaatgatgt ccagtatcag gggcattact atgaatggct tc
#cacgatat    240
aatgatcctg ctgccccgtg tgcactcaag tgtcatgcac aaggacaaaa ct
#tggtggtg    300
gagctggcac ctaaggtact ggatggaact cgttgcaaca cggactcctt gg
#acatgtgt    360
atcagtggca tctgtcaggc agtgggctgc gatcggcaac tgggaagcaa tg
#ccaaggag    420
gacaactgtg gagtctgtgc cggcgatggc tccacctgca ggcttgtacg gg
#gacaatca    480
aagtcacacg tttctcctga aaaaagagaa gaaaatgtaa ttgctgttcc tt
#tgggaagt    540
cgaagtgtga gaattacagt gaaaggacct gcccacctct ttattgaatc aa
#aaacactt    600
caaggaagca aaggagaaca cagctttaac agccccggcg tctttgtcgt ag
#aaaacaca    660
acagtggaat ttcagagggg ctccgagagg caaactttta agattccagg ac
#ctctgatg    720
gctgatttca tcttcaagac caggtacact gcagccaaag acagcgtggt tc
#agttcttc    780
ttttaccagc ccatcagtca tcagtggaga caaactgact tctttccctg ca
#ctgtgacg    840
tgtggaggag gttatcagct caattctgct gaatgtgtgg atatccgctt ga
#agagggta    900
gttcctgacc attattgtca ctactaccct gaaaatgtaa aaccaaaacc aa
#aactgaag    960
gaatgcagca tggatccctg cccatcaagt gatggattta aagagataat gc
#cctatgac   1020
cacttccaac ctcttcctcg ctgggaacat aatccttgga ctgcatgttc cg
#tgtcctgt   1080
ggaggaggga ttcagagacg gagctttgtg tgtgtagagg aatccatgca tg
#gagagata   1140
ttgcaggtgg aagaatggaa gtgcatgtac gcacccaaac ccaaggttat gc
#aaacttgt   1200
aatctgtttg attgccccaa gtggattgcc atggagtggt ctcagtgcac ag
#tgacttgt   1260
ggccgagggt tacggtaccg ggttgttctg tgtattaacc accgcggaga gc
#atgttggg   1320
ggctgcaatc cacaactgaa gttacacatc aaagaagaat gtgtcattcc ca
#tcccgtgt   1380
tataaaccaa aagaaaaaag tccagtggaa gcaaaattgc cttggctgaa ac
#aagcacaa   1440
gaactagaag agaccagaat agcaacagaa gaaccaacgt tcattccaga ac
#cctggtca   1500
gcctgcagta ccacgtgtgg gccaggtgtg caggtccgcg aggtgaagtg cc
#gtgtgctc   1560
ctcacattca cgcagactga gactgagctg cccgaggaag agtgtgaagg cc
#ccaagctg   1620
cccaccgaac ggccctgcct cctggaagca tgtgatgaga gcccggcctc cc
#gagagcta   1680
gacatccctc tccctgagga cagtgagacg acttacgact gggagtacgc tg
#ggttcacc   1740
ccttgcacag caacatgctt gggaggccat caagaagcca tagcagtgtg ct
#tacatatc   1800
cagacccagc agacagtcaa tgacagcttg tgtgatatgg tccaccgtcc tc
#cagccatg   1860
agccaggcct gtaacacaga gccctgtccc cccaggtggc atgtgggctc tt
#gggggccc   1920
tgctcagcta cctgtggagt tggaattcag acccgagatg tgtactgcct gc
#acccaggg   1980
gagacccctg cccctcctga ggagtgccga gatgaaaagc cccatgcttt ac
#aagcatgc   2040
aatcagtttg actgccctcc tggctggcac attgaagaat ggcagcagtg tt
#ccaggact   2100
tgtggcgggg gaactcagaa cagaagagtc acctgtcggc agctgctaac gg
#atggcagc   2160
tttttgaatc tctcagatga attgtgccaa ggacccaagg catcgtctca ca
#agtcctgt   2220
gccaggacag actgtcctcc acatttagct gtgggagact ggtcgaagtg tt
#ctgtcagt   2280
tgtggtgttg gaatccagag aagaaagcag gtgtgtcaaa ggctggcagc ca
#aaggtcgg   2340
cgcatccccc tcagtgagat gatgtgcagg gatctaccag ggttccctct tg
#taagatct   2400
tgccagatgc ctgagtgcag taaaatcaaa tcagagatga agacaaaact tg
#gtgagcag   2460
ggtccgcaga tcctcagtgt ccagagagtc tacattcaga caagggaaga ga
#agcgtatt   2520
aacctgacca ttggtagcag agcctatttg ctgcccaaca catccgtgat ta
#ttaagtgc   2580
cccgtgcgac gattccagaa atctctgatc cagtgggaga aggatggccg tt
#gcctgcag   2640
aactccaaac ggcttggcat caccaagtca ggctcactaa aaatccacgg tc
#ttgctgcc   2700
cccgacatcg gcgtgtaccg gtgcattgca ggctctgcac aggaaacagt tg
#tgctcaag   2760
ctcattggta ctgacaaccg gctcatcgca cgcccagccc tcagggagcc ta
#tgagggaa   2820
tatcctggga tggaccacag cgaagccaat agtttgggag tcacatggca ca
#aaatgagg   2880
caaatgtgga ataacaaaaa tgacctttat ctggatgatg accacattag ta
#accagcct   2940
ttcttgagag ctctgttagg ccactgcagc aattctgcag gaagcaccaa ct
#cctgggag   3000
ttgaagaata agcagtttga agcagcagtt aaacaaggag catatagcat gg
#atacagcc   3060
cagtttgatg agctgataag aaacatgagt cagctcatgg aaaccggaga gg
#tcagcgat   3120
gatcttgcgt cccagctgat atatcagctg gtggccgaat tagccaaggc ac
#agccaaca   3180
cacatgcagt ggcggggcat ccaggaagag acacctcctg ctgctcagct ca
#gaggggaa   3240
acagggagtg tgtcccaaag ctcgcatgca aaaaactcag gcaagctgac at
#tcaagccg   3300
aaaggacctg ttctcatgag gcaaagccaa cctccctcaa tttcatttaa ta
#aaacaata   3360
aattccagga ttggaaatac agtatacatt acaaaaagga cagaggtcat ca
#atatactg   3420
tgtgacctta ttacccccag tgaggccaca tatacatgga ccaaggatgg aa
#ccttgtta   3480
cagccctcag taaaaataat tttggatgga actgggaaga tacagataca ga
#atcctaca   3540
aggaaagaac aaggcatata tgaatgttct gtagctaatc atcttggttc ag
#atgtggaa   3600
agttcttctg tgctgtatgc agaggcacct gtcatcttgt ctgttgaaag aa
#atatcacc   3660
aaaccagagc acaaccatct gtctgttgtg gttggaggca tcgtggaggc ag
#cccttgga   3720
gcaaacgtga caatccgatg tcctgtaaaa ggtgtccctc agcctaatat aa
#cttggttg   3780
aagagaggag gatctctgag tggcaatgtt tccttgcttt tcaatggatc cc
#tgttgttg   3840
cagaatgttt cccttgaaaa tgaaggaacc tacgtctgca tagccaccaa tg
#ctcttgga   3900
aaggcagtgg caacatctgt actccacttg ctggaacgaa gatggccaga ga
#gtagaatc   3960
gtatttctgc aaggacataa aaagtacatt ctccaggcaa ccaacactag aa
#ccaacagc   4020
aatgacccaa caggagaacc cccgcctcaa gagccttttt gggagcctgg ta
#actggtca   4080
cattgttctg ccacctgtgg tcatttggga gcccgcattc agagacccca gt
#gtgtgatg   4140
gccaatgggc aggaagtgag tgaggccctg tgtgatcacc tccagaagcc ac
#tggctggg   4200
tttgagccct gtaacatccg ggactgccca gcgaggtggt tcacaagtgt gt
#ggtcacag   4260
tgctctgtgt cttgcggtga aggataccac agtcggcagg tgacgtgcaa gc
#ggacaaaa   4320
gccaatggaa ctgtgcaggt ggtgtctcca agagcatgtg cccctaaaga cc
#ggcctctg   4380
ggaagaaaac catgttttgg tcatccatgt gttcagtggg aaccagggaa cc
#ggtgtcct   4440
ggacgttgca tgggccgtgc tgtgaggatg cagcagcgtc acacagcttg tc
#aacacaac   4500
agctctgact ccaactgtga tgacagaaag agacccacct taagaaggaa ct
#gcacatca   4560
ggggcctgtg atgtgtgttg gcacacaggc ccttggaagc cctgtacagc ag
#cctgtggc   4620
aggggtttcc agtctcggaa agtcgactgt atccacacaa ggagttgcaa ac
#ctgtggcc   4680
aagagacact gtgtacagaa aaagaaacca atttcctggc ggcactgtct tg
#ggccctcc   4740
tgtgatagag actgcacaga cacaactcac tactgtatgt ttgtaaaaca tc
#ttaatttg   4800
tgttctctag accgctacaa acaaaggtgc tgccagtcat gtcaagaggg at
#aa         4854
<210> SEQ ID NO 16
<211> LENGTH: 1617
<212> TYPE: PRT
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 16
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Le
#u Ile Gly Met Val Phe
1               5
#                10
#                15
Met His Ser Pro Leu Pro Gln Thr Thr Ala Gl
#u Lys Ser Pro Gly Arg
20
#            25
#            30
Asn Cys Glu Gly Gln Asn Ile Arg Tyr Lys Th
#r Cys Ser Asn His Asp
35
#        40
#        45
Cys Pro Pro Asp Ala Glu Asp Phe Arg Ala Gl
#n Gln Cys Ser Ala Tyr
50
#    55
#    60
Asn Asp Val Gln Tyr Gln Gly His Tyr Tyr Gl
#u Trp Leu Pro Arg Tyr
65
#70
#75
#80
Asn Asp Pro Ala Ala Pro Cys Ala Leu Lys Cy
#s His Ala Gln Gly Gln
85
#                90
#                95
Asn Leu Val Val Glu Leu Ala Pro Lys Val Le
#u Asp Gly Thr Arg Cys
100
#           105
#           110
Asn Thr Asp Ser Leu Asp Met Cys Ile Ser Gl
#y Ile Cys Gln Ala Val
115
#       120
#       125
Gly Cys Asp Arg Gln Leu Gly Ser Asn Ala Ly
#s Glu Asp Asn Cys Gly
130
#   135
#   140
Val Cys Ala Gly Asp Gly Ser Thr Cys Arg Le
#u Val Arg Gly Gln Ser
145                 1
#50                 1
#55                 1
#60
Lys Ser His Val Ser Pro Glu Lys Arg Glu Gl
#u Asn Val Ile Ala Val
165
#               170
#               175
Pro Leu Gly Ser Arg Ser Val Arg Ile Thr Va
#l Lys Gly Pro Ala His
180
#           185
#           190
Leu Phe Ile Glu Ser Lys Thr Leu Gln Gly Se
#r Lys Gly Glu His Ser
195
#       200
#       205
Phe Asn Ser Pro Gly Val Phe Val Val Glu As
#n Thr Thr Val Glu Phe
210
#   215
#   220
Gln Arg Gly Ser Glu Arg Gln Thr Phe Lys Il
#e Pro Gly Pro Leu Met
225                 2
#30                 2
#35                 2
#40
Ala Asp Phe Ile Phe Lys Thr Arg Tyr Thr Al
#a Ala Lys Asp Ser Val
245
#               250
#               255
Val Gln Phe Phe Phe Tyr Gln Pro Ile Ser Hi
#s Gln Trp Arg Gln Thr
260
#           265
#           270
Asp Phe Phe Pro Cys Thr Val Thr Cys Gly Gl
#y Gly Tyr Gln Leu Asn
275
#       280
#       285
Ser Ala Glu Cys Val Asp Ile Arg Leu Lys Ar
#g Val Val Pro Asp His
290
#   295
#   300
Tyr Cys His Tyr Tyr Pro Glu Asn Val Lys Pr
#o Lys Pro Lys Leu Lys
305                 3
#10                 3
#15                 3
#20
Glu Cys Ser Met Asp Pro Cys Pro Ser Ser As
#p Gly Phe Lys Glu Ile
325
#               330
#               335
Met Pro Tyr Asp His Phe Gln Pro Leu Pro Ar
#g Trp Glu His Asn Pro
340
#           345
#           350
Trp Thr Ala Cys Ser Val Ser Cys Gly Gly Gl
#y Ile Gln Arg Arg Ser
355
#       360
#       365
Phe Val Cys Val Glu Glu Ser Met His Gly Gl
#u Ile Leu Gln Val Glu
370
#   375
#   380
Glu Trp Lys Cys Met Tyr Ala Pro Lys Pro Ly
#s Val Met Gln Thr Cys
385                 3
#90                 3
#95                 4
#00
Asn Leu Phe Asp Cys Pro Lys Trp Ile Ala Me
#t Glu Trp Ser Gln Cys
405
#               410
#               415
Thr Val Thr Cys Gly Arg Gly Leu Arg Tyr Ar
#g Val Val Leu Cys Ile
420
#           425
#           430
Asn His Arg Gly Glu His Val Gly Gly Cys As
#n Pro Gln Leu Lys Leu
435
#       440
#       445
His Ile Lys Glu Glu Cys Val Ile Pro Ile Pr
#o Cys Tyr Lys Pro Lys
450
#   455
#   460
Glu Lys Ser Pro Val Glu Ala Lys Leu Pro Tr
#p Leu Lys Gln Ala Gln
465                 4
#70                 4
#75                 4
#80
Glu Leu Glu Glu Thr Arg Ile Ala Thr Glu Gl
#u Pro Thr Phe Ile Pro
485
#               490
#               495
Glu Pro Trp Ser Ala Cys Ser Thr Thr Cys Gl
#y Pro Gly Val Gln Val
500
#           505
#           510
Arg Glu Val Lys Cys Arg Val Leu Leu Thr Ph
#e Thr Gln Thr Glu Thr
515
#       520
#       525
Glu Leu Pro Glu Glu Glu Cys Glu Gly Pro Ly
#s Leu Pro Thr Glu Arg
530
#   535
#   540
Pro Cys Leu Leu Glu Ala Cys Asp Glu Ser Pr
#o Ala Ser Arg Glu Leu
545                 5
#50                 5
#55                 5
#60
Asp Ile Pro Leu Pro Glu Asp Ser Glu Thr Th
#r Tyr Asp Trp Glu Tyr
565
#               570
#               575
Ala Gly Phe Thr Pro Cys Thr Ala Thr Cys Le
#u Gly Gly His Gln Glu
580
#           585
#           590
Ala Ile Ala Val Cys Leu His Ile Gln Thr Gl
#n Gln Thr Val Asn Asp
595
#       600
#       605
Ser Leu Cys Asp Met Val His Arg Pro Pro Al
#a Met Ser Gln Ala Cys
610
#   615
#   620
Asn Thr Glu Pro Cys Pro Pro Arg Trp His Va
#l Gly Ser Trp Gly Pro
625                 6
#30                 6
#35                 6
#40
Cys Ser Ala Thr Cys Gly Val Gly Ile Gln Th
#r Arg Asp Val Tyr Cys
645
#               650
#               655
Leu His Pro Gly Glu Thr Pro Ala Pro Pro Gl
#u Glu Cys Arg Asp Glu
660
#           665
#           670
Lys Pro His Ala Leu Gln Ala Cys Asn Gln Ph
#e Asp Cys Pro Pro Gly
675
#       680
#       685
Trp His Ile Glu Glu Trp Gln Gln Cys Ser Ar
#g Thr Cys Gly Gly Gly
690
#   695
#   700
Thr Gln Asn Arg Arg Val Thr Cys Arg Gln Le
#u Leu Thr Asp Gly Ser
705                 7
#10                 7
#15                 7
#20
Phe Leu Asn Leu Ser Asp Glu Leu Cys Gln Gl
#y Pro Lys Ala Ser Ser
725
#               730
#               735
His Lys Ser Cys Ala Arg Thr Asp Cys Pro Pr
#o His Leu Ala Val Gly
740
#           745
#           750
Asp Trp Ser Lys Cys Ser Val Ser Cys Gly Va
#l Gly Ile Gln Arg Arg
755
#       760
#       765
Lys Gln Val Cys Gln Arg Leu Ala Ala Lys Gl
#y Arg Arg Ile Pro Leu
770
#   775
#   780
Ser Glu Met Met Cys Arg Asp Leu Pro Gly Ph
#e Pro Leu Val Arg Ser
785                 7
#90                 7
#95                 8
#00
Cys Gln Met Pro Glu Cys Ser Lys Ile Lys Se
#r Glu Met Lys Thr Lys
805
#               810
#               815
Leu Gly Glu Gln Gly Pro Gln Ile Leu Ser Va
#l Gln Arg Val Tyr Ile
820
#           825
#           830
Gln Thr Arg Glu Glu Lys Arg Ile Asn Leu Th
#r Ile Gly Ser Arg Ala
835
#       840
#       845
Tyr Leu Leu Pro Asn Thr Ser Val Ile Ile Ly
#s Cys Pro Val Arg Arg
850
#   855
#   860
Phe Gln Lys Ser Leu Ile Gln Trp Glu Lys As
#p Gly Arg Cys Leu Gln
865                 8
#70                 8
#75                 8
#80
Asn Ser Lys Arg Leu Gly Ile Thr Lys Ser Gl
#y Ser Leu Lys Ile His
885
#               890
#               895
Gly Leu Ala Ala Pro Asp Ile Gly Val Tyr Ar
#g Cys Ile Ala Gly Ser
900
#           905
#           910
Ala Gln Glu Thr Val Val Leu Lys Leu Ile Gl
#y Thr Asp Asn Arg Leu
915
#       920
#       925
Ile Ala Arg Pro Ala Leu Arg Glu Pro Met Ar
#g Glu Tyr Pro Gly Met
930
#   935
#   940
Asp His Ser Glu Ala Asn Ser Leu Gly Val Th
#r Trp His Lys Met Arg
945                 9
#50                 9
#55                 9
#60
Gln Met Trp Asn Asn Lys Asn Asp Leu Tyr Le
#u Asp Asp Asp His Ile
965
#               970
#               975
Ser Asn Gln Pro Phe Leu Arg Ala Leu Leu Gl
#y His Cys Ser Asn Ser
980
#           985
#           990
Ala Gly Ser Thr Asn Ser Trp Glu Leu Lys As
#n Lys Gln Phe Glu Ala
995
#       1000
#      1005
Ala Val Lys Gln Gly Ala Tyr Ser Met Asp Th
#r Ala Gln Phe Asp Glu
1010
#   1015
#  1020
Leu Ile Arg Asn Met Ser Gln Leu Met Glu Th
#r Gly Glu Val Ser Asp
1025                1030
#                1035
#               1040
Asp Leu Ala Ser Gln Leu Ile Tyr Gln Leu Va
#l Ala Glu Leu Ala Lys
1045
#               1050
#              1055
Ala Gln Pro Thr His Met Gln Trp Arg Gly Il
#e Gln Glu Glu Thr Pro
1060
#           1065
#          1070
Pro Ala Ala Gln Leu Arg Gly Glu Thr Gly Se
#r Val Ser Gln Ser Ser
1075
#       1080
#      1085
His Ala Lys Asn Ser Gly Lys Leu Thr Phe Ly
#s Pro Lys Gly Pro Val
1090
#   1095
#  1100
Leu Met Arg Gln Ser Gln Pro Pro Ser Ile Se
#r Phe Asn Lys Thr Ile
1105                1110
#                1115
#               1120
Asn Ser Arg Ile Gly Asn Thr Val Tyr Ile Th
#r Lys Arg Thr Glu Val
1125
#               1130
#              1135
Ile Asn Ile Leu Cys Asp Leu Ile Thr Pro Se
#r Glu Ala Thr Tyr Thr
1140
#           1145
#          1150
Trp Thr Lys Asp Gly Thr Leu Leu Gln Pro Se
#r Val Lys Ile Ile Leu
1155
#       1160
#      1165
Asp Gly Thr Gly Lys Ile Gln Ile Gln Asn Pr
#o Thr Arg Lys Glu Gln
1170
#   1175
#  1180
Gly Ile Tyr Glu Cys Ser Val Ala Asn His Le
#u Gly Ser Asp Val Glu
1185                1190
#                1195
#               1200
Ser Ser Ser Val Leu Tyr Ala Glu Ala Pro Va
#l Ile Leu Ser Val Glu
1205
#               1210
#              1215
Arg Asn Ile Thr Lys Pro Glu His Asn His Le
#u Ser Val Val Val Gly
1220
#           1225
#          1230
Gly Ile Val Glu Ala Ala Leu Gly Ala Asn Va
#l Thr Ile Arg Cys Pro
1235
#       1240
#      1245
Val Lys Gly Val Pro Gln Pro Asn Ile Thr Tr
#p Leu Lys Arg Gly Gly
1250
#   1255
#  1260
Ser Leu Ser Gly Asn Val Ser Leu Leu Phe As
#n Gly Ser Leu Leu Leu
1265                1270
#                1275
#               1280
Gln Asn Val Ser Leu Glu Asn Glu Gly Thr Ty
#r Val Cys Ile Ala Thr
1285
#               1290
#              1295
Asn Ala Leu Gly Lys Ala Val Ala Thr Ser Va
#l Leu His Leu Leu Glu
1300
#           1305
#          1310
Arg Arg Trp Pro Glu Ser Arg Ile Val Phe Le
#u Gln Gly His Lys Lys
1315
#       1320
#      1325
Tyr Ile Leu Gln Ala Thr Asn Thr Arg Thr As
#n Ser Asn Asp Pro Thr
1330
#   1335
#  1340
Gly Glu Pro Pro Pro Gln Glu Pro Phe Trp Gl
#u Pro Gly Asn Trp Ser
1345                1350
#                1355
#               1360
His Cys Ser Ala Thr Cys Gly His Leu Gly Al
#a Arg Ile Gln Arg Pro
1365
#               1370
#              1375
Gln Cys Val Met Ala Asn Gly Gln Glu Val Se
#r Glu Ala Leu Cys Asp
1380
#           1385
#          1390
His Leu Gln Lys Pro Leu Ala Gly Phe Glu Pr
#o Cys Asn Ile Arg Asp
1395
#       1400
#      1405
Cys Pro Ala Arg Trp Phe Thr Ser Val Trp Se
#r Gln Cys Ser Val Ser
1410
#   1415
#  1420
Cys Gly Glu Gly Tyr His Ser Arg Gln Val Th
#r Cys Lys Arg Thr Lys
1425                1430
#                1435
#               1440
Ala Asn Gly Thr Val Gln Val Val Ser Pro Ar
#g Ala Cys Ala Pro Lys
1445
#               1450
#              1455
Asp Arg Pro Leu Gly Arg Lys Pro Cys Phe Gl
#y His Pro Cys Val Gln
1460
#           1465
#          1470
Trp Glu Pro Gly Asn Arg Cys Pro Gly Arg Cy
#s Met Gly Arg Ala Val
1475
#       1480
#      1485
Arg Met Gln Gln Arg His Thr Ala Cys Gln Hi
#s Asn Ser Ser Asp Ser
1490
#   1495
#  1500
Asn Cys Asp Asp Arg Lys Arg Pro Thr Leu Ar
#g Arg Asn Cys Thr Ser
1505                1510
#                1515
#               1520
Gly Ala Cys Asp Val Cys Trp His Thr Gly Pr
#o Trp Lys Pro Cys Thr
1525
#               1530
#              1535
Ala Ala Cys Gly Arg Gly Phe Gln Ser Arg Ly
#s Val Asp Cys Ile His
1540
#           1545
#          1550
Thr Arg Ser Cys Lys Pro Val Ala Lys Arg Hi
#s Cys Val Gln Lys Lys
1555
#       1560
#      1565
Lys Pro Ile Ser Trp Arg His Cys Leu Gly Pr
#o Ser Cys Asp Arg Asp
1570
#   1575
#  1580
Cys Thr Asp Thr Thr His Tyr Cys Met Phe Va
#l Lys His Leu Asn Leu
1585                1590
#                1595
#               1600
Cys Ser Leu Asp Arg Tyr Lys Gln Arg Cys Cy
#s Gln Ser Cys Gln Glu
1605
#               1610
#              1615
Gly
<210> SEQ ID NO 17
<211> LENGTH: 8578
<212> TYPE: DNA
<213> ORGANISM: homo sapiens
<400> SEQUENCE: 17
cgggctggag gccggcgtcg gggaaggtcc tggtgccgga ttccgcacga gg
#tgttgacg     60
ggcggcttct gccaacttct ccccagcgcg cgccgagccc gcgcggcccc gg
#ggctgcac    120
gtcccagata cttctgcggc gcaaggctac aactgagacc cggaggagac ta
#gaccccat    180
ggcttcctgg acgagcccct ggtgggtgct gatagggatg gtcttcatgc ac
#tctcccct    240
cccgcagacc acagctgaga aatctcctgg agcctatttc cttcccgagt tt
#gcactttc    300
tcctcaggga agttttctgg aagacacaac aggggagcag ttcctcactt at
#cgctatga    360
tgaccagacc tcaagaaaca ctcgttcaga tgaagacaaa gatggcaact gg
#gatgcttg    420
gggcgactgg agtgactgct cccggacctg tgggggagga gcatcatatt ct
#ctgcggag    480
atgtttgact ggaaggaatt gtgaagggca gaacattcgg tacaagacat gc
#agcaatca    540
tgactgccct ccagatgcag aagatttcag agcccagcag tgctcagcct ac
#aatgatgt    600
ccagtatcag gggcattact atgaatggct tccacgatat aatgatcctg ct
#gccccgtg    660
tgcactcaag tgtcatgcac aaggacaaaa cttggtggtg gagctggcac ct
#aaggtact    720
ggatggaact cgttgcaaca cggactcctt ggacatgtgt atcagtggca tc
#tgtcaggc    780
agtgggctgc gatcggcaac tgggaagcaa tgccaaggag gacaactgtg ga
#gtctgtgc    840
cggcgatggc tccacctgca ggcttgtacg gggacaatca aagtcacacg tt
#tctcctga    900
aaaaagagaa gaaaatgtaa ttgctgttcc tttgggaagt cgaagtgtga ga
#attacagt    960
gaaaggacct gcccacctct ttattgaatc aaaaacactt caaggaagca aa
#ggagaaca   1020
cagctttaac agccccggcg tctttgtcgt agaaaacaca acagtggaat tt
#cagagggg   1080
ctccgagagg caaactttta agattccagg acctctgatg gctgatttca tc
#ttcaagac   1140
caggtacact gcagccaaag acagcgtggt tcagttcttc ttttaccagc cc
#atcagtca   1200
tcagtggaga caaactgact tctttccctg cactgtgacg tgtggaggag gt
#tatcagct   1260
caattctgct gaatgtgtgg atatccgctt gaagagggta gttcctgacc at
#tattgtca   1320
ctactaccct gaaaatgtaa aaccaaaacc aaaactgaag gaatgcagca tg
#gatccctg   1380
cccatcaagt gatggattta aagagataat gccctatgac cacttccaac ct
#cttcctcg   1440
agctgggaac ataatccttg gactgcatgt tccgtgtcct gtggaggagg ga
#ttcagaga   1500
cggagctttg tgtgtgtaga ggaatccatg catggagaga tattgcaggt gg
#aagaatgg   1560
aagtgcatgt acgcacccaa acccaaggtt atgcaaactt gtaatctgtt tg
#attgcccc   1620
aagtggattg ccatggagtg gtctcagtgc acagtgactt gtggccgagg gt
#tacggtac   1680
cgggttgttc tgtgtattaa ccaccgcgga gagcatgttg ggggctgcaa tc
#cacaactg   1740
aagttacaca tcaaagaaga atgtgtcatt cccatcccgt gttataaacc aa
#aagaaaaa   1800
agtccagtgg aagcaaaatt gccttggctg aaacaagcac aagaactaga ag
#agaccaga   1860
atagcaacag aagaaccaac gttcattcca gaaccctggt cagcctgcag ta
#ccacgtgt   1920
gggccaggtg tgcaggtccg cgaggtgaag tgccgtgtgc tcctcacatt ca
#cgcagact   1980
gagactgagc tgcccgagga agagtgtgaa ggccccaagc tgcccaccga ac
#ggccctgc   2040
ctcctggaag catgtgatga gagcccggcc tcccgagagc tagacatccc tc
#tccctgag   2100
gacagtgaga cgacttacga ctgggagtac gctgggttca ccccttgcac ag
#caacatgc   2160
ttgggaggcc atcaagaagc catagcagtg tgcttacata tccagaccca gc
#agacagtc   2220
aatgacagct tgtgtgatat ggtccaccgt cctccagcca tgagccaggc ct
#gtaacaca   2280
gagccctgtc cccccaggag agagccagca gcttgtagaa gcatgccggg tt
#acataatg   2340
gtcctgctag tctgaggaga gccttcttct ctaacaggat tcaacactgc ta
#gggaagaa   2400
aggaggaaag caagaggcaa tagtgatgtg tttctgtacc agcttgttac ct
#atttcttg   2460
atataaaaaa caattcttta ttgagttcat tgtctgtgaa taagaaattg tt
#gcccattt   2520
cttaaataaa aacagctcca tctccaaaaa aaaaaaaaaa aaatggcatg tg
#ggctcttg   2580
ggggccctgc tcagctacct gtggagttgg aattcagacc cgagatgtgt ac
#tgcctgca   2640
cccaggggag acccctgccc ctcctgagga gtgccgagat gaaaagcccc at
#gctttaca   2700
agcatgcaat cagtttgact gccctcctgg ctggcacatt gaagaatggc ag
#cagtgttc   2760
caggacttgt ggcgggggaa ctcagaacag aagagtcacc tgtcggcagc tg
#ctaacgga   2820
tggcagcttt ttgaatctct cagatgaatt gtgccaagga cccaaggcat cg
#tctcacaa   2880
gtcctgtgcc aggacagact gtcctccaca tttagctgtg ggagactggt cg
#aaggagca   2940
ttcaatgcaa gaggacaatg gagcaggatc tacacaattc taaagaaaag ca
#agcatgac   3000
tcaaggattt cctcttcatc ctgtgttctt catgtagaga gacagcagag ag
#gcagtcag   3060
agaatactgt ctgataagcc cttgaaaaag ctgtagggcc aagatgagat ac
#agagatga   3120
ctcaaaacag agaatccagg aatgcataga tcctggtaaa aaaggtggga ga
#tgagtaat   3180
aaattcattt gtgtaggatt aagactaatc aactaacaat tatattatag aa
#cataacat   3240
aaatatcaga aatcttgaca ttatctaaat aataaaatga aaactaattg ag
#atttggag   3300
agatgaggta gatgatatag tttggctgtg tccccaccca aatctcatct tg
#aattgtag   3360
ttcccataat tcccatgtgt tgtgggaggg actcagttgg agataattga at
#catggggg   3420
cagtttccct catactgttc tcgtggtggt aaatgagtct cacgagatct ga
#tggtttta   3480
taaggggttt cccttttcgc ttggctctca ttctctcttg cctgctgcca tg
#taagacgt   3540
ccctttgccc ttcctttgtc ttctgccatg attgtgaggc ttccctagcc ac
#gtggaact   3600
gagtctatta aacctctttc ctttataact tacccagtct tgggtatgtc tt
#tattaaca   3660
acataagatt ggactaatac agtagaggaa atgtaagtgt gcttatttcc tc
#atccttct   3720
tagtagcaag tcaataaata ctctcctaag tcaaattgtc attaaaaata ac
#tatccaaa   3780
tctcttgttg gtttatttaa tcttctttat taactttaga gtgttctttc gg
#gaattaat   3840
catggtttaa aaaatatcaa acattcaaca actctaattt tactttaatg tc
#tttttttc   3900
taatatatct aataaaattg cattaaattt ttaagttgaa aaaaaaaaaa aa
#aaaaaaat   3960
gttctgtcag ttgtggtgtt ggaatccaga gaagaaagca ggtgtgtcaa ag
#gctggcag   4020
ccaaaggtcg gcgcatcccc ctcagtgaga tgatgtgcag ggatctacca gg
#gttccctc   4080
ttgtaagatc ttgccagatg cctgagtgca gtaaaatcaa atcagagatg aa
#gacaaaac   4140
ttggtgagca gggtccgcag atcctcagtg tccagagagt ctacattcag ac
#aagggaag   4200
agaagcgtat taacctgacc attggtagca gagcctattt gctgcccaac ac
#atccgtga   4260
ttattaagtg ccccgtgcga cgattccaga aatctctgat ccagtgggag aa
#ggatggcc   4320
gttgcctgca gaactccaaa cggcttggca tcaccaagtc aggctcacta aa
#aatccacg   4380
gtcttgctgc ccccgacatc ggcgtgtacc ggtgcattgc aggctctgca ca
#ggaaacag   4440
ttgtgctcaa gctcattggt actgacaacc ggctcatcgc acgcccagcc ct
#cagggagc   4500
ctatgaggga atatcctggg atggaccaca gcgaagccaa tagtttggga gt
#cacatggc   4560
acaaaatgag gcaaatgtgg aataacaaaa atgaccttta tctggatgat ga
#ccacatta   4620
gtaaccagcc tttcttgaga gctctgttag gccactgcag caattctgca gg
#aagcacca   4680
actcctggga gttgaagaat aagcagtttg aagcagcagt taaacaagga gc
#atatagca   4740
tggatacagc ccagtttgat gagctgataa gaaacatgag tcagctcatg ga
#aaccggag   4800
aggtcagcga tgatcttgcg tcccagctga tatatcagct ggtggccgaa tt
#agccaagg   4860
cacagccaac acacatgcag tggcggggca tccaggaaga gacacctcct gc
#tgctcagc   4920
tcagagggga aacagggagt gtgtcccaaa gctcgcatgc aaaaaactca gg
#caagctga   4980
cattcaagcc gaaaggacct gttctcatga ggcaaagcca acctccctca at
#ttcattta   5040
ataaaacaat aaattccagg attggaaata cagtatacat tacaaaaagg ac
#agaggtca   5100
tcaatatact gtgtgacctt attaccccca gtgaggccac atatacatgg ac
#caaggatg   5160
gaaccttgtt acagccctca gtaaaaataa ttttggatgg aactgggaag at
#acagatac   5220
agaatcctac aaggaaagaa caaggcatat atgaatgttc tgtagctaat ca
#tcttggtt   5280
cagatgtgga aagttcttct gtgctgtatg cagaggcacc tgtcatcttg tc
#tgttgaaa   5340
gaaatatcac caaaccagag cacaaccatc tgtctgttgt ggttggaggc at
#cgtggagg   5400
cagcccttgg agcaaacgtg acaatccgat gtcctgtaaa aggtgtccct ca
#gcctaata   5460
taacttggtt gaagagagga ggatctctga gtggcaatgt ttccttgctt tt
#caatggat   5520
ccctgttgtt gcagaatgtt tcccttgaaa atgaaggaac ctacgtctgc at
#agccacca   5580
atgctcttgg aaaggcagtg gcaacatctg tactccactt gctggaacga ag
#atggccag   5640
agagtagaat cgtatttctg caaggacata aaaagtacat tctccaggca ac
#caacacta   5700
gaaccaacag caatgaccca acaggagaac ccccgcctca agagcctttt tg
#ggagcctg   5760
gtaactggtc acattgttct gccacctgtg gtcatttggg agcccgcatt ca
#gagacccc   5820
agtgtgtgat ggccaatggg caggaagtga gtgaggccct gtgtgatcac ct
#ccagaagc   5880
cactggctgg gtttgagccc tgtaacatcc gggactgccc agcgaggtgg tt
#cacaagtg   5940
tgtggtcaca gtgctctgtg tcttgcggtg aaggatacca cagtcggcag gt
#gacgtgca   6000
agcggacaaa agccaatgga actgtgcagg tggtgtctcc aagagcatgt gc
#ccctaaag   6060
accggcctct gggaagaaaa ccatgttttg gtcatccatg tgttcagtgg ga
#accaggga   6120
accggtgtcc tggacgttgc atgggccgtg ctgtgaggat gcagcagcgt ca
#cacagctt   6180
gtcaacacaa cagctctgac tccaactgtg atgacagaaa gagacccacc tt
#aagaagga   6240
actgcacatc aggggcctgt gatgtgtgtt ggcacacagg cccttggaag cc
#ctgtacag   6300
cagcctgtgg caggggtttc cagtctcgga aagtcgactg tatccacaca ag
#gagttgca   6360
aacctgtggc caagagacac tgtgtacaga aaaagaaacc aatttcctgg cg
#gcactgtc   6420
ttgggccctc ctgtgataga gactgcacag acacaactca ctactgtatg tt
#tgtaaaac   6480
atcttaattt gtgttctcta gaccgctaca aacaaaggtg ctgccagtca tg
#tcaagagg   6540
gataaacctt tggaggggtc atgatgctgc tgtgaagata aaagtagaat at
#aaaagctc   6600
ttttccccat gtcgctgatt caaaaacatg tatttcttaa aagactagat tc
#tatggatc   6660
aaacagaggt tgatgcaaaa acaccactgt taaggtgtaa agtgaaattt tc
#caatggta   6720
gttttatatt ccaatttttt aaaatgatgt attcaaggat gaacaaaata ct
#atagcatg   6780
catgccactg cacttgggac ctcatcatgt cagttgaatc gagaaatcac ca
#agattatg   6840
agtgcatcct cacgtgctgc ctctttcctg tgatatgtag actagcacag ag
#tggtacat   6900
cctaaaaact tgggaaacac agcaacccat gacttcctct tctctcaagt tg
#caggtttt   6960
caacagtttt ataaggtatt tgcattttag aagctctggc cagtagttgt ta
#agatgttg   7020
gcattaatgg cattttcata gatccttggt ttagtctgtg aaaaagaaac ca
#tctctctg   7080
gataggctgt cacactgact gacctaaggg ttcatggaag catggcatct tg
#tccttgct   7140
tttagaacac ccatggaaga aaacacagag tagatattgc tgtcatttat ac
#aactacag   7200
aaatttatct atgacctaat gaggcatctc ggaagtcaaa gaagagggaa ag
#ttaacctt   7260
ttctactgat ttcgtagtat attcagagct ttcttttaag agctgtgaat ga
#aacttttt   7320
ctaagcacta ttctattgca cacaaacaga aaaccaaagc cttattagac ct
#aatttatg   7380
cataaagtag tattcctgag aactttattt tggaaaattt ataagaaagt aa
#tccaaata   7440
agaaacacga tagttgaaaa taatttttat agtaaataat tgttttgggc tg
#atttttca   7500
gtaaatccaa agtgacttag gttagaagtt acactaagga ccaggggttg ga
#atcagaat   7560
ttagtttaag atttgaggaa aagggtaagg gttagtttca gttttaggat ta
#gagctaga   7620
attgggttag gtgagaaaga aagttaaggt taaggctaga gttgtcttta ag
#ggttaggg   7680
ttaggaccag gttaggtcag ggttggattg ggtttagatt ggggccagtg ct
#ggtgttag   7740
tgatagtgtc aggatggagg ttaggtttgg agtaagcgtt gttgctgaag tg
#agttcagg   7800
ctagcattaa attgtaagtt ctgaagctga tttggttatg gggtctttcc cc
#tgtatact   7860
accagttgtg tctttagatg gcacacaagt ccaaataagt ggtcatactt ct
#ttattcag   7920
ggtctcagct gcctgtacac ctgctgccta catcttcttg gcaacaaagt ta
#cctgccac   7980
aggctctgct gagcctagtt cctggtcagt aataactgaa cagtgcattt tg
#gctttgga   8040
tgtgtctgtg gacaagcttg ctgagtttct ctaccatatt ctgagcacac gg
#tctctttt   8100
gttctaattt cagcttcact gacactgggt tgagcactac tgtatgtgga gg
#gtttggtg   8160
attgggaatg gatgggggac agtgaggagg acacaccagc ccattagttg tt
#aatcatca   8220
atcacatctg attgttgaag gttattaaat taaaagaaag atcatttgta ac
#atactctt   8280
tgtatatatt tattatatga aaggtgcaat attttatttt gtacagtatg ta
#ataaagac   8340
atgggacata tatttttctt attaacaaaa tttcatatta aattgcttca ct
#ttgtattt   8400
aaagttaaaa gttactattt ttcatttgct attgtacttt cattgttgtc at
#tcaattga   8460
cattcctgtg tactgtattt tactactgtt tttataacat gagagttaat gt
#ttctgttt   8520
catgatcctt atgtaattca gaaataaatt tactttgatt attcagtggc at
#ccttat     8578

Claims

1. An isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1.

2. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the amino acid sequence shown in SEQ ID NO: 2.

3. A recombinant expression vector comprising the isolated nucleic acid molecule of claim 2.

4. The recombinant expression vector of claim 3, wherein the isolated nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO:1.

5. A host cell comprising the recombinant expression vector of claim 3.