Transcriptional Biomarkers And Methods For Detecting And Isolating Cancer Cells In Body Fluids And Tissue Specimens

Abstract

The invention provides molecules that target cancer-specific transcription complexes (CSTC), compositions and kits comprising CSTC-targeting molecules, and methods of using CSTC-targeting molecules for the treatment, detection and monitoring of cancer.

Description

[0001] This application is a continuation of application Ser. No. 11/777,271, filed Jul. 12, 2007, now U.S. Pat. No. ______, issued ______, 2011, which claims priority to U.S. provisional patent application No. 60/807,190, filed Jul. 12, 2006, the entire contents of each of which is incorporated herein by reference. Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention pertains.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates generally to detection and therapy of cancer. The invention is more specifically related to novel molecules directed against cancer-specific transcription complexes. The molecules of the invention can be used in vaccines and pharmaceutical compositions for the treatment of various cancers expressing the targeted transcription complexes, as well as in methods of detecting and assessing the malignancy of such cancers.

BACKGROUND OF THE INVENTION

[0003] Cancer remains a significant health problem throughout the world. Current therapies, which are generally based on a combination of chemotherapy or surgery and radiation, continue to prove inadequate in many patients.

[0004] Among cancers, melanoma is well known both for its rapidly increasing incidence and its resistance to virtually all but surgical therapies. Melanoma arises from melanocytes, neural crest derived pigment cells in the skin and eye. During melanoma carcinogenesis, many of the normal markers of the melanocyte lineage become lost. Gene expression patterns in melanoma cells and melanocytes have significant differences that reflect the cancerous nature of melanoma. In general, gene expression is regulated by two types of factors--DNA binding transcription factors and co-regulators which form cell type specific complexes including mediator complex and chromatin remodeling complex that control activity of RNA polymerase two (pol II). Cofactor complexes integrate signals from DNA binding transcription factors as well as from different signaling systems to control RNA synthesis. Cofactor complexes are highly cell- and stimulus-specific, and vary from one physiological stage to another. Cancer cells express transcriptional co-factors with modified structure that is a result of mutations, post-translational modifications, alternative splicing, fusion of different fragments of different proteins to name but a few.

[0005] Transcriptional Control of Melanoma and Melanocyte Development

[0006] Despite altered gene expression patterns, most, if not all, melanomas retain expression of the basic/helix-loop-helix/leucine-zipper (bHLHzip) transcription factor Microphthalmia-associated transcription factor (MITF) (King et al., 1999) that is characteristic for melanocytes. Published data suggests a role for MITF in the commitment, proliferation, and survival of melanocytes before and/or during neural crest cell migration (Opdecamp et al., 1997). Numerous studies also suggest that MITF, in addition to its role in differentiation pathways such as pigmentation, may have an important role in the proliferation and/or survival of developing melanocytes. The retention of MITF expression in the vast majority of human primary melanomas, including nonpigmented tumors, is consistent with this possibility and has also led to the widespread use of MITF as a diagnostic marker in this malignancy (King et al., 1999; Salti et al., 2000; Chang and Folpe, 2001; Miettinen et al., 2001). Wnt signaling pathway and beta-catenin are significant regulators of melanoma cell growth, with MITF as a critical downstream target. Importantly, disruption of the canonical Wnt pathway abrogates growth of melanoma cells, and constitutive overexpression of MITF rescues the growth suppression.

[0007] The invention disclosed herein arises from a search for MITF target genes, which influence cell cycle progression, to examine the possibility that MITF contributes to maintenance of the cell cycle machinery while perhaps not directly participating in the mitogenic response. Cell cycle targets of Wnt signaling such as c-Myc, Cyclin D1 (He et al., 1998; Tetsu and McCormick, 1999; Shtutman et al., 1999), and others may more directly mediate beta-catenin's mitogenic effects. In addition, it has been shown that MITF serves as an upstream regulator of a variety of proliferation related genes such as CDK2, p21 (Cip1), INK4A. MITF interacts with several transcription factors (TFs) including Rb, TFEB, ITF2, PIAS3 and STAT3, to regulate a network of downstream genes that are related to different aspects of melanocyte and melanoma development.

[0008] In addition to the MITF pathway, several other signaling pathways have been reported to be associated with melanoma cells, including NOTCH, interferon, nuclear hormone receptor and immune modulatory pathways. Some differentially expressed genes reside on chromosomal regions displaying common loss or gain in melanomas or are known to be regulated by CpG promoter methylation. Several data also indicate that transcription cofactors are differentially expressed in melanomas compared to melanocytes. Goldberg et al. (2003) reported that tumor suppressor genes TXNIP and KISS1, which are down-regulated in metastatic melanomas, are controlled by transcriptional factor DRIP130/CRSP3. DRIP130/CRSP3 is located in chromosome 6 in the region that is frequently deleted in melanomas.

[0009] Transcriptional Control

[0010] Precise temporal and spatial regulation of the transcription of protein-encoding genes by RNA polymerase II (pol II) is vital to the execution of complex gene expression programs in response to growth, developmental and homeostatic signals. The molecular circuitry that enables coordinated gene expression is largely based on DNA-binding transcription factors (TFs) that bring regulatory information to the target genes. As a rule, DNA binding TFs do not interact directly with pol II and other basal transcriptional complex components. Group of factors called co-regulators including co-activators, co-repressors and a mediator complex have emerged as central players in the process of transcription. These co-regulators mediate DNA binding TFs and pol II complex to control transcriptional activity of specific genes.

[0011] Although it has been realized that co-regulators are universally required for the expression of almost all genes, the full implications of a requirement for a multi-subunit co-regulator complex are not yet readily apparent. By inserting itself between the DNA binding TFs and the basal transcriptional machinery, the mediator complex probably affords additional opportunities to control the diverse regulatory inputs received both from the DNA-binding factors and, most likely, from other signals and to present an appropriately calibrated output to the pol II machinery. In its capacity as a processor of diverse signals in the form of activators and repressors that impinge on it, and its location at the interface of pol II and general transcription factors (GTFs), the mediator represents a final check-point before pol II transcription actually commences. The central role of co-regulator complexes in transcriptional control makes them an attractive drug target. Interference at this point of transcription machinery could enable researchers and clinicians to control or correct expression of a large number of genes. Transcriptional complex that contains 70-80 subunits has a different composition in different cell types and on different promoters. This cell specific variability of transcriptional complex assures specificity of potential treatments that target transcriptional machinery.

[0012] There remains a need for molecules useful in the treatment of cancer. The invention disclosed herein meets this need by providing isoforms of transcription factors and molecules that specifically target the transcription complexes found in cancer.

SUMMARY OF THE INVENTION

[0013] The present invention identifies cancer specific transcriptional complexes (CSTCs) that contain isoforms of individual cofactors in melanoma cells. The melanoma specific isoform related transcriptional complexes (TFCs) have altered function compared to wild type TFCs and are part of the molecular machinery that is responsible for malignant transformation. Therefore, melanoma specific TFCs represent attractive drug targets for treatment of melanoma. In addition, these specific TFCs can be used as diagnostic and prognostic biomarkers. Since individual melanomas express different sets of cofactors and TFCs, the efficacy of many current and novel drugs likely depend on composition of TFCs. Modified TFCs provide tools for theranostics, i.e., to select patients who will have favorable response to specific treatments. Moreover, the cancer-specific isoforms of transcriptional co-regulators described herein are expressed in a variety of other cancers, extending the usefulness of the disclosed molecules and methods beyond melanoma.

[0014] The invention provides molecules that target cancer-specific transcription complexes (CSTCs), compositions and kits comprising CSTC-targeting molecules, and methods of using CSTC-targeting molecules for the treatment and detection of cancer. In one embodiment, the invention provides an expression vector comprising a nucleic acid molecule that encodes a CSTC-targeting molecule operably linked to an expression control sequence. In another embodiment, the invention provides an oligonucleotide that encodes a CSTC-targeting molecule. The nucleic acid molecule may encode the CSTC-targeting molecule in a sense or anti-sense orientation, depending on the intended use. Also provided are host cells containing such expression vectors, which can be used for the production of CSTC-targeting molecules. In some embodiments, the nucleic acid molecule is labeled with a detectable marker, or provided in a composition with a pharmaceutically acceptable carrier.

[0015] The invention additionally provides CSTC-targeting peptides and small molecules, including peptides that target transcription complexes modified by cancer-specific isoforms of transcriptional co-regulators. More specifically, the CSTC-targeting molecules of the invention include molecules that modulate the activity of a cancer-specific mediator complex, containing MED24/TRAP100 and isoforms thereof, and a cancer-specific chromatin modifying complex, containing BAF57 and isoforms thereof. The CSTC-targeting molecule may be provided in a variety of forms, as appropriate for a particular use, including, for example, in a soluble form, immobilized on a substrate, or in combination with a pharmaceutically acceptable carrier. In some embodiments, the CSTC-targeting molecule is labeled with a detectable marker, or provided in a composition with a pharmaceutically acceptable carrier.

[0016] The methods provided by the invention include a method for inhibiting proliferation of cancer cells comprising contacting a cancer cell with a CSTC-targeting molecule of the invention. Typically, the molecule comprises a peptide, oligonucleotide (e.g., siRNA) or small molecule that modulates the activity of a cancer-specific mediator complex containing MED24/TRAP100 and its isoforms, and a cancer-specific chromatin modifying complex containing BAF57 and its isoforms. In one embodiment, the peptide comprises the amino acid sequence PQMQQNVFQYPGAGMVPQGEANF (SEQ ID NO: 1) or NDRLSDGDSKYSQTSHKLVQLL (SEQ ID NO: 2), that interfere with the function of cancer-specific isoforms of TRAP100 and BAF57, respectively. In a typical embodiment, the peptide further comprises additional sequence selected to facilitate delivery into cells and into nuclei. For example, a cell penetrating peptide (CPP) can be added, such as the following amino acid sequence: RRRRRRR (SEQ ID NO: 3). An example of a peptide that facilitates nuclear delivery is the nucleus localizing signal (NLS) having the amino acid sequence PKKRKV (SEQ ID NO: 4). A peptide of the invention is exemplified by the peptide having the amino acid sequence of PKKRKVRRRRRRRPQMQQNVFQYPGAGMVPQGEANF (TRAP100 P05; SEQ ID NO: 5) or PKKRKVRRRRRRRNDRLSDGDSKYSQTSHKLVQLL (BAF57 P12; SEQ ID NO: 6).

[0017] Other methods provided include a method for treating cancer in a subject by administering to the subject a CSTC-targeting molecule of the invention, a method of inhibiting tumor growth, a method for detecting cancer, and a method for inducing apoptosis. The method for inhibiting tumor growth, and the method for inducing apoptosis, comprises contacting a tumor or cancer cell with a CSTC-targeting molecule. The method for detecting cancer comprises contacting a tissue specimen with a detectable molecule that specifically binds a CSTC and detecting binding of the detectable molecule. Binding of the detectable molecule is indicative of cancer. Examples of a detectable molecule include a peptide, antibody or other molecule that specifically binds to a CSTC. Typically, the cancer is melanoma.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention is based on the discovery of cancer-specific transcription complexes (CSTCs) that contain isoforms of transcriptional co-regulators specific to human cancers. These molecules provide novel targets for treatment and detection of cancer. Moreover, the data described herein show that molecules directed against the CSTC of the invention are effective in inhibiting proliferation of cancer cells, inducing apoptosis and inhibiting tumor growth. This invention thus provides CSTC-targeting molecules as diagnostic and therapeutic agents for the detection, monitoring and treatment of various cancers.

[0019] Transcriptional Complexes as Novel Promising Drug Targets

[0020] Transcriptional regulators determine regulatory networks that control gene-specific transcription. The misregulation of these networks is correlated with a growing number of human diseases that are characterized by altered gene expression patterns. This has spurred intense efforts toward the development of artificial transcriptional regulators and/or molecules that modify TFCs to correct and restore "normal" expression of affected genes. Numerous research groups and companies are focusing on development of treatment strategies that target signaling systems, mostly kinases and phosphatases, and cell surface molecules that control gene expression and regulate cell division and differentiation. All potential treatments that target signaling and cell surface molecules have one critical problem--cell type specificity. To be effective with minimal side effects, treatments have to affect only diseased cells.

[0021] Signaling systems and surface molecules are expressed and function in a wide variety of cell populations that makes achieving localized/restricted effects extremely difficult.

[0022] It is well known that transcriptional control of individual genes is cell type specific and that different transcription factor complexes are responsible for this specificity. We propose to use the cell type specificity of TFCs to control expression of proteins that are critical for cancer development. Achieving this goal will allow us to manipulate growth and apoptosis of cancer cells. For a long time TFs have been considered to be difficult targets for effective drug development. Recently numerous reports show that small molecules can be developed that interact with specific TFs and control activity of specific TFCs.

[0023] Peptide Drugs--Targeting Transcription Complexes

[0024] The ultimate action of TFs on target genes, after site-specific DNA binding, is to enhance the recruitment and/or function of the general transcription machinery (RNA polymerase II and general transcription factors TFII-A, -B, -D, -E, -F, and -H; Roeder, 1996) on cognate core promoter elements. Recent studies have implicated a large multisubunit coactivator complex, a mediator, as the main pathway for direct communication between DNA binding TFs and the general transcription machinery (reviewed in Malik and Roeder, 2000). Large number of protein/protein interactions determines specificity and function of mediator complex. Peptides that represent interaction surfaces of different transcription factors have been designed and used to manipulate expression of target genes (Kalinichenko et al., 2004, Chinmay et al., 2005, Gail et al., 2005) and control disease.

[0025] Prediction of the structures of multimolecular complexes has largely not been addressed, probably due to the magnitude of the combinatorial complexity of the problem. Docking applications have traditionally been used to predict pairwise interactions between molecules. Several algorithms that extend the application of docking to multimolecular assemblies have been developed. We apply these algorithms to predict quaternary structures of both oligomers and multi-protein complexes. These algorithms have predicted well a near-native arrangement of the subunits of mediator complexes. We have used these computational tools to design a small library of peptides that interact with a cancer specific mediator complex and a cancer specific chromatin modifying complex containing cancer specific isoforms of MED24/TRAP100 and BAF57 respectively. Screening of these libraries has identified peptides that affect growth and apoptosis of melanoma cells.

[0026] Another critical issue is delivery of therapeutic peptides to cell nucleus where transcription factor complexes are localized and where they perform their function. Cell membranes act as protective walls to exclude peptides that are not actively imported by living cells. In order to overcome this barrier for effective delivery of membrane-impermeable peptides, several chemical and physical methods have been developed including electroporation and cationic lipids/liposomes. These methods have been shown to be effective for delivering hydrophobic macromolecules. The drawbacks of these harsh methods are, primarily, the unwanted cellular effects exerted by them, and, secondly, their limitation to in vitro applications. The last decade's discovery of cell-penetrating peptides (CPP) translocating themselves across cell membranes of various cell lines, along with a cargo 100-fold their own size, via a seemingly energy independent process, opens up the possibility for efficient delivery of proteins, peptides and small molecules into cells both in vitro and in vivo. The only consistently found feature present in all CPPs is the high content of basic amino acids, resulting in a positive net charge. Rothbard et al. (2000) showed that cyclosporin A was efficiently delivered into dermal T lymphocytes and inhibited inflammation by linking to a hepta-arginine segment, suggesting that positive charge is the required feature for cellular translocation. CPPs possess an appealing set of desirable features for cellular targeting, such as effective delivery in vivo, targeting of the nucleus, applicability to all cell types, no apparent size constraint of cargo and seemingly no immunogenic, antigenic or inflammatory properties.

[0027] As delivery vectors, cell-penetrating peptides definitely have proven their value. Their ability to effectively deliver hydrophobic macromolecules into practically all types of cells in vitro, as well as in vivo, without marked levels of cytotoxicity, is impressive.

[0028] Combining CPP and TFC interfering peptides opens a new and more effective approach to the targeting of transcriptional complexes with therapeutic peptides.

[0029] Cancer and Transcriptional Control

[0030] Cancer is a disease of enormous complexity. To date, thousands of genes representing virtually every sub-group of genes have been implicated in cancer. Currently, cancer is thought to develop from proliferating stem or progenitor cells with either mutated genes or rearranged chromosomes. As a result of these genetic alterations, tumor cells also possess an altered gene and protein expression compared with non-malignant cells. Whole-genome analysis of gene expression clearly shows specific differences between normal and cancerous cells as well as between cancer types. This suggests that regulatory networks determining the expression of specific genes are different in malignant and non-malignant cells.

[0031] Cancer patients have a highly variable clinical course and outcome. Intrinsic genetic heterogeneity of the primary tumor has been suggested to play a role in this variability and may explain it in part (Chang, et al., 2003). Pathological and clinical factors are insufficient to capture the complex cascade of events that drive the clinical behavior of tumors. Extensive analyses of gene expression patterns of a variety of tumors have resulted in an understanding that histologically similar tumors have different gene expression patterns. Oligonucleotide and cDNA microarray techniques have identified molecular subgroups of specific types of cancer (Perou et al., 2000, Hedenfalk et al., 2001, West et al., 2001, Zajchowski et al., 2001). Molecular profiling of tumors has also been used to predict survival of patients and to select patients for adjuvant therapy (van't Veer et al., 2002, van de Vijever et al., 2002).

[0032] Cancer Specific TFCs--Novel Drug Targets with High Specificity

[0033] Well-known characteristics of cancer cells are mutations in variety of regulatory molecules including transcription factors, misexpression of transcription factors, expression of mRNA splice variants encoding specific isoforms of proteins and presence of posttranslational modifications that are not present in normal cells. Mutations and expression of fusion proteins are described in almost every single type of cancer (Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C., CEBPA point mutations in hematological malignancies. Leukemia. 2005 March; 19(3):329-34; Xia and Barr, Chromosome translocations in sarcomas and the emergence of oncogenic transcription factors. Eur J Cancer. 2005 November; 41(16):2513-27). Large number of papers report identification of cancer specific or enriched mRNA alternative splice variants. For example, a genome-wide computational screening of 11014 genes using 3,471,822 human expressed sequence tag (EST) sequences identified 26,258 alternatively spliced transcripts/mRNAs of which 845 were significantly associated with cancer (Wang et al., 2003). Several of the gene-specific splice variants have been shown to have a prognostic value. Patients with a high expression of the alternative splice variant of helix-loop-helix transcription factor ARNT have a worse relapse-free and overall survival than patients with a low expression (Qin et al., 2001). As a rule the expression of cancer-specific or enriched alternatively spliced mRNAs is not related to the mutations in splice donor or acceptor sites but due to the changes in the expression of splicing factors.

[0034] Our in silico analysis using variety of gene expression and EST databases has revealed a large number of alternative splice variants of transcriptional coactivators including mediator complex that have cell type and diseases specific expression. Not all of these splice variants result in protein isoforms with altered function but represent a cryptic splicing that leads to degradation of mRNAs. However, a number of splice variants become translated into functional proteins that will become part of cancer specific TFCs. These changed TFCs may contribute to the development of cancer. We have generated peptides that affect specifically MED24/TRAP100 and BAF57 isoform containing TFCs and block proliferation and induce apoptosis of melanoma cells.

[0035] Therapeutic Approach

[0036] Our therapeutic approach is based on identification of cancer specific transcription factor complexes (TFC) that contain mutated and/or altered by posttranslational modifications, and/or alternative splicing, and/or TFC components that are modified by a genomic rearrangement. These cancer specific TFCs have structure and function that are different from structure and function of TFCs in normal, non-cancerous cells.

[0037] As an example of our approach, we have specifically identified a number of novel isoforms of transcriptional co-regulators that are components of cancer specific TFCs, including but not limited to mediator complex and chromatin remodeling complex. We have focused on two of these altered complexes: [0038] 1. Mediator complex that contains cancer specific isoform of MED24/TRAP100. [0039] 2. Chromatin modifying complex that contains cancer specific isoform of BAF57.

[0040] Using different modeling tools and current understanding of composition, structure and function of mediator and chromatin remodeling complexes we identified potential interactions that are unique in complexes that contain cancer specific isoforms of MED24 and BAF57 and identified potential therapeutic peptides. These peptides interact with a MED and chromatin remodeling complexes and alter the function of transcriptional machinery that results in apoptosis and growth arrest of melanoma cells.

[0041] MED24 Isoform Containing Complex

[0042] Mediator complex consists of approximately 30 proteins that have different functions and participate in different signaling pathways to respond variety of regulatory signals. MED24 is a part of a MED complex "tail" subunit that is present in specific MED complexes. MED 24 co-precipitates with MED16, MED23 and MED25 that are other subunits of "tail" module. Incorporation of MED24 isoform into "tail" subunit modifies interactions of subunit components and opens opportunity to design interfering molecules that target MED24 isoform specific complex. Therapeutic peptide TRAP100 P05 likely interacts with a "tail" complex structure that is composed of MED16, MED23, MED24 and MED25.

[0043] Based on these potential interactions, we have designed a small library of peptides that interact with a cancer specific mediator complex "tail" subunit containing cancer specific isoform of MED24/TRAP100. Screening of these libraries has identified a peptide that affects growth and apoptosis of melanoma cells. This peptide does not have a sequence of MED24 isoform and was found to affect transcription via binding to altered structure of "tail" subunit of MED complex.

[0044] Chromatin Modifying Complex

[0045] Chromatin modifying complex consists of a large number of SWI/SNF/SMARC/BAF proteins, histone acetylases (HAT) and histone deacetylases (HDAC). BAF 57, a specific member of BAF complex and it interacts directly with BAF155, BAF170, steroid hormone receptor co-activators and several HDAC proteins. BAF57 melanoma specific isoform modifies structure and function of a chromatin modifying complex. We have used modeling tools to predict changes in the structure and interactions of chromatin modifying complex containing isoform of BAF57. Based on this information, we have designed a peptide library and screening of this library resulted in the identification of peptides that affect growth and apoptosis of melanoma cells. Specifically, therapeutic peptide which we denoted as BAF57 P12 likely interacts with a chromatin modifying complex subunit that contains BAF155, BAF170 and one or more different HDAC molecules.

[0046] Definitions

[0047] All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.

[0048] As used herein, "peptide" or "polypeptide" includes fragments of proteins, and peptides, whether isolated from natural sources, produced by recombinant techniques or chemically synthesized. Polypeptides (and peptides) of the invention typically comprise at least about 6 amino acids.

[0049] As used herein, "CSTC-targeting molecule" includes CSTC-targeting peptides, polynucleotides encoding CSTC-targeting peptides, polynucleotides complementary to those encoding CSTC-targeting peptides, antibodies that specifically recognize and bind CSTCs, and other small molecules exhibiting the same targeting activity.

[0050] A "small molecule" means a molecule having a molecular weight of less than 2000 daltons, in some embodiments less than 1000 daltons, and in still other embodiments less than 500 daltons or less. Such molecules include, for example, heterocyclic compounds, carboxylic compounds, sterols, amino acids, lipids, and nucleic acids.

[0051] As used herein, "CSTC-targeting" refers to the specific binding of a CSTC-targeting molecule to a cancer-specific transcription complex, wherein the specificity is such that the CSTC-targeting molecule essentially does not bind normal or native transcription complex.

[0052] As used herein, "vector" means a construct, which is capable of delivering, and preferably expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[0053] As used herein, "expression control sequence" means a nucleic acid sequence that directs transcription of a nucleic acid. An expression control sequence can be a promoter, such as a constitutive or an inducible promoter, or an enhancer. The expression control sequence is operably linked to the nucleic acid sequence to be transcribed.

[0054] The term "nucleic acid" or "polynucleotide" refers to a deoxyribonucleotide or ribonucleotide polymer in either single- or double-stranded form, and unless otherwise limited, encompasses known analogs of natural nucleotides that hybridize to nucleic acids in a manner similar to naturally-occurring nucleotides.

[0055] As used herein, "tumor protein" is a protein that is expressed by tumor cells. A tumor protein is tumor specific if it is not expressed in non-tumor cells.

[0056] As used herein, "pharmaceutically acceptable carrier" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline.

[0057] Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990).

[0058] As used herein, "a" or "an" means at least one, unless clearly indicated otherwise.

[0059] CSTC-Targeting Peptides

[0060] CSTC-targeting peptides and polypeptides as described herein may be of any length. Additional sequences derived from the native protein and/or heterologous sequences may be present, and such sequences retain the ability to modulate transcription complex. Preferred peptides comprise the amino acid sequence PQMQQNVFQYPGAGMVPQGEANF (SEQ ID NO: 1) or NDRLSDGDSKYSQTSHKLVQLL (SEQ ID NO: 2), peptides that interfere with function of CSTCs containing cancer-specific isoforms of TRAP100 P05 and BAF57, respectively. In a typical embodiment, the peptide further comprises additional sequence selected to facilitate delivery into cells and into nuclei. For example, a cell penetrating peptide (CPP) can be added, such as the following amino acid sequence: RRRRRRR (SEQ ID NO: 3). Those skilled in the art are aware of other CPPs that can be suitable for use with the invention, such as those described in Ulo Langel, ed., Cell-Penetrating Peptides: Processes and Applications, Culinary & Hospitality Industry Publications Services (CHIPS), Weimar, Tex., 2002. An example of a peptide that facilitates nuclear delivery is a nuclear localizing signal (NLS). Typically, this signal consists of a few short sequences of positively charged lysines or arginines, such as PPKKRKV (SEQ ID NO: 9). In one embodiment, the NLS has the amino acid sequence PKKRKV (SEQ ID NO: 4). A peptide of the invention is exemplified by the peptide having the amino acid sequence of PKKRKVRRRRRRRPQMQQNVFQ YPGAGMVPQGEANF (TRAP100 P05; SEQ ID NO: 5) or PKKRKVRRRRRRR NDRLSDGDSKYSQTSHKLVQLL (BAF57 P12; SEQ ID NO: 6).

[0061] Those skilled in the art will appreciate that certain variants thereof will be useful in the treatment and detection of cancer. A peptide "variant," as used herein, is a peptide that differs from a native CSTC-targeting peptide in one or more substitutions, deletions, additions and/or insertions, such that the transcription complex targeting activity of the peptide is not substantially diminished. In other words, the ability of a variant to bind the transcription complex may be enhanced or unchanged, relative to the native peptide, or may be diminished by less than 50%, and preferably less than 20%, relative to the native peptide. Such variants may generally be identified by modifying one of the above peptide sequences and evaluating the binding of the modified peptide with the targeted transcription complex as described herein. Peptide variants preferably exhibit at least about 70%, more preferably at least about 90% and most preferably at least about 95% identity (determined as described above) to the identified peptides.

[0062] Preferably, a variant contains conservative substitutions. A "conservative substitution" is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the peptide to be substantially unchanged. Amino acid substitutions may generally be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gln, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. A variant may also, or alternatively, contain nonconservative changes. In a preferred embodiment, variant peptides differ from a native sequence by substitution, deletion or addition of five amino acids or fewer.

[0063] Specifically, amino acid residues of the peptides of the invention can be varied as follows:

TABLE-US-00001 Variant Residues for MED24 P05 (SEQ ID NO: 7) PQ(N)MQ(N)Q(N)N(Q)VFQ(N)YPG(A)A(G)G(A)MV(L)PQ(N)G E(D)A(G)N(Q)F; Variant Residues for BAF57 P12 (SEQ ID NO: 8) ND(E)R(K)L(V)SD(E)GD(E)SK(R)YSQ(N)TSHK(R)L(V)V(L) QL(V)L(V);

[0064] wherein each indicated native residue that is followed by an alternative in parentheses can optionally be substituted with that alternative residue. One or more of the indicated alternatives can be employed in a given variant peptide. Such variant peptides are referred to herein as "conservatively modified variants".

[0065] Recombinant peptides encoded by DNA sequences as described herein may be readily prepared from the DNA sequences using any of a variety of expression vectors known to those of ordinary skill in the art. Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant peptide. Suitable host cells include prokaryotes, yeast and higher eukaryotic cells. Preferably, the host cells employed are E. coli, yeast, insect cells or a mammalian cell line such as COS or CHO. Supernatants from suitable host/vector systems that secrete recombinant protein or peptide into culture media may be first concentrated using a commercially available filter. Following concentration, the concentrate may be applied to a suitable purification matrix such as an affinity matrix or an ion exchange resin. Finally, one or more reverse phase HPLC steps can be employed to further purify a recombinant peptide.

[0066] Portions and other variants having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may also be generated by synthetic means, using techniques well known to those of ordinary skill in the art. For example, such peptides may be synthesized using any of the commercially available solid-phase techniques, such as the Merrifield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain. See Merrifield, J. Am. Chem. Soc. 85:2149-2146, 1963. Equipment for automated synthesis of peptides is commercially available from suppliers such as Perkin Elmer/Applied BioSystems Division (Foster City, Calif.), and may be operated according to the manufacturer's instructions.

[0067] Peptides can be synthesized on a Perkin Elmer/Applied Biosystems Division 430A peptide synthesizer using FMOC chemistry with HPTU (O-BenzotriazoleN,N,N',N'-tetramethyluronium hexafluorophosphate) activation. A Gly-Cys-Gly sequence may be attached to the amino terminus of the peptide to provide a method of conjugation, binding to an immobilized surface, or labeling of the peptide. Cleavage of the peptides from the solid support may be carried out using the following cleavage mixture: trifluoroacetic acid:ethanedithiol:thioanisole:water:phenol (40:1:2:2:3). After cleaving for 2 hours, the peptides may be precipitated in cold methyl-t-butyl-ether. The peptide pellets may then be dissolved in water containing 0.1% trifluoroacetic acid (TFA) and lyophilized prior to purification by C18 reverse phase HPLC. A gradient of 0%-60% acetonitrile (containing 0.1% TFA) in water may be used to elute the peptides. Following lyophilization of the pure fractions, the peptides may be characterized using electrospray or other types of mass spectrometry and by amino acid analysis.

[0068] In general, peptides (including fusion proteins) and polynucleotides as described herein are isolated. An "isolated" peptide or polynucleotide is one that is removed from its original environment. For example, a naturally occurring protein is isolated if it is separated from some or all of the coexisting materials in the natural system. Preferably, such peptides are at least about 90% pure, more preferably at least about 95% pure and most preferably at least about 99% pure. A polynucleotide is considered to be isolated if, for example, it is cloned into a vector that is not a part of the natural environment.

[0069] Polynucleotides of the Invention

[0070] The invention provides polynucleotides that encode one or more CSTC-targeting peptides, as described above. Preferred polynucleotides comprise at least 15 consecutive nucleotides, preferably at least 30 consecutive nucleotides and more preferably 35 consecutive nucleotides, that encode a CSTC-targeting peptide. Polynucleotides that are fully complementary to any such sequences are also encompassed by the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials. Portions of such CSTC-targeting polynucleotides can be useful as primers and probes for the amplification and detection of CSTC-targeting molecules.

[0071] Polynucleotides may comprise a native sequence (i.e., a sequence that encodes a CSTC-targeting peptide as described above or a portion thereof) or may comprise a variant of such a sequence. Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions such that the specific CSTC binding of the encoded peptide is not diminished, relative to a native peptide. Variants preferably exhibit at least about 70% identity, more preferably at least about 80% identity and most preferably at least about 90% identity to a polynucleotide sequence that encodes a native CSTC-targeting peptide or a portion thereof.

[0072] Two polynucleotide or peptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A "comparison window" as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0073] Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, Wis.), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M. O. (1978) A model of evolutionary change in proteins--Matrices for detecting distant relationships. In Dayhoff, M. O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington D.C. Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, Calif.; Higgins, D. G. and Sharp, P. M. (1989) CABIOS 5:151-153; Myers, E. W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E. D. (1971) Comb. Theor. 11:105; Santou, N., Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P. H. A. and Sokal, R. R. (1973) Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, Calif.; Wilbur, W. J. and Lipman, D. J. (1983) Proc. Natl. Acad. Sci. USA 80:726-730.

[0074] Preferably, the "percentage of sequence identity" is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or peptide sequence in the comparison window may comprise additions or deletions (i.e. gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0075] Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native protein (or a complementary sequence).

[0076] Suitable "moderately stringent conditions" include prewashing in a solution of 5.times.SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50.degree. C.-65.degree. C., 5.times.SSC, overnight; followed by washing twice at 65.degree. C. for 20 minutes with each of 2.times., 0.5.times. and 0.2.times.SSC containing 0.1% SDS.

[0077] As used herein, "highly stringent conditions" or "high stringency conditions" are those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50.degree. C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide, 5.times.SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5.times. Denhardt's solution, sonicated salmon sperm DNA (50 .mu.g/ml), 0.1% SDS, and 10% dextran sulfate at 42.degree. C., with washes at 42.degree. C. in 0.2.times.SSC (sodium chloride/sodium citrate) and 50% formamide at 55.degree. C., followed by a high-stringency wash consisting of 0.1.times.SSC containing EDTA at 55.degree. C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

[0078] It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a peptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).

[0079] Polynucleotides may be prepared using any of a variety of techniques known in the art, including, for example, oligonucleotide synthesis. Libraries can be screened with probes designed to identify the gene of interest or the peptide encoded by it. Screening the cDNA or other library with the selected probe may be conducted using standard procedures, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989).

[0080] The oligonucleotide sequences selected as probes should be sufficiently long and sufficiently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels, such as .sup.32P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.

[0081] Polynucleotide variants may generally be prepared by any method known in the art, including chemical synthesis by, for example, solid phase phosphoramidite chemical synthesis. Modifications in a polynucleotide sequence may also be introduced using standard mutagenesis techniques, such as oligonucleotide-directed site-specific mutagenesis (see Adelman et al., DNA 2:183, 1983). Alternatively, RNA molecules may be generated by in vitro or in vivo transcription of DNA sequences encoding a CSTC-targeting peptide, or portion thereof, provided that the DNA is incorporated into a vector with a suitable RNA polymerase promoter (such as T7 or SP6). Certain portions may be used to prepare an encoded peptide, as described herein. In addition, or alternatively, a portion may be administered to a patient such that the encoded peptide is generated in vivo (e.g., by transfecting antigen-presenting cells, such as dendritic cells, with a cDNA construct encoding a CSTC-targeting peptide, and administering the transfected cells to the patient).

[0082] Any polynucleotide may be further modified to increase stability in vivo. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends; the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages in the backbone; and/or the inclusion of nontraditional bases such as inosine, queosine and wybutosine, as well as acetyl- methyl-, thio- and other modified forms of adenine, cytidine, guanine, thymine and uridine.

[0083] Nucleotide sequences can be joined to a variety of other nucleotide sequences using established recombinant DNA techniques. For example, a polynucleotide may be cloned into any of a variety of cloning vectors, including plasmids, phagemids, lambda phage derivatives and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors. In general, a vector will contain an origin of replication functional in at least one organism, convenient restriction endonuclease sites and one or more selectable markers. Other elements will depend upon the desired use, and will be apparent to those of ordinary skill in the art.

[0084] Within certain embodiments, polynucleotides may be formulated so as to permit entry into a cell of a mammal, and to permit expression therein. Such formulations are particularly useful for therapeutic purposes, as described below. Those of ordinary skill in the art will appreciate that there are many ways to achieve expression of a polynucleotide in a target cell, and any suitable method may be employed. For example, a polynucleotide may be incorporated into a viral vector such as, but not limited to, adenovirus, adeno-associated virus, retrovirus, or vaccinia or other pox virus (e.g., avian pox virus). Techniques for incorporating DNA into such vectors are well known to those of ordinary skill in the art. A retroviral vector may additionally transfer or incorporate a gene for a selectable marker (to aid in the identification or selection of transduced cells) and/or a targeting moiety, such as a gene that encodes a ligand for a receptor on a specific target cell, to render the vector target specific. Targeting may also be accomplished using an antibody, by methods known to those of ordinary skill in the art. Some embodiments of the peptides of the invention have been described herein with a cell penetrating peptide (CPP) incorporated into the peptide for facilitation of entry into a cell.

[0085] Other formulations for therapeutic purposes include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A preferred colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (i.e., an artificial membrane vesicle). The preparation and use of such systems is well known in the art.

[0086] Antisense and Inhibitory Nucleic Acid Molecules

[0087] The antisense molecules of the present invention comprise a sequence substantially complementary, or preferably fully complementary, to all or a fragment of a nucleic acid molecule that encodes a CSTC-targeting peptide and/or a cancer-specific isoform of a transcription modulator as described herein. Included are fragments of oligonucleotides within a coding sequence, and inhibitory nucleotides that inhibit the expression of CSTCs and/or cancer-specific isoforms of transcription modulators. Antisense oligonucleotides of DNA or RNA complementary to sequences at the boundary between introns and exons can be employed to prevent the maturation of newly-generated nuclear RNA transcripts of specific genes into mRNA for transcription. Antisense RNA, including siRNA, complementary to specific genes can hybridize with the mRNA for that gene and prevent its translation. The antisense molecule can be DNA, RNA, or a derivative or hybrid thereof. Examples of such derivative molecules include, but are not limited to, peptide nucleic acid (PNA) and phosphorothioate-based molecules such as deoxyribonucleic guanidine (DNG) or ribonucleic guanidine (RNG).

[0088] Antisense RNA can be provided to the cell as "ready-to-use" RNA synthesized in vitro or as an antisense gene stably transfected into cells which will yield antisense RNA upon transcription. Hybridization with mRNA results in degradation of the hybridized molecule by RNAse H and/or inhibition of the formation of translation complexes. Both result in a failure to produce the product of the original gene.

[0089] Both antisense RNA and DNA molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of RNA molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro or in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly can be introduced into cell lines, cells or tissues.

[0090] DNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences of the 5' and/or 3' ends of the molecule or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. Other modifications include the use of chimeric antisense compounds. Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos. 5,700,922 and 6,277,603.

[0091] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.

[0092] Antisense compositions of the invention include oligonucleotides formed of homopyrimidines that can recognize local stretches of homopurines in the DNA double helix and bind to them in the major groove to form a triple helix. See: Helen, C and Toulme, J J. Specific regulation of gene expression by antisense, sense, and antigene nucleic acids. Biochem. Biophys Acta, 1049:99-125, 1990. Formation of the triple helix would interrupt the ability of the specific gene to undergo transcription by RNA polymerase. Triple helix formation using myc-specific oligonucleotides has been observed. See: Cooney, M, et al. Science 241:456-459.

[0093] Antisense sequences of DNA or RNA can be delivered to cells. Several chemical modifications have been developed to prolong the stability and improve the function of these molecules without interfering with their ability to recognize specific sequences. These include increasing their resistance to degradation by DNases, including phosphotriesters, methylphosphonates, phosphorothioates, alpha-anomers, increasing their affinity for binding partners by covalent linkage to various intercalating agents such as psoralens, and increasing uptake by cells by conjugation to various groups including polylysine. These molecules recognize specific sequences encoded in mRNA and their hybridization prevents translation of and increases the degradation of these messages.

[0094] Antisense compositions including oligonucleotides, derivatives and analogs thereof, conjugation protocols, and antisense strategies for inhibition of transcription and translation are generally described in: Antisense Research and Applications, Crooke, S. and B. Lebleu, eds. CRC Press, Inc. Boca Raton Fla. 1993; Nucleic Acids in Chemistry and Biology Blackburn, G. and M. J. Gait, eds. IRL Press at Oxford University Press, Inc. New York 1990; and Oligonucleotides and Analogues: A Practical Approach Eckstein, F. ed., IRL Press at Oxford University Press, Inc. New York 1991; which are each hereby incorporated herein by reference including all references cited therein which are hereby incorporated herein by reference.

[0095] Pharmaceutical Compositions and Vaccines

[0096] The invention provides CSTC-targeting peptides, cancer-specific isoforms of transcription modulators, polynucleotides, T cells and/or antigen presenting cells that are incorporated into pharmaceutical compositions. Pharmaceutical compositions comprise one or more such compounds and, optionally, a physiologically acceptable carrier. Vaccines may comprise one or more such compounds and an adjuvant that serves as a non-specific immune response enhancer. The adjuvant may be any substance that enhances an immune response to an exogenous antigen. Examples of adjuvants include conventional adjuvants, biodegradable microspheres (e.g., polylactic galactide), immunostimulatory oligonucleotides and liposomes (into which the compound is incorporated; see e.g., Fullerton, U.S. Pat. No. 4,235,877). Vaccine preparation is generally described in, for example, M. F. Powell and M. J. Newman, eds., "Vaccine Design (the subunit and adjuvant approach)," Plenum Press (NY, 1995). Pharmaceutical compositions and vaccines within the scope of the present invention may also contain other compounds that may be biologically active or inactive. For example, one or more immunogenic portions of other tumor antigens may be present, either incorporated into a fusion polypeptide or as a separate compound, within the composition or vaccine.

[0097] A pharmaceutical composition can contain DNA encoding one or more of the peptides as described above, such that the peptide is generated in situ. As noted above, the DNA may be present within any of a variety of delivery systems known to those of ordinary skill in the art, including nucleic acid expression systems, bacteria and viral expression systems. Numerous gene delivery techniques are well known in the art, such as those described by Rolland, Crit. Rev. Therap. Drug Carrier Systems 15:143-198, 1998, and references cited therein. Appropriate nucleic acid expression systems contain the necessary DNA sequences for expression in the patient (such as a suitable promoter and terminating signal). Bacterial delivery systems involve the administration of a bacterium (such as Bacillus-Calmette-Guerrin) that expresses an immunogenic portion of the polypeptide on its cell surface or secretes such an epitope.

[0098] In a preferred embodiment, the DNA may be introduced using a viral expression system (e.g., vaccinia or other pox virus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic (defective), replication competent virus. Suitable systems are disclosed, for example, in Fisher-Hoch et al., Proc. Natl. Acad. Sci. USA 86:317-321, 1989; Flexner et al., Ann. N.Y. Acad Sci. 569:86-103, 1989; Flexner et al., Vaccine 8:17-21, 1990; U.S. Pat. Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89/01973; U.S. Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91/02805; Berkner-Biotechniques 6:616-627, 1988; Rosenfeld et al., Science 252:431-434, 1991; Kolls et al., Proc. Natl. Acad. Sci. USA 91:215-219, 1994; Kass-Eisler et al., Proc. Natl. Acad. Sci. USA 90:11498-11502, 1993; Guzman et al., Circulation 88:2838-2848, 1993; and Guzman et al., Cir. Res. 73:1202-1207, 1993. Techniques for incorporating DNA into such expression systems are well known to those of ordinary skill in the art. The DNA may also be "naked," as described, for example, in Ulmer et al., Science 259:1745-1749, 1993 and reviewed by Cohen, Science 259:1691-1692, 1993. The uptake of naked DNA may be increased by coating the DNA onto biodegradable beads, which are efficiently transported into the cells.

[0099] While any suitable carrier known to those of ordinary skill in the art may be employed in the pharmaceutical compositions of this invention, the type of carrier will vary depending on the mode of administration. Compositions of the present invention may be formulated for any appropriate manner of administration, including for example, topical, oral, nasal, intravenous, intracranial, intraperitoneal, subcutaneous, intradermal or intramuscular administration. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a fat, a wax or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, may be employed. Biodegradable microspheres (e.g., polylactate polyglycolate) may also be employed as carriers for the pharmaceutical compositions of this invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Pat. Nos. 4,897,268 and 5,075,109.

[0100] In addition, the carrier may contain other pharmacologically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation. Similarly, the carrier may contain still other pharmacologically-acceptable excipients for modifying or maintaining the stability, rate of dissolution, release, or absorption or penetration across the blood-brain barrier of the delivered molecule. Such excipients are those substances usually and customarily employed to formulate dosages for parenteral administration in either unit dose or multi-dose form or for direct infusion into the CSF by continuous or periodic infusion from an implanted pump.

[0101] Such compositions may also comprise buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, adjuvants (e.g., aluminum hydroxide) and/or preservatives. Alternatively, compositions of the present invention may be formulated as a lyophilizate. Compounds may also be encapsulated within liposomes using well known technology.

[0102] Any of a variety of adjuvants may be employed in the vaccines of this invention. Most adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a stimulator of immune responses, such as lipid A, Bortadella pertussis or Mycobacterium tuberculosis derived proteins. Suitable adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, Mich.); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.); aluminum salts such as aluminum hydroxide gel (alum) or aluminum phosphate; salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes biodegradable microspheres; monophosphoryl lipid A and quil A. Cytokines, such as GM CSF or interleukin-2, -7, or -12, may also be used as adjuvants.

[0103] Within the vaccines provided herein, the adjuvant composition is preferably designed to induce an immune response predominantly of the Th1 type. High levels of Th1-type cytokines (e.g., IFN-.alpha., IL-2 and IL-12) tend to favor the induction of cell mediated immune responses to an administered antigen. In contrast, high levels of Th2-type cytokines (e.g., IL-4, IL-5, IL-6, IL-10 and TNF-.beta.) tend to favor the induction of humoral immune responses. Following application of a vaccine as provided herein, a patient will support an immune response that includes Th1- and Th2-type responses. Within a preferred embodiment, in which a response is predominantly Th1 -type, the level of Th1 -type cytokines will increase to a greater extent than the level of Th2-type cytokines. The levels of these cytokines may be readily assessed using standard assays. For a review of the families of cytokines, see Mosmann and Coffman, Ann. Rev. Immunol. 7:145-173, 1989.

[0104] The compositions described herein may be administered as part of a sustained release formulation (i.e., a formulation such as a capsule or sponge that effects a slow release of compound following administration). Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site, such as a site of surgical excision of a tumor. Sustained-release formulations may contain a peptide, polynucleotide or antibody dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of active compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.

[0105] Therapeutic and Prophylactic Methods

[0106] Treatment includes prophylaxis and therapy. Prophylaxis or therapy can be accomplished by a single direct injection at a single time point or multiple time points to a single or multiple sites. Administration can also be nearly simultaneous to multiple sites. Patients or subjects include mammals, such as human, bovine, equine, canine, feline, porcine, and ovine animals. The subject is preferably a human.

[0107] A cancer may be diagnosed using criteria generally accepted in the art, including the presence of a malignant tumor. Pharmaceutical compositions and vaccines may be administered either prior to or following surgical removal of primary tumors and/or treatment such as administration of radiotherapy or conventional chemotherapeutic drugs.

[0108] Within certain embodiments, immunotherapy may be active immunotherapy, in which treatment relies on the in vivo stimulation of the endogenous host immune system to react against tumors or infected cells with the administration of immune response-modifying agents (such as peptides and polynucleotides disclosed herein).

[0109] Within other embodiments, immunotherapy may be passive immunotherapy, in which treatment involves the delivery of agents with established tumor-immune reactivity (such as effector cells or antibodies) that can directly or indirectly mediate antitumor effects and does not necessarily depend on an intact host immune system. Examples of effector cells include T cells as discussed above, T lymphocytes (such as CD8+ cytotoxic T lymphocytes and CD4+ T-helper tumor-infiltrating lymphocytes), killer cells (such as Natural Killer cells and lymphokine-activated killer cells), B cells and antigen-presenting cells (such as dendritic cells and macrophages) expressing a peptide provided herein. In a preferred embodiment, dendritic cells are modified in vitro to present the peptide, and these modified APCs are administered to the subject. T cell receptors and antibody receptors specific for the peptides recited herein may be cloned, expressed and transferred into other vectors or effector cells for adoptive immunotherapy. The peptides provided herein may also be used to generate antibodies or anti-idiotypic antibodies (as described above and in U.S. Pat. No. 4,918,164) for passive immunotherapy.

[0110] Administration and Dosage

[0111] The compositions are administered in any suitable manner, often with pharmaceutically acceptable carriers. Suitable methods of administering cells in the context of the present invention to a subject are available, and, although more than one route can be used to administer a particular cell composition, a particular route can often provide a more immediate and more effective reaction than another route.

[0112] The dose administered to a patient, in the context of the present invention, should be sufficient to effect a beneficial therapeutic response in the patient over time, or to inhibit disease progression. Thus, the composition is administered to a subject in an amount sufficient to alleviate, reduce, cure or at least partially arrest symptoms and/or complications from the disease and/or to elicit an effective immune response to the specific antigens. An amount adequate to accomplish this is defined as a "therapeutically effective dose."

[0113] Routes and frequency of administration of the therapeutic compositions disclosed herein, as well as dosage, will vary from individual to individual, and may be readily established using standard techniques. In general, the pharmaceutical compositions and vaccines may be administered, by injection (e.g., intracutaneous, intratumoral, intramuscular, intraperitoneal, intravenous or subcutaneous), intranasally (e.g., by aspiration) or orally. Preferably, between 1 and 10 doses may be administered over a 52 week period. Preferably, 6 doses are administered, at intervals of 1 month, and booster vaccinations may be given periodically thereafter. Alternate protocols may be appropriate for individual patients. In one embodiment, 2 intradermal injections of the composition are administered 10 days apart. In another embodiment, a dose is administered daily or once every 2 or 3 days over an extended period, such as weeks or months.

[0114] A suitable dose is an amount of a compound that, when administered as described above, is capable of promoting an anti-tumor response, and is at least 10-50% above the basal (i.e., untreated) level. Such response can be monitored, for example, by measuring reduction in tumor size or the level of anti-tumor antibodies in a patient or by vaccine-dependent generation of cytolytic effector cells capable of killing the patient's tumor cells in vitro. Such therapies should also be capable of causing a response that leads to an improved clinical outcome (e.g., more frequent remissions, complete or partial or longer disease-free survival) in patients as compared to untreated patients. In general, for pharmaceutical compositions and vaccines comprising one or more peptides, the amount of each peptide present in a dose ranges from about 100 .mu.g to 5 mg per kg of host. Suitable volumes will vary with the size of the patient, but will typically range from about 0.1 mL to about 5 mL.

[0115] In general, an appropriate dosage and treatment regimen provides the active compound(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit. Such a response can be monitored by establishing an improved clinical outcome (e.g., more frequent remissions, complete or partial, or longer disease-free survival) in treated patients as compared to non-treated patients. Increases in preexisting immune responses to a tumor protein generally correlate with an improved clinical outcome. Such immune responses may generally be evaluated using standard proliferation, cytotoxicity or cytokine assays, which may be performed using samples obtained from a patient before and after treatment.

[0116] Diagnostic Methods

[0117] The invention provides a method for detecting cancer in a tissue comprising contacting the tissue with a molecule that recognizes and binds a CSTC or cancer-specific isoform of a transcription modulator described herein. The molecule can be, for example, a CSTC-targeting peptide, an antibody directed against a CSTC or cancer-specific isoform of a transcription modulator, or an oligonucleotide probe or antisense molecule directed against a cancer-specific molecule. The tissue can be from a mammal, such as human, bovine, equine, canine, feline, porcine, and ovine tissue. The tissue is preferably a human. The tissue can comprise a tumor specimen, cerebrospinal fluid, or other suitable specimen. In one embodiment, the method comprises use of an ELISA type assay. Those skilled in the art will appreciate additional variations suitable for the method of detecting cancer in tissue through detection of a cancer-specific molecule in a specimen. This method can also be used to monitor levels of the cancer-specific molecule in tissue of a patient undergoing treatment for cancer. The suitability of a CSTC-targeted therapeutic regimen for initial or continued treatment can be determined by monitoring such levels using this method.

[0118] The invention additionally provides a method for identifying a molecule that inhibits proliferation of cancer cells. The method comprises contacting a candidate molecule with a CSTC and determining whether the candidate molecule disrupts the biological activity of the CSTC. Disruption of the biological activity of the CSTC is indicative of a molecule that inhibits proliferation of cancer cells. Representative molecules include antibodies, proteins, peptides and nucleotides.

[0119] Kits

[0120] For use in the diagnostic and therapeutic applications described herein, kits are also within the scope of the invention. Such kits can comprise a carrier, package or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in the method. For example, the container(s) can comprise a probe that is or can be detectably labeled. The probe can be an antibody or polynucleotide specific for a cancer-specific molecule of the invention. The kit can also include containers containing nucleotide(s) for amplification of a target nucleic acid sequence and/or a container comprising a reporter-means, such as a biotin-binding protein, e.g., avidin or streptavidin, bound to a detectable label, e.g., an enzymatic, fluorescent, or radioisotope label. The kit can include all or part of an amino acid sequence of the sequences described herein, or a nucleic acid molecule that encodes such amino acid sequences.

[0121] The kit of the invention will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In addition, a label can be provided on the container to indicate that the composition is used for a specific therapeutic or non-therapeutic application, and can also indicate directions for either in vivo or in vitro use, such as those described above. Directions and or other information can also be included on an insert which is included with the kit.

EXAMPLES

[0122] The following examples are presented to illustrate the present invention and to assist one of ordinary skill in making and using the same. The examples are not intended in any way to otherwise limit the scope of the invention.

Example 1

Identification of Isoforms of Transcriptional Co-Regulators

[0123] This example demonstrates the results of an extensive in silico analysis of components of transcriptional co-regulators and use of PCR primers designed to identify novel iosforms with altered activity.

[0124] Material & Methods

[0125] Primary Tumors

[0126] Surgical specimens were obtained from human patients undergoing surgery for melanoma. Specimens were trypsinized and prepared for analysis using conventional techniques. RNA isolation was performed as described below.

[0127] Cell Culture

[0128] Human melanoma cell lines SK-MEL-28 and WM-266-4 were obtained from the American Type Culture Collection (ATCC; Manassas, Va.; SK-MEL-28 deposited by T. Takehashi and subject to release terms set by The Memorial Sloan-Kettering Cancer Center; WM-266-4 deposited by M. Herlyn). Cells were cultured according to recommendations of ATCC (DMEM, 10% FCS, penicillin+streptomycin) and used in experiments after two passages in the laboratory. Cells were grown in 24 well plates, each treatment in triplicates. Cells were plated 16 hours prior treatments started. Peptides were added to the media, and media was changed every day during 7 day experiment. CPP concentration was 10 .mu.M.

[0129] For cell counting, cells were trypsinized (0.25% Trypsin, 2 mM EDTA) in Ca+2, Mg+2 free PBS. Cells were precipitated and resuspended in 100 .mu.l of PBS, and 5 .mu.l were removed for counting

[0130] Apoptosis was analyzed using Biovision Annexin V-Cy3 Apoptosis Kit according to manufacturer's protocols.

[0131] Identification of Isoforms of Transcriptional Co-Regulators in Melanoma Cells

[0132] RNA was isolated from human melanoma cell lines SK-MEL-28 and WM 266-4 and primary tumors using RNA isolation KIT (Qiagen). RT-PCR was used to identify isoforms of co-regulators. Primers used to analyze isoforms are presented in Table. 1.

[0133] First strand cDNAs were synthesized with reverse transcriptase (Superscriptll, Life Technologies Inc.) using 5-10 .mu.g of mRNA from different cell lines as a template. PCR reactions were performed in the volume of 25 .mu.l containing one tenth of RT reaction as a template and GC-Rich PCR System or the Expand.TM.. Long Distance PCR System kit (Roche) according to manufacturer's instructions. All amplified PCR products were sequenced and sequences analyzed to identify novel functional isoforms of transcriptional co-regulators.

TABLE-US-00002 TABLE 1 Oligonucleotide primers used to isolate and characterize isoforms of transcriptional co-regulators in human melanoma cells. ##STR00001## ##STR00002## ##STR00003## ##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##

[0134] Peptides

[0135] We generated small libraries of CPP-NLS-interfering peptides that potentially interact with melanoma expressed TFCs containing isoforms of co-regulator proteins BAF57 and TRAP100. Initial screening of these libraries identified the two following peptides that were further analyzed.

TABLE-US-00003 (1) (SEQ ID NO: 6) BAF57 P12-PKKRKVRRRRRRRNDRLSDGDSKYSQTSHKLVQLL (2) (SEQ ID NO: 5) TRAP100 P05-PKKRKVRRRRRRRPQMQQNVFQYPGAGMVPQGEANF First portion-NLS, underlined-CPP; last portion-mimicking domains NLS--nucleus localizing signal; CPP--cell penetrating peptide

[0136] Results

[0137] Isoforms of Transcriptional Co-Regulators

[0138] We have conducted an extensive in silico analysis of components of transcriptional co-regulators and designed PCR primers to identify novel isoforms with altered function (activity). Identified isoforms are presented in Table 1.

[0139] Based on the known assembly and composition of TFCs and function of individual components of TFCs, we predicted changes in TFCs that contain isoforms of MED24. Since these isoforms and corresponding TFCs are expressed specifically in melanoma cells, these TFCs represent a suitable target for drug development. We therefore designed peptides that interact with a melanoma specific TFC and in this way disrupt its function, leading to cell death (apoptosis) and/or cessation of cell proliferation.

Example 2

Effect of Interfering Peptides on Proliferation and Apoptosis of Melanoma Cells

[0140] Modeling of TFCs that contain isoforms of BAF57 and TRAP100 identified specific interactions that enabled us to synthesize small peptide libraries. Screening of these libraries using melanoma cell line SK-MEL-28 resulted in two peptides, denoted by us as BAF57 P12 and TRAP100 P05 that were found to stimulate apoptosis and inhibit growth of melanoma cells in vitro.

[0141] Amino acid sequences of SMARCE1/BAF57 and TRAP100 isoforms. Unique, isoform specific sequences are underlined.

TABLE-US-00004 SMARCE1/BAF57 (SEQ ID NO: 10) MSKRPSYAPPPTPAPATQMPSTPGFVGYNPYSHLAYNNYRLGGNPGTNSRVTASSGITIPKPPKPPDKPLMPYM- RYSRKVWDQVK ASNPDLKLWEIGKIIGGMWRDLTDEEKQEYLNEYEAEKIEYNESMKAYHNSPAYLAYINAKSRAEAALEEESRQ- RQSRMEKGEPY MSIQPAEDPDDYDDGFSMKHTATARFQRNHRLISEILSESVVPDVRSVVTTARMQVLKRQVQSLMVHQRKLEAE- LLQIEERHQEK KRKFLESTDSFNNELKRLCGLKVEVDMEKIAAEIAQAEEQARKRQEEREKEAAEQAERSQSSIVPEEEQAANKG- EEKKDDENIPM ETEETHLEETTESQQNGEEGTSTPEDKESGQEGVDSMAEEGTSDSNTGSESNSATVEEPPTDPIPEDEKKE SMARCE1/BAF57 isoform 1 (SEQ ID NO: 11) MSKRPSYAPPPTPAPATQMPSTPGFVGYNPYSHLAYNNYRLGGNPGTNSRVTTLFIGDFLGPCSSVSTVLPASP- LEIESRKLERE LLLEVGFLIVARKETVQKWKHILQKHSPASSGITIPKPPKPPDKPLMPYMRYSRKVWDQVKASNPDLKLWEIGK- IIGGMWRDLTD EEKQEYLNEYEAEKIEYNESMKAYHNSPAYLAYINAKSRAEAALEEESRQRQSRMEKGEPYMSIQPAEDPDDYD- DGFSMKHTATA RFQRNHRLISEILSESVVPDVRSVVTTARMQVLKRQVQSLMVHQRKLEAELLQIEERHQEKKRKFLESTDSFNN- ELKRLCGLKVE VDMEKIAAEIAQAEEQARKRQEEREKEAAEQAERSQSSIVPEEEQAANKGEEKKDDENIPMETEETHLEETTES- QQNGEEGTSTP EDKESGQEGVDSMAEEGTSDSNTGSESNSATVEEPPTDPIPEDEKKE TRAP100 (SEQ ID NO: 12) MKVVNLKQAILQAWKERWSYYQWAINMKKFFPKGATWDILNLADALLEQAMIGPSPNPLILSYLKYAISSQMVS- YSSVLTAISKF DDFSRDLCVQALLDIMDMFCDRLSCHGKAEECIGLCRALLSALHWLLRCTAASAERLREGLEAGTPAAGEKQLA- MCLQRLEKTLS STKNRALLHIAKLEEASSWTAIEHSLLKLGEILTNLSNPQLRSQAEQCGTLIRSIPTMLSVHAEQMHKTGFPTV- HAVILLEGTMN LTGETQSLVEQLTMVKRMQHIPTPLFVLEIWKACFVGLIESPEGTEELKWTAFTFLKIPQVLVKLKKYSHGDKD- FTEDVNCAFEF LLKLTPLLDKADQRCNCDCTNFLLQECGKQGLLSEASVNNLMAKRKADREHAPQQKSGENANIQPNIQLILRAE- PTVTNILKTMD ADHSKSPEGLLGVLGHMLSGKSLDLLLAAAAATGKLKSFARKFINLNEFTTYGSEESTKPASVRALLFDISFLM- LCHVAQTYGSE VILSESRTGAEVPFFETWMQTCMPEEGKILNPDHPCFRPDSTKVESLVALLNNSSEMKLVQMKWHEACLSISAA- ILEILNAWENG VLAFESIQKITDNIKGKVCSLAVCAVAWLVAHVRMLGLDEREKSLQMIRQLAGPLFSENTLQFYNERVVIMNSI- LERMCADVLQQ TATQIKFPSTGVDTMPYWNLLPPKRPIKEVLTDIFAKVLEKGWVDSRSIHIFDTLLHMGGVYWFCNNLIKELLK- ETRKEHTLRAV ELLYSIFCLDMQQVTLVLLGHILPGLLTDSSKWHSLMDPPGTALAKLAVWCALSSYSSHKGQASTRQKKRHRED- IEDYISLFPLD DVQPSKLMRLLSSNEDDANILSSPTDRSMSSSLSASQLHTVNMRDPLNRVLANLFLLISSILGSRTAGPHTQFV- QWFMEECVDCL EQGGRGSVLQFMPFTTVSELVKVSAMSSPKVVLAITDLSLPLGRQVAAKAIAAL TRAP100 isoform 1 (SEQ ID NO: 13) MKVVNLKQAILQAWKERWSYYQWAINMKKFFPKGATWDILNLADALLEQAMIGPSPNPLILSYLKYAISSQMVS- YSSVLTAISKF DDFSRDLCVQALLDIMDMFCDRLSCHGKAEECIGLCRALLSALHWLLRCTAASAERLREGLEAGTPAAGEKQLA- MCLQRLEKTLS STKNRALLHIAKLEEACPHQALLVGSKTSTSQTRKKLEDKTSTVSIIVFVSMILIAWKQMTLVFECYLKCSSWT- AIEHSLLKLGE ILTNLSNPQLRSQAEQCGTLIRSIPTMLSVHAEQMHKTGFPTVHAVILLEGTMNLTGETQSLVEQLTMVKRMQH- IPTPLFVLEIW KACFVGLIESPEGTEELKWTAFTFLKIPQVLVKLKKYSHGDKDFTEDVNCAFEFLLKLTPLLDKADQRCNCDCT- NFLLQECGKQG LLSEASVNNLMAKRKADREHAPQQKSGENANIQPNIQLILRAEPTVTNILKTMDADHSKSPEGLLGVLGHMLSG- KSLDLLLAAAA ATGKLKSFARKFINLNEFTTYGSEESTKPASVRALLFDISFLMLCHVAQTYGSEVILSESRTGAEVPFFETWMQ- TCMPEEGKILN PDHPCFRPDSTKVESLVALLNNSSEMKLVQMKWHEACLSISAAILEILNAWENGVLAFESIQKITDNIKGKVCS- LAVCAVAWLVA HVRMLGLDEREKSLQMIRQLAGPLFSENTLQFYNERVVIMNSILERMCADVLQQTATQIKFPSTGVDTMPYWNL- LPPKRPIKEVL TDIFAKVLEKGWVDSRSIHIFDTLLHMGGVYWFCNNLIKELLKETRKEHTLRAVELLYSIFCLDMQQVTLVLLG- HILPGLLTDSS KWHSLMDPPGTALAKLAVWCALSSYSSHKGQASTRQKKRHREDIEDYISLFPLDDVQPSKLMRLLSSNEDDANI- LSSPTDRSMSS SLSASQLHTVNMRDPLNRVLANLFLLISSILGSRTAGPHTQFVQWFMEECVDCLEQGGRGSVLQFMPFTTVSEL- VKVSAMSSPKV VLAITDLSLPLGRQVAAKAIAAL

[0142] Effects of peptide drug candidates BAF57 P12 and TRAP100 P05 on cell proliferation and apoptosis were analyzed using human melanoma cell lines SK-MEL-28 and WM 266-4. Therapeutic peptides were added at a concentration of 10 .mu.M directly to culture media. Internalization and translocation of the therapeutic peptide(s) into the cell nucleus was studied using fluorescein labeled peptides. Peptides showed prominent nuclear localization following 8 hours of incubation with cells. This pattern remained unchanged for 7 days in cells that do not become apoptotic. As controls we used scrambled peptides. Results of these experiments (Table 2) clearly show that peptides BAF57P12 and TRAP100P05 suppress significantly proliferation and induce apoptosis. Simultaneous incubation of melanoma cells with both peptides caused complete inhibition of proliferation and induction of apoptosis in almost all treated cells.

TABLE-US-00005 TABLE 2 Effect of peptides BAF57P12 and TRAP100P05 on proliferation and apoptosis of human melanoma SK-MEL-28 and WM 266-4 cells. Cell Concen- Cell Count 7 Apoptosis line Peptide tration Start days 7 days/% SK- no 10 57 0 MEL-28 scrambled BAF 10 54 0 BAF57 P12 10 .mu.M 10 16 65 Scrambled TRAP 10 .mu.M 10 58 0 TRAP100 P05 10 .mu.M 10 12 78 scrambled BAF + 10 .mu.M 10 46 4 TRAP BAF57 P12 + 10 .mu.M 10 9 95 TRAP100 P05 WM no 10 .mu.M 10 39 0 266-4 scrambled BAF 10 .mu.M 10 37 0 BAF57 P12 10 .mu.M 10 17 59 Scrambled TRAP 10 .mu.M 10 34 1 TRAP100 P05 10 .mu.M 10 15 78 scrambled BAF + 10 .mu.M 10 32 8 TRAP BAF57 P12 + 10 .mu.M 10 8 98 TRAP100 P05

[0143] The results of testing and validation of our peptide drug candidates demonstrated that our therapeutic peptides are viable drug candidates for treatment of melanoma in situ as well as metastatic melanoma.

Example 3

Treatment of Human Melanoma Xenografts Using CSTC-Targeting Peptides

[0144] This example demonstrates the effect of therapeutic peptides on development of human melanomas in 4-week-old BALB/cOlaHsd-nu mice (Harlan, UK). Seven days after injection of melanoma cells, mice were randomly divided into 2 groups, 10 animals each. Control animals received intravenous (tail vein) injections of 50 microliters of phosphate buffer solution (PBS) every other day for 3 weeks. Test animals received intravenous (tail vein) injections of peptides BAF57 P12 and TRAP100 P05 (together) at a concentration of 0.5 mM each in 50 microliters of PBS every other day for 3 weeks. Last 2 injections were done using peptides labeled with fluorescein.

[0145] Therapeutic Peptides

TABLE-US-00006 BAF57 P12-PKKRKVRRRRRRRNDRLSDGDSKYSQTSHKLVQLL TRAP100 P05-PKKRKVRRRRRRRPQMQQNVFQYPGAGMVPQGEANF Red-NLS, blue-CPP and black-mimicking domains

[0146] One day following the last injection, animals were sacrificed and subcutaneous tumors were removed, weighed and measured. Tumor tissue samples were obtained and subjected to molecular analysis.

[0147] Results

[0148] It was found that in SCID mice bearing cutaneous human melanomas, intravenous (systemic) treatment with our peptide drug candidates reduced the weight and size of melanoma tumors by 57.+-.18% (33-85%) compared to matched control animals receiving intravenous injections of PBS (Table 3).

TABLE-US-00007 TABLE 3 Effect of BAF57 P12 and TRAP100 P05 on tumor growth in vivo. Control tumors Peptide treated tumors Tumor Tumor Animal weight (g) Animal weight (g) Reduction (%) C1 0.6 T1 0.2 33 C2 0.5 T2 0.1 85 C3 0.9 T3 0.4 56 C4 0.6 T4 0.3 50 C5 0.4 T5 0.1 75 C6 0.7 T6 0.3 57 C7 0.9 T7 0.6 34 C8 died T8 0.4 -- C9 0.9 T9 0.5 46 C10 0.4 T10 0.1 75 Mean .+-. SD 6.8 .+-. 2.0 g 3.0 .+-. 1.8 g 57 .+-. 18%

[0149] Treatment of immune-compromised mice with cutaneous human melanomas with our two peptide drug candidates BAF57 P12 and TRAP100 P05 demonstrated that said therapeutic peptides are viable drug candidates for treatment of melanoma in situ as well as metastatic melanoma.

Example 4

Expression of BAF57 and MED24 Isoforms in Different Cancer Types

[0150] This example demonstrates that the cancer-specific isoforms of BAF57 and MED24 described herein are not limited to melanoma, but are also expressed in other types of cancer, including, colorectal, breast and brain cancers. In this study, surgically removed tumor samples from 21 melanoma, 25 colorectal cancer, 27 breast cancer and 11 glioblastoma patients were used to isolate RNA and analyze expression of BAF57 and MED24 isoforms using RT-PCR technique. Results of the analysis are presented in Table 4.

[0151] RNA was isolated from surgically removed tumor samples using RNA isolation KIT (Qiagen). RT-PCR was used to identify isoforms of co-regulators. First strand cDNAs were synthesized with reverse transcriptase (Superscriptll, Life Technologies Inc.) using 5-10 .mu.g of mRNA. PCR reactions were performed in the volume of 25 .mu.l containing one tenth of RT reaction as a template and GC-Rich PCR System or the Expand.TM.. Long Distance PCR System kit (Roche) was used in accordance with manufacturer's instructions.

TABLE-US-00008 TABLE 4 Expression of isoforms of BAF57 and MED24 in tumor samples. # of samples # of samples Cancer with BAF57 with MED24 type # of samples isoform isoform Melanoma 21 12 16 Colorectal 25 3 15 Breast 27 1 1 glioblastoma 11 8 9

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[0179] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Sequence CWU 1

1

175123PRTHomo sapiens 1Pro Gln Met Gln Gln Asn Val Phe Gln Tyr Pro Gly Ala Gly Met Val1 5 10 15Pro Gln Gly Glu Ala Asn Phe 20222PRTHomo sapiens 2Asn Asp Arg Leu Ser Asp Gly Asp Ser Lys Tyr Ser Gln Thr Ser His1 5 10 15Lys Leu Val Gln Leu Leu 2037PRTHomo sapiens 3Arg Arg Arg Arg Arg Arg Arg1 546PRTHomo sapiens 4Pro Lys Lys Arg Lys Val1 5536PRTHomo sapiens 5Pro Lys Lys Arg Lys Val Arg Arg Arg Arg Arg Arg Arg Pro Gln Met1 5 10 15Gln Gln Asn Val Phe Gln Tyr Pro Gly Ala Gly Met Val Pro Gln Gly 20 25 30Glu Ala Asn Phe 35635PRTHomo sapiens 6Pro Lys Lys Arg Lys Val Arg Arg Arg Arg Arg Arg Arg Asn Asp Arg1 5 10 15Leu Ser Asp Gly Asp Ser Lys Tyr Ser Gln Thr Ser His Lys Leu Val 20 25 30Gln Leu Leu 35723PRTHomo sapiensQ(N)(2)..(9)Xaa is Q or N 7Pro Xaa Met Xaa Xaa Xaa Val Phe Xaa Tyr Pro Xaa Xaa Xaa Met Xaa1 5 10 15Pro Xaa Gly Xaa Xaa Xaa Phe 20822PRTHomo sapiensMISC_FEATURE(2)..(2)X is D or E 8Asn Xaa Xaa Xaa Ser Xaa Gly Xaa Ser Xaa Tyr Ser Xaa Thr Ser His1 5 10 15Xaa Xaa Xaa Gln Xaa Xaa 2097PRTHomo sapiens 9Pro Pro Lys Lys Arg Lys Val1 510411PRTHomo sapiens 10Met Ser Lys Arg Pro Ser Tyr Ala Pro Pro Pro Thr Pro Ala Pro Ala1 5 10 15Thr Gln Met Pro Ser Thr Pro Gly Phe Val Gly Tyr Asn Pro Tyr Ser 20 25 30His Leu Ala Tyr Asn Asn Tyr Arg Leu Gly Gly Asn Pro Gly Thr Asn 35 40 45Ser Arg Val Thr Ala Ser Ser Gly Ile Thr Ile Pro Lys Pro Pro Lys 50 55 60Pro Pro Asp Lys Pro Leu Met Pro Tyr Met Arg Tyr Ser Arg Lys Val65 70 75 80Trp Asp Gln Val Lys Ala Ser Asn Pro Asp Leu Lys Leu Trp Glu Ile 85 90 95Gly Lys Ile Ile Gly Gly Met Trp Arg Asp Leu Thr Asp Glu Glu Lys 100 105 110Gln Glu Tyr Leu Asn Glu Tyr Glu Ala Glu Lys Ile Glu Tyr Asn Glu 115 120 125Ser Met Lys Ala Tyr His Asn Ser Pro Ala Tyr Leu Ala Tyr Ile Asn 130 135 140Ala Lys Ser Arg Ala Glu Ala Ala Leu Glu Glu Glu Ser Arg Gln Arg145 150 155 160Gln Ser Arg Met Glu Lys Gly Glu Pro Tyr Met Ser Ile Gln Pro Ala 165 170 175Glu Asp Pro Asp Asp Tyr Asp Asp Gly Phe Ser Met Lys His Thr Ala 180 185 190Thr Ala Arg Phe Gln Arg Asn His Arg Leu Ile Ser Glu Ile Leu Ser 195 200 205Glu Ser Val Val Pro Asp Val Arg Ser Val Val Thr Thr Ala Arg Met 210 215 220Gln Val Leu Lys Arg Gln Val Gln Ser Leu Met Val His Gln Arg Lys225 230 235 240Leu Glu Ala Glu Leu Leu Gln Ile Glu Glu Arg His Gln Glu Lys Lys 245 250 255Arg Lys Phe Leu Glu Ser Thr Asp Ser Phe Asn Asn Glu Leu Lys Arg 260 265 270Leu Cys Gly Leu Lys Val Glu Val Asp Met Glu Lys Ile Ala Ala Glu 275 280 285Ile Ala Gln Ala Glu Glu Gln Ala Arg Lys Arg Gln Glu Glu Arg Glu 290 295 300Lys Glu Ala Ala Glu Gln Ala Glu Arg Ser Gln Ser Ser Ile Val Pro305 310 315 320Glu Glu Glu Gln Ala Ala Asn Lys Gly Glu Glu Lys Lys Asp Asp Glu 325 330 335Asn Ile Pro Met Glu Thr Glu Glu Thr His Leu Glu Glu Thr Thr Glu 340 345 350Ser Gln Gln Asn Gly Glu Glu Gly Thr Ser Thr Pro Glu Asp Lys Glu 355 360 365Ser Gly Gln Glu Gly Val Asp Ser Met Ala Glu Glu Gly Thr Ser Asp 370 375 380Ser Asn Thr Gly Ser Glu Ser Asn Ser Ala Thr Val Glu Glu Pro Pro385 390 395 400Thr Asp Pro Ile Pro Glu Asp Glu Lys Lys Glu 405 41011472PRTHomo sapiens 11Met Ser Lys Arg Pro Ser Tyr Ala Pro Pro Pro Thr Pro Ala Pro Ala1 5 10 15Thr Gln Met Pro Ser Thr Pro Gly Phe Val Gly Tyr Asn Pro Tyr Ser 20 25 30His Leu Ala Tyr Asn Asn Tyr Arg Leu Gly Gly Asn Pro Gly Thr Asn 35 40 45Ser Arg Val Thr Thr Leu Phe Ile Gly Asp Phe Leu Gly Pro Cys Ser 50 55 60Ser Val Ser Thr Val Leu Pro Ala Ser Pro Leu Glu Ile Glu Ser Arg65 70 75 80Lys Leu Glu Arg Glu Leu Leu Leu Glu Val Gly Phe Leu Ile Val Ala 85 90 95Arg Lys Glu Thr Val Gln Lys Trp Lys His Ile Leu Gln Lys His Ser 100 105 110Pro Ala Ser Ser Gly Ile Thr Ile Pro Lys Pro Pro Lys Pro Pro Asp 115 120 125Lys Pro Leu Met Pro Tyr Met Arg Tyr Ser Arg Lys Val Trp Asp Gln 130 135 140Val Lys Ala Ser Asn Pro Asp Leu Lys Leu Trp Glu Ile Gly Lys Ile145 150 155 160Ile Gly Gly Met Trp Arg Asp Leu Thr Asp Glu Glu Lys Gln Glu Tyr 165 170 175Leu Asn Glu Tyr Glu Ala Glu Lys Ile Glu Tyr Asn Glu Ser Met Lys 180 185 190Ala Tyr His Asn Ser Pro Ala Tyr Leu Ala Tyr Ile Asn Ala Lys Ser 195 200 205Arg Ala Glu Ala Ala Leu Glu Glu Glu Ser Arg Gln Arg Gln Ser Arg 210 215 220Met Glu Lys Gly Glu Pro Tyr Met Ser Ile Gln Pro Ala Glu Asp Pro225 230 235 240Asp Asp Tyr Asp Asp Gly Phe Ser Met Lys His Thr Ala Thr Ala Arg 245 250 255Phe Gln Arg Asn His Arg Leu Ile Ser Glu Ile Leu Ser Glu Ser Val 260 265 270Val Pro Asp Val Arg Ser Val Val Thr Thr Ala Arg Met Gln Val Leu 275 280 285Lys Arg Gln Val Gln Ser Leu Met Val His Gln Arg Lys Leu Glu Ala 290 295 300Glu Leu Leu Gln Ile Glu Glu Arg His Gln Glu Lys Lys Arg Lys Phe305 310 315 320Leu Glu Ser Thr Asp Ser Phe Asn Asn Glu Leu Lys Arg Leu Cys Gly 325 330 335Leu Lys Val Glu Val Asp Met Glu Lys Ile Ala Ala Glu Ile Ala Gln 340 345 350Ala Glu Glu Gln Ala Arg Lys Arg Gln Glu Glu Arg Glu Lys Glu Ala 355 360 365Ala Glu Gln Ala Glu Arg Ser Gln Ser Ser Ile Val Pro Glu Glu Glu 370 375 380Gln Ala Ala Asn Lys Gly Glu Glu Lys Lys Asp Asp Glu Asn Ile Pro385 390 395 400Met Glu Thr Glu Glu Thr His Leu Glu Glu Thr Thr Glu Ser Gln Gln 405 410 415Asn Gly Glu Glu Gly Thr Ser Thr Pro Glu Asp Lys Glu Ser Gly Gln 420 425 430Glu Gly Val Asp Ser Met Ala Glu Glu Gly Thr Ser Asp Ser Asn Thr 435 440 445Gly Ser Glu Ser Asn Ser Ala Thr Val Glu Glu Pro Pro Thr Asp Pro 450 455 460Ile Pro Glu Asp Glu Lys Lys Glu465 47012989PRTHomo sapiens 12Met Lys Val Val Asn Leu Lys Gln Ala Ile Leu Gln Ala Trp Lys Glu1 5 10 15Arg Trp Ser Tyr Tyr Gln Trp Ala Ile Asn Met Lys Lys Phe Phe Pro 20 25 30Lys Gly Ala Thr Trp Asp Ile Leu Asn Leu Ala Asp Ala Leu Leu Glu 35 40 45Gln Ala Met Ile Gly Pro Ser Pro Asn Pro Leu Ile Leu Ser Tyr Leu 50 55 60Lys Tyr Ala Ile Ser Ser Gln Met Val Ser Tyr Ser Ser Val Leu Thr65 70 75 80Ala Ile Ser Lys Phe Asp Asp Phe Ser Arg Asp Leu Cys Val Gln Ala 85 90 95Leu Leu Asp Ile Met Asp Met Phe Cys Asp Arg Leu Ser Cys His Gly 100 105 110Lys Ala Glu Glu Cys Ile Gly Leu Cys Arg Ala Leu Leu Ser Ala Leu 115 120 125His Trp Leu Leu Arg Cys Thr Ala Ala Ser Ala Glu Arg Leu Arg Glu 130 135 140Gly Leu Glu Ala Gly Thr Pro Ala Ala Gly Glu Lys Gln Leu Ala Met145 150 155 160Cys Leu Gln Arg Leu Glu Lys Thr Leu Ser Ser Thr Lys Asn Arg Ala 165 170 175Leu Leu His Ile Ala Lys Leu Glu Glu Ala Ser Ser Trp Thr Ala Ile 180 185 190Glu His Ser Leu Leu Lys Leu Gly Glu Ile Leu Thr Asn Leu Ser Asn 195 200 205Pro Gln Leu Arg Ser Gln Ala Glu Gln Cys Gly Thr Leu Ile Arg Ser 210 215 220Ile Pro Thr Met Leu Ser Val His Ala Glu Gln Met His Lys Thr Gly225 230 235 240Phe Pro Thr Val His Ala Val Ile Leu Leu Glu Gly Thr Met Asn Leu 245 250 255Thr Gly Glu Thr Gln Ser Leu Val Glu Gln Leu Thr Met Val Lys Arg 260 265 270Met Gln His Ile Pro Thr Pro Leu Phe Val Leu Glu Ile Trp Lys Ala 275 280 285Cys Phe Val Gly Leu Ile Glu Ser Pro Glu Gly Thr Glu Glu Leu Lys 290 295 300Trp Thr Ala Phe Thr Phe Leu Lys Ile Pro Gln Val Leu Val Lys Leu305 310 315 320Lys Lys Tyr Ser His Gly Asp Lys Asp Phe Thr Glu Asp Val Asn Cys 325 330 335Ala Phe Glu Phe Leu Leu Lys Leu Thr Pro Leu Leu Asp Lys Ala Asp 340 345 350Gln Arg Cys Asn Cys Asp Cys Thr Asn Phe Leu Leu Gln Glu Cys Gly 355 360 365Lys Gln Gly Leu Leu Ser Glu Ala Ser Val Asn Asn Leu Met Ala Lys 370 375 380Arg Lys Ala Asp Arg Glu His Ala Pro Gln Gln Lys Ser Gly Glu Asn385 390 395 400Ala Asn Ile Gln Pro Asn Ile Gln Leu Ile Leu Arg Ala Glu Pro Thr 405 410 415Val Thr Asn Ile Leu Lys Thr Met Asp Ala Asp His Ser Lys Ser Pro 420 425 430Glu Gly Leu Leu Gly Val Leu Gly His Met Leu Ser Gly Lys Ser Leu 435 440 445Asp Leu Leu Leu Ala Ala Ala Ala Ala Thr Gly Lys Leu Lys Ser Phe 450 455 460Ala Arg Lys Phe Ile Asn Leu Asn Glu Phe Thr Thr Tyr Gly Ser Glu465 470 475 480Glu Ser Thr Lys Pro Ala Ser Val Arg Ala Leu Leu Phe Asp Ile Ser 485 490 495Phe Leu Met Leu Cys His Val Ala Gln Thr Tyr Gly Ser Glu Val Ile 500 505 510Leu Ser Glu Ser Arg Thr Gly Ala Glu Val Pro Phe Phe Glu Thr Trp 515 520 525Met Gln Thr Cys Met Pro Glu Glu Gly Lys Ile Leu Asn Pro Asp His 530 535 540Pro Cys Phe Arg Pro Asp Ser Thr Lys Val Glu Ser Leu Val Ala Leu545 550 555 560Leu Asn Asn Ser Ser Glu Met Lys Leu Val Gln Met Lys Trp His Glu 565 570 575Ala Cys Leu Ser Ile Ser Ala Ala Ile Leu Glu Ile Leu Asn Ala Trp 580 585 590Glu Asn Gly Val Leu Ala Phe Glu Ser Ile Gln Lys Ile Thr Asp Asn 595 600 605Ile Lys Gly Lys Val Cys Ser Leu Ala Val Cys Ala Val Ala Trp Leu 610 615 620Val Ala His Val Arg Met Leu Gly Leu Asp Glu Arg Glu Lys Ser Leu625 630 635 640Gln Met Ile Arg Gln Leu Ala Gly Pro Leu Phe Ser Glu Asn Thr Leu 645 650 655Gln Phe Tyr Asn Glu Arg Val Val Ile Met Asn Ser Ile Leu Glu Arg 660 665 670Met Cys Ala Asp Val Leu Gln Gln Thr Ala Thr Gln Ile Lys Phe Pro 675 680 685Ser Thr Gly Val Asp Thr Met Pro Tyr Trp Asn Leu Leu Pro Pro Lys 690 695 700Arg Pro Ile Lys Glu Val Leu Thr Asp Ile Phe Ala Lys Val Leu Glu705 710 715 720Lys Gly Trp Val Asp Ser Arg Ser Ile His Ile Phe Asp Thr Leu Leu 725 730 735His Met Gly Gly Val Tyr Trp Phe Cys Asn Asn Leu Ile Lys Glu Leu 740 745 750Leu Lys Glu Thr Arg Lys Glu His Thr Leu Arg Ala Val Glu Leu Leu 755 760 765Tyr Ser Ile Phe Cys Leu Asp Met Gln Gln Val Thr Leu Val Leu Leu 770 775 780Gly His Ile Leu Pro Gly Leu Leu Thr Asp Ser Ser Lys Trp His Ser785 790 795 800Leu Met Asp Pro Pro Gly Thr Ala Leu Ala Lys Leu Ala Val Trp Cys 805 810 815Ala Leu Ser Ser Tyr Ser Ser His Lys Gly Gln Ala Ser Thr Arg Gln 820 825 830Lys Lys Arg His Arg Glu Asp Ile Glu Asp Tyr Ile Ser Leu Phe Pro 835 840 845Leu Asp Asp Val Gln Pro Ser Lys Leu Met Arg Leu Leu Ser Ser Asn 850 855 860Glu Asp Asp Ala Asn Ile Leu Ser Ser Pro Thr Asp Arg Ser Met Ser865 870 875 880Ser Ser Leu Ser Ala Ser Gln Leu His Thr Val Asn Met Arg Asp Pro 885 890 895Leu Asn Arg Val Leu Ala Asn Leu Phe Leu Leu Ile Ser Ser Ile Leu 900 905 910Gly Ser Arg Thr Ala Gly Pro His Thr Gln Phe Val Gln Trp Phe Met 915 920 925Glu Glu Cys Val Asp Cys Leu Glu Gln Gly Gly Arg Gly Ser Val Leu 930 935 940Gln Phe Met Pro Phe Thr Thr Val Ser Glu Leu Val Lys Val Ser Ala945 950 955 960Met Ser Ser Pro Lys Val Val Leu Ala Ile Thr Asp Leu Ser Leu Pro 965 970 975Leu Gly Arg Gln Val Ala Ala Lys Ala Ile Ala Ala Leu 980 985131043PRTHomo sapiens 13Met Lys Val Val Asn Leu Lys Gln Ala Ile Leu Gln Ala Trp Lys Glu1 5 10 15Arg Trp Ser Tyr Tyr Gln Trp Ala Ile Asn Met Lys Lys Phe Phe Pro 20 25 30Lys Gly Ala Thr Trp Asp Ile Leu Asn Leu Ala Asp Ala Leu Leu Glu 35 40 45Gln Ala Met Ile Gly Pro Ser Pro Asn Pro Leu Ile Leu Ser Tyr Leu 50 55 60Lys Tyr Ala Ile Ser Ser Gln Met Val Ser Tyr Ser Ser Val Leu Thr65 70 75 80Ala Ile Ser Lys Phe Asp Asp Phe Ser Arg Asp Leu Cys Val Gln Ala 85 90 95Leu Leu Asp Ile Met Asp Met Phe Cys Asp Arg Leu Ser Cys His Gly 100 105 110Lys Ala Glu Glu Cys Ile Gly Leu Cys Arg Ala Leu Leu Ser Ala Leu 115 120 125His Trp Leu Leu Arg Cys Thr Ala Ala Ser Ala Glu Arg Leu Arg Glu 130 135 140Gly Leu Glu Ala Gly Thr Pro Ala Ala Gly Glu Lys Gln Leu Ala Met145 150 155 160Cys Leu Gln Arg Leu Glu Lys Thr Leu Ser Ser Thr Lys Asn Arg Ala 165 170 175Leu Leu His Ile Ala Lys Leu Glu Glu Ala Cys Pro His Gln Ala Leu 180 185 190Leu Val Gly Ser Lys Thr Ser Thr Ser Gln Thr Arg Lys Lys Leu Glu 195 200 205Asp Lys Thr Ser Thr Val Ser Ile Ile Val Phe Val Ser Met Leu Leu 210 215 220Ile Ala Trp Lys Gln Met Thr Leu Val Phe Glu Cys Tyr Leu Lys Cys225 230 235 240Ser Ser Trp Thr Ala Ile Glu His Ser Leu Leu Lys Leu Gly Glu Ile 245 250 255Leu Thr Asn Leu Ser Asn Pro Gln Leu Arg Ser Gln Ala Glu Gln Cys 260 265 270Gly Thr Leu Ile Arg Ser Ile Pro Thr Met Leu Ser Val His Ala Glu 275 280 285Gln Met His Lys Thr Gly Phe Pro Thr Val His Ala Val Ile Leu Leu 290 295 300Glu Gly Thr Met Asn Leu Thr Gly Glu Thr Gln Ser Leu Val Glu Gln305 310 315 320Leu Thr Met Val Lys Arg Met Gln His Ile Pro Thr Pro Leu Phe Val 325 330 335Leu Glu Ile Trp Lys Ala Cys Phe Val Gly Leu Ile Glu Ser Pro Glu 340 345 350Gly Thr Glu Glu Leu Lys Trp Thr Ala Phe Thr Phe Leu Lys Ile Pro 355 360 365Gln Val Leu Val Lys Leu Lys Lys Tyr Ser His Gly Asp Lys Asp Phe 370 375 380Thr Glu Asp Val Asn

Cys Ala Phe Glu Phe Leu Leu Lys Leu Thr Pro385 390 395 400Leu Leu Asp Lys Ala Asp Gln Arg Cys Asn Cys Asp Cys Thr Asn Phe 405 410 415Leu Leu Gln Glu Cys Gly Lys Gln Gly Leu Leu Ser Glu Ala Ser Val 420 425 430Asn Asn Leu Met Ala Lys Arg Lys Ala Asp Arg Glu His Ala Pro Gln 435 440 445Gln Lys Ser Gly Glu Asn Ala Asn Ile Gln Pro Asn Ile Gln Leu Ile 450 455 460Leu Arg Ala Glu Pro Thr Val Thr Asn Ile Leu Lys Thr Met Asp Ala465 470 475 480Asp His Ser Lys Ser Pro Glu Gly Leu Leu Gly Val Leu Gly His Met 485 490 495Leu Ser Gly Lys Ser Leu Asp Leu Leu Leu Ala Ala Ala Ala Ala Thr 500 505 510Gly Lys Leu Lys Ser Phe Ala Arg Lys Phe Ile Asn Leu Asn Glu Phe 515 520 525Thr Thr Tyr Gly Ser Glu Glu Ser Thr Lys Pro Ala Ser Val Arg Ala 530 535 540Leu Leu Phe Asp Ile Ser Phe Leu Met Leu Cys His Val Ala Gln Thr545 550 555 560Tyr Gly Ser Glu Val Ile Leu Ser Glu Ser Arg Thr Gly Ala Glu Val 565 570 575Pro Phe Phe Glu Thr Trp Met Gln Thr Cys Met Pro Glu Glu Gly Lys 580 585 590Ile Leu Asn Pro Asp His Pro Cys Phe Arg Pro Asp Ser Thr Lys Val 595 600 605Glu Ser Leu Val Ala Leu Leu Asn Asn Ser Ser Glu Met Lys Leu Val 610 615 620Gln Met Lys Trp His Glu Ala Cys Leu Ser Ile Ser Ala Ala Ile Leu625 630 635 640Glu Ile Leu Asn Ala Trp Glu Asn Gly Val Leu Ala Phe Glu Ser Ile 645 650 655Gln Lys Ile Thr Asp Asn Ile Lys Gly Lys Val Cys Ser Leu Ala Val 660 665 670Cys Ala Val Ala Trp Leu Val Ala His Val Arg Met Leu Gly Leu Asp 675 680 685Glu Arg Glu Lys Ser Leu Gln Met Ile Arg Gln Leu Ala Gly Pro Leu 690 695 700Phe Ser Glu Asn Thr Leu Gln Phe Tyr Asn Glu Arg Val Val Ile Met705 710 715 720Asn Ser Ile Leu Glu Arg Met Cys Ala Asp Val Leu Gln Gln Thr Ala 725 730 735Thr Gln Ile Lys Phe Pro Ser Thr Gly Val Asp Thr Met Pro Tyr Trp 740 745 750Asn Leu Leu Pro Pro Lys Arg Pro Ile Lys Glu Val Leu Thr Asp Ile 755 760 765Phe Ala Lys Val Leu Glu Lys Gly Trp Val Asp Ser Arg Ser Ile His 770 775 780Ile Phe Asp Thr Leu Leu His Met Gly Gly Val Tyr Trp Phe Cys Asn785 790 795 800Asn Leu Ile Lys Glu Leu Leu Lys Glu Thr Arg Lys Glu His Thr Leu 805 810 815Arg Ala Val Glu Leu Leu Tyr Ser Ile Phe Cys Leu Asp Met Gln Gln 820 825 830Val Thr Leu Val Leu Leu Gly His Ile Leu Pro Gly Leu Leu Thr Asp 835 840 845Ser Ser Lys Trp His Ser Leu Met Asp Pro Pro Gly Thr Ala Leu Ala 850 855 860Lys Leu Ala Val Trp Cys Ala Leu Ser Ser Tyr Ser Ser His Lys Gly865 870 875 880Gln Ala Ser Thr Arg Gln Lys Lys Arg His Arg Glu Asp Ile Glu Asp 885 890 895Tyr Ile Ser Leu Phe Pro Leu Asp Asp Val Gln Pro Ser Lys Leu Met 900 905 910Arg Leu Leu Ser Ser Asn Glu Asp Asp Ala Asn Ile Leu Ser Ser Pro 915 920 925Thr Asp Arg Ser Met Ser Ser Ser Leu Ser Ala Ser Gln Leu His Thr 930 935 940Val Asn Met Arg Asp Pro Leu Asn Arg Val Leu Ala Asn Leu Phe Leu945 950 955 960Leu Ile Ser Ser Ile Leu Gly Ser Arg Thr Ala Gly Pro His Thr Gln 965 970 975Phe Val Gln Trp Phe Met Glu Glu Cys Val Asp Cys Leu Glu Gln Gly 980 985 990Gly Arg Gly Ser Val Leu Gln Phe Met Pro Phe Thr Thr Val Ser Glu 995 1000 1005Leu Val Lys Val Ser Ala Met Ser Ser Pro Lys Val Val Leu Ala 1010 1015 1020Ile Thr Asp Leu Ser Leu Pro Leu Gly Arg Gln Val Ala Ala Lys 1025 1030 1035Ala Ile Ala Ala Leu 10401423DNAArtificial sequencePrimer 14acttcctgtc tagagttgta gcs 231524DNAArtificial sequenceprimer 15gtaagtcagc tatactaagt tctg 241667PRTArtificial sequencePrimer 16Met Ala Thr Ser Ser Glu Glu Val Leu Leu Ile Val Lys Lys Val Arg1 5 10 15Gln Lys Lys Gln Asp Gly Ala Leu Tyr Leu Met Ala Glu Arg Ile Ala 20 25 30Trp Ala Pro Glu Gly Lys Asp Arg Phe Thr Ile Ser His Met Tyr Ala 35 40 45Asp Ile Lys Cys Lys Ser Ala Ile Leu Ser Ser Asp Val Phe Val Cys 50 55 60His Ser Cys6517548PRTHomo sapiens 17Met Ala Thr Ser Ser Glu Glu Val Leu Leu Ile Val Lys Lys Val Arg1 5 10 15Gln Lys Lys Gln Asp Gly Ala Leu Tyr Leu Met Ala Glu Arg Ile Ala 20 25 30Trp Ala Pro Glu Gly Lys Asp Arg Phe Thr Ile Ser His Met Tyr Ala 35 40 45Asp Ile Lys Cys Gln Lys Ile Ser Pro Glu Gly Lys Ala Lys Ile Gln 50 55 60Leu Gln Leu Val Leu His Ala Gly Asp Thr Thr Asn Phe His Phe Ser65 70 75 80Asn Glu Ser Thr Ala Val Lys Glu Arg Asp Ala Val Lys Asp Leu Leu 85 90 95Gln Gln Leu Leu Pro Lys Phe Lys Arg Lys Ala Asn Lys Glu Leu Glu 100 105 110Glu Lys Asn Arg Met Leu Gln Glu Asp Pro Val Leu Phe Gln Leu Tyr 115 120 125Lys Asp Leu Val Val Ser Gln Val Ile Ser Ala Glu Glu Phe Trp Ala 130 135 140Asn Arg Leu Asn Val Asn Ala Thr Asp Ser Ser Ser Thr Ser Asn His145 150 155 160Lys Gln Asp Val Gly Ile Ser Ala Ala Phe Leu Ala Asp Val Arg Pro 165 170 175Gln Thr Asp Gly Cys Asn Gly Leu Arg Tyr Asn Leu Thr Ser Asp Ile 180 185 190Ile Glu Ser Ile Phe Arg Thr Tyr Pro Ala Val Lys Met Lys Tyr Ala 195 200 205Glu Asn Val Pro His Asn Met Thr Glu Lys Glu Phe Trp Thr Arg Phe 210 215 220Phe Gln Ser His Tyr Phe His Arg Asp Arg Leu Asn Thr Gly Ser Lys225 230 235 240Asp Leu Phe Ala Glu Cys Ala Lys Ile Asp Glu Lys Gly Leu Lys Thr 245 250 255Met Val Ser Leu Gly Val Lys Asn Pro Leu Leu Asp Leu Thr Ala Leu 260 265 270Glu Asp Lys Pro Leu Asp Glu Gly Tyr Gly Ile Ser Ser Val Pro Ser 275 280 285Ala Ser Asn Ser Lys Ser Ile Lys Glu Asn Ser Asn Ala Ala Ile Ile 290 295 300Lys Arg Phe Asn His His Ser Ala Met Val Leu Ala Ala Gly Leu Arg305 310 315 320Lys Gln Glu Ala Gln Asn Glu Gln Thr Ser Glu Pro Ser Asn Met Asp 325 330 335Gly Asn Ser Gly Asp Ala Asp Cys Phe Gln Pro Ala Val Lys Arg Ala 340 345 350Lys Leu Gln Glu Ser Ile Glu Tyr Glu Asp Leu Gly Lys Asn Asn Ser 355 360 365Val Lys Thr Ile Ala Leu Asn Leu Lys Lys Ser Asp Arg Tyr Tyr His 370 375 380Gly Pro Thr Pro Ile Gln Ser Leu Gln Tyr Ala Thr Ser Gln Asp Ile385 390 395 400Ile Asn Ser Phe Gln Ser Ile Arg Gln Glu Met Glu Ala Tyr Thr Pro 405 410 415Lys Leu Thr Gln Val Leu Ser Ser Ser Ala Ala Ser Ser Thr Ile Thr 420 425 430Ala Leu Ser Pro Gly Gly Ala Leu Met Gln Gly Gly Thr Gln Gln Ala 435 440 445Ile Asn Gln Met Val Pro Asn Asp Ile Gln Ser Glu Leu Lys His Leu 450 455 460Tyr Val Ala Val Gly Glu Leu Leu Arg His Phe Trp Ser Cys Phe Pro465 470 475 480Val Asn Thr Pro Phe Leu Glu Glu Lys Val Val Lys Met Lys Ser Asn 485 490 495Leu Glu Arg Phe Gln Val Thr Lys Leu Cys Pro Phe Gln Glu Lys Ile 500 505 510Arg Arg Gln Tyr Leu Ser Thr Asn Leu Val Ser His Ile Glu Glu Met 515 520 525Leu Gln Thr Ala Tyr Asn Lys Leu His Thr Trp Gln Ser Arg Arg Leu 530 535 540Met Lys Lys Thr5451820DNAArtificial sequencePrimer 18tttccggctg agagtccttc 201921DNAArtificial sequencePrimer 19cacatcactt cagcttaact c 2120165PRTHomo sapiens 20Met Asp Glu Glu Pro Glu Arg Thr Lys Arg Trp Glu Gly Gly Tyr Glu1 5 10 15Arg Thr Trp Glu Ile Leu Lys Glu Asp Glu Ser Gly Ser Leu Lys Ala 20 25 30Thr Ile Glu Asp Ile Leu Phe Lys Ala Lys Arg Lys Arg Val Phe Glu 35 40 45His His Gly Gln Val Arg Leu Gly Met Met Arg His Leu Tyr Val Val 50 55 60Val Asp Gly Ser Arg Thr Met Glu Asp Gln Asp Leu Lys Pro Asn Arg65 70 75 80Leu Thr Cys Thr Leu Lys Leu Leu Glu Tyr Phe Val Glu Glu Tyr Phe 85 90 95Asp Gln Asn Pro Ile Ser Gln Ile Gly Ile Ile Val Thr Lys Ser Lys 100 105 110Arg Ala Glu Lys Leu Thr Glu Leu Ser Gly Asn Pro Arg Lys His Ile 115 120 125Thr Ser Leu Lys Lys Ala Val Asp Met Thr Cys His Gly Glu Pro Ser 130 135 140Leu Tyr Asn Ser Leu Ser Ile Ala Met Gln Thr Leu Lys Leu Val Leu145 150 155 160Tyr Ile Met Tyr Asn 16521395PRTHomo sapiens 21Met Asp Glu Glu Pro Glu Arg Thr Lys Arg Trp Glu Gly Gly Tyr Glu1 5 10 15Arg Thr Trp Glu Ile Leu Lys Glu Asp Glu Ser Gly Ser Leu Lys Ala 20 25 30Thr Ile Glu Asp Ile Leu Phe Lys Ala Lys Arg Lys Arg Val Phe Glu 35 40 45His His Gly Gln Val Arg Leu Gly Met Met Arg His Leu Tyr Val Val 50 55 60Val Asp Gly Ser Arg Thr Met Glu Asp Gln Asp Leu Lys Pro Asn Arg65 70 75 80Leu Thr Cys Thr Leu Lys Leu Leu Glu Tyr Phe Val Glu Glu Tyr Phe 85 90 95Asp Gln Asn Pro Ile Ser Gln Ile Gly Ile Ile Val Thr Lys Ser Lys 100 105 110Arg Ala Glu Lys Leu Thr Glu Leu Ser Gly Asn Pro Arg Lys His Ile 115 120 125Thr Ser Leu Lys Lys Ala Val Asp Met Thr Cys His Gly Glu Pro Ser 130 135 140Leu Tyr Asn Ser Leu Ser Ile Ala Met Gln Thr Leu Lys His Met Pro145 150 155 160Gly His Thr Ser Arg Glu Val Leu Ile Ile Phe Ser Ser Leu Thr Thr 165 170 175Cys Asp Pro Ser Asn Ile Tyr Asp Leu Ile Lys Thr Leu Lys Ala Ala 180 185 190Lys Ile Arg Val Ser Val Ile Gly Leu Ser Ala Glu Val Arg Val Cys 195 200 205Thr Val Leu Ala Arg Glu Thr Gly Gly Thr Tyr His Val Ile Leu Asp 210 215 220Glu Ser His Tyr Lys Glu Leu Leu Thr His His Val Ser Pro Pro Pro225 230 235 240Ala Ser Ser Ser Ser Glu Cys Ser Leu Ile Arg Met Gly Phe Pro Gln 245 250 255His Thr Ile Ala Ser Leu Ser Asp Gln Asp Ala Lys Pro Ser Phe Ser 260 265 270Met Ala His Leu Asp Gly Asn Thr Glu Pro Gly Leu Thr Leu Gly Gly 275 280 285Tyr Phe Cys Pro Gln Cys Arg Ala Lys Tyr Cys Glu Leu Pro Val Glu 290 295 300Cys Lys Ile Cys Gly Leu Thr Leu Val Ser Ala Pro His Leu Ala Arg305 310 315 320Ser Tyr His His Leu Phe Pro Leu Asp Ala Phe Gln Glu Ile Pro Leu 325 330 335Glu Glu Tyr Asn Gly Glu Arg Phe Cys Tyr Gly Cys Gln Gly Glu Leu 340 345 350Lys Asp Gln His Val Tyr Val Cys Ala Val Cys Gln Asn Val Phe Cys 355 360 365Val Asp Cys Asp Val Phe Val His Asp Ser Leu His Cys Cys Pro Gly 370 375 380Cys Ile His Lys Ile Pro Ala Pro Ser Gly Val385 390 3952224DNAArtificial sequencePrimer 22gaggatgtga aggagcttgt gaag 242322DNAArtificial sequencePrimer 23caagtacagt gcaaacgcga ac 2224154PRTHomo sapiens 24Met Arg His Leu Tyr Val Val Val Asp Gly Ser Arg Thr Met Glu Asp1 5 10 15Gln Asp Leu Lys Pro Asn Arg Leu Thr Cys Thr Leu Lys Leu Leu Glu 20 25 30Tyr Phe Val Glu Glu Tyr Phe Asp Gln Asn Pro Ile Ser Gln Ile Gly 35 40 45Ile Ile Val Thr Lys Ser Lys Arg Ala Glu Lys Leu Thr Glu Leu Ser 50 55 60Gly Asn Pro Arg Lys His Ile Thr Ser Leu Lys Lys Ala Val Asp Met65 70 75 80Thr Cys His Gly Glu Pro Ser Leu Tyr Asn Ser Leu Ser Ile Ala Met 85 90 95Gln Thr Leu Lys His Met Pro Gly His Thr Ser Arg Glu Val Leu Ile 100 105 110Ile Phe Ser Ser Leu Thr Thr Cys Asp Pro Ser Asn Ile Tyr Asp Leu 115 120 125Ile Lys Thr Leu Lys Ala Ala Lys Ile Arg Val Ser Val Ile Gly Leu 130 135 140Ser Ala Glu Val Arg Val Cys Thr Val Leu145 15025240PRTHomo sapiens 25Met Asp Glu Glu Pro Glu Arg Thr Lys Arg Trp Glu Gly Gly Tyr Glu1 5 10 15Arg Thr Trp Glu Ile Leu Lys Glu Asp Glu Ser Gly Ser Leu Lys Ala 20 25 30Thr Ile Glu Asp Ile Leu Phe Lys Ala Lys Arg Lys Arg Val Phe Glu 35 40 45His His Gly Gln Val Arg Leu Gly Met Met Arg His Leu Tyr Val Val 50 55 60Val Asp Gly Ser Arg Thr Met Glu Asp Gln Asp Leu Lys Pro Asn Arg65 70 75 80Leu Thr Cys Thr Leu Lys Leu Leu Glu Tyr Phe Val Glu Glu Tyr Phe 85 90 95Asp Gln Asn Pro Ile Ser Gln Ile Gly Ile Ile Val Thr Lys Ser Lys 100 105 110Arg Ala Glu Lys Leu Thr Glu Leu Ser Gly Asn Pro Arg Lys His Ile 115 120 125Thr Ser Leu Lys Lys Ala Val Asp Met Thr Cys His Gly Glu Pro Ser 130 135 140Leu Tyr Asn Ser Leu Ser Ile Ala Met Gln Thr Leu Lys His Met Pro145 150 155 160Gly His Thr Ser Arg Glu Val Leu Ile Ile Phe Ser Ser Leu Thr Thr 165 170 175Cys Asp Pro Ser Asn Ile Tyr Asp Leu Ile Lys Thr Leu Lys Ala Ala 180 185 190Lys Ile Arg Val Ser Val Ile Gly Leu Ser Ala Glu Val Arg Val Cys 195 200 205Thr Val Leu Ala Arg Glu Thr Gly Gly Thr Tyr His Val Ile Leu Asp 210 215 220Glu Ser His Tyr Lys Glu Leu Leu Thr His His Val Ser Pro Pro Pro225 230 235 2402620DNAArtificial sequencePrimer 26gacagccatg gtttcagacg 202721DNAArtificial sequencePrimer 27cagaaacttt gctggcagga t 2128267PRTHomo sapiens 28Met Val Leu Gly Asn Ser His Leu Phe Met Asn Arg Ser Asn Lys Leu1 5 10 15Ala Val Ile Ala Ser His Ile Gln Glu Ser Arg Phe Leu Tyr Pro Gly 20 25 30Lys Asn Gly Arg Leu Gly Asp Phe Phe Gly Asp Pro Gly Asn Pro Pro 35 40 45Glu Phe Asn Pro Ser Gly Ser Lys Asp Gly Lys Tyr Glu Leu Leu Thr 50 55 60Ser Ala Asn Glu Val Ile Val Glu Glu Ile Lys Asp Leu Met Thr Lys65 70 75 80Ser Asp Ile Lys Gly Gln His Thr Glu Thr Leu Leu Ala Gly Ser Leu 85 90 95Ala Lys Ala Leu Cys Tyr Ile His Arg Met Asn Lys Glu Val Lys Asp 100 105 110Asn Gln Glu Met Lys Ser Arg Ile Leu Val Ile Lys

Ala Ala Glu Asp 115 120 125Ser Ala Leu Gln Tyr Met Asn Phe Met Asn Val Ile Phe Ala Ala Gln 130 135 140Lys Gln Asn Ile Leu Ile Asp Ala Cys Val Leu Asp Ser Asp Ser Gly145 150 155 160Leu Leu Gln Gln Ala Cys Asp Ile Thr Gly Gly Leu Tyr Leu Lys Val 165 170 175Pro Gln Met Pro Ser Leu Leu Gln Tyr Leu Leu Trp Val Phe Leu Pro 180 185 190Asp Gln Asp Gln Arg Ser Gln Leu Ile Leu Pro Pro Pro Val His Val 195 200 205Asp Tyr Arg Ala Ala Cys Phe Cys His Arg Asn Leu Ile Glu Ile Gly 210 215 220Tyr Val Cys Ser Val Cys Leu Ser Ile Phe Cys Asn Phe Ser Pro Ile225 230 235 240Cys Thr Thr Cys Glu Thr Ala Phe Lys Ile Ser Leu Pro Pro Val Leu 245 250 255Lys Ala Lys Lys Lys Lys Leu Lys Val Ser Ala 260 26529308PRTHomo sapiens 29Met Val Ser Asp Glu Asp Glu Leu Asn Leu Leu Val Ile Val Val Asp1 5 10 15Ala Asn Pro Ile Trp Trp Gly Lys Gln Ala Leu Lys Glu Ser Gln Phe 20 25 30Thr Leu Ser Lys Cys Ile Asp Ala Val Met Val Leu Gly Asn Ser His 35 40 45Leu Phe Met Asn Arg Ser Asn Lys Leu Ala Val Ile Ala Ser His Ile 50 55 60Gln Glu Ser Arg Phe Leu Tyr Pro Gly Lys Asn Gly Arg Leu Gly Asp65 70 75 80Phe Phe Gly Asp Pro Gly Asn Pro Pro Glu Phe Asn Pro Ser Gly Ser 85 90 95Lys Asp Gly Lys Tyr Glu Leu Leu Thr Ser Ala Asn Glu Val Ile Val 100 105 110Glu Glu Ile Lys Asp Leu Met Thr Lys Ser Asp Ile Lys Gly Gln His 115 120 125Thr Glu Thr Leu Leu Ala Gly Ser Leu Ala Lys Ala Leu Cys Tyr Ile 130 135 140His Arg Met Asn Lys Glu Val Lys Asp Asn Gln Glu Met Lys Ser Arg145 150 155 160Ile Leu Val Ile Lys Ala Ala Glu Asp Ser Ala Leu Gln Tyr Met Asn 165 170 175Phe Met Asn Val Ile Phe Ala Ala Gln Lys Gln Asn Ile Leu Ile Asp 180 185 190Ala Cys Val Leu Asp Ser Asp Ser Gly Leu Leu Gln Gln Ala Cys Asp 195 200 205Ile Thr Gly Gly Leu Tyr Leu Lys Val Pro Gln Met Pro Ser Leu Leu 210 215 220Gln Tyr Leu Leu Trp Val Phe Leu Pro Asp Gln Asp Gln Arg Ser Gln225 230 235 240Leu Ile Leu Pro Pro Pro Val His Val Asp Tyr Arg Ala Ala Cys Phe 245 250 255Cys His Arg Asn Leu Ile Glu Ile Gly Tyr Val Cys Ser Val Cys Leu 260 265 270Ser Ile Phe Cys Asn Phe Ser Pro Ile Cys Thr Thr Cys Glu Thr Ala 275 280 285Phe Lys Ile Ser Leu Pro Pro Val Leu Lys Ala Lys Lys Lys Lys Leu 290 295 300Lys Val Ser Ala3053020DNAArtificial sequencePrimer 30gacagccatg gtttcagacg 203122DNAArtificial sequencePrimer 31cgtggtgaaa acatggtgaa ac 223234PRTHomo sapiens 32Met Val Ser Asp Glu Asp Glu Leu Asn Leu Leu Val Ile Val Val Asp1 5 10 15Ala Asn Pro Ile Trp Trp Gly Lys Gln Ala Leu Lys Glu Ser Gln Pro 20 25 30Pro Lys33119PRTHomo sapiens 33Met Val Ser Asp Glu Asp Glu Leu Asn Leu Leu Val Ile Val Val Asp1 5 10 15Ala Asn Pro Thr Trp Trp Gly Lys Gln Ala Leu Lys Glu Ser Gln Phe 20 25 30Thr Leu Ser Lys Cys Ile Asp Ala Val Met Val Leu Gly Asn Ser His 35 40 45Leu Phe Met Asn Arg Ser Asn Lys Leu Ala Val Ile Ala Ser His Ile 50 55 60Gln Glu Ser Arg Phe Leu Tyr Pro Gly Lys Asn Gly Arg Leu Gly Asp65 70 75 80Phe Phe Gly Asp Pro Gly Asn Pro Pro Glu Phe Asn Pro Ser Gly Ser 85 90 95Lys Asp Gly Lys Tyr Glu Leu Leu Thr Ser Ala Ser Gln Val Ala Gly 100 105 110Ile Thr Thr Leu Leu Asn Pro 11534109PRTHomo sapiens 34Met Val Ser Asp Glu Asp Glu Leu Asn Leu Leu Val Ile Val Val Asp1 5 10 15Ala Asn Pro Ile Trp Trp Gly Lys Gln Ala Leu Lys Glu Ser Gln Phe 20 25 30Thr Leu Ser Lys Cys Ile Asp Ala Val Met Val Leu Gly Asn Ser His 35 40 45Leu Phe Met Asn Arg Ser Asn Lys Leu Ala Val Ile Ala Ser His Ile 50 55 60Gln Glu Ser Arg Phe Leu Tyr Pro Gly Phe Thr Pro Phe Ser Cys Leu65 70 75 80Ser Leu Pro Ser Ser Trp Asp Tyr Tyr Ser Thr Glu Pro Met Arg Gln 85 90 95Lys Phe Glu Thr Ile Leu Pro Asn Val Val Lys Thr Trp 100 10535255PRTHomo sapiens 35Met Val Leu Gly Asn Ser His Leu Phe Met Asn Arg Ser Asn Lys Leu1 5 10 15Ala Val Ile Ala Ser His Ile Gln Glu Ser Arg Phe Leu Tyr Pro Gly 20 25 30Lys Asn Gly Arg Leu Gly Asp Phe Phe Gly Asp Pro Gly Asn Pro Pro 35 40 45Glu Phe Asn Pro Ser Gly Ser Lys Asp Gly Lys Tyr Glu Leu Leu Thr 50 55 60Ser Ala Asn Glu Val Ile Val Glu Glu Ile Lys Asp Leu Met Thr Lys65 70 75 80Ser Asp Ile Lys Gly Gln His Thr Glu Thr Leu Leu Ala Gly Ser Leu 85 90 95Ala Lys Ala Leu Cys Tyr Ile His Arg Met Asn Lys Glu Val Lys Asp 100 105 110Asn Gln Glu Met Lys Ser Arg Ile Leu Val Ile Lys Ala Ala Glu Asp 115 120 125Ser Ala Leu Gln Tyr Met Asn Phe Met Asn Val Ile Phe Ala Ala Gln 130 135 140Lys Gln Asn Ile Leu Ile Asp Ala Cys Val Leu Asp Ser Asp Ser Gly145 150 155 160Leu Leu Gln Gln Ala Cys Asp Ile Thr Gly Gly Leu Tyr Leu Lys Val 165 170 175Pro Gln Met Pro Ser Leu Leu Gln Tyr Leu Leu Trp Val Phe Leu Pro 180 185 190Asp Gln Asp Gln Arg Ser Gln Leu Ile Leu Pro Pro Pro Val His Val 195 200 205Asp Tyr Arg Ala Ala Cys Phe Cys His Arg Asn Leu Ile Glu Ile Gly 210 215 220Tyr Val Cys Ser Val Cys Leu Ser Ile Phe Cys Asn Phe Ser Pro Ile225 230 235 240Cys Thr Thr Cys Glu Thr Ala Phe Lys Ile Ser Gln Pro Pro Lys 245 250 2553621DNAArtificial SequencePrimer 36gagactttgg ctccgattaa g 213720DNAArtificial sequencePrimer 37gaagtgctcc aaggaacagc 203881PRTHomo sapiens 38Met Glu Ser Thr Pro Ser Arg Gly Leu Asn Arg Val His Leu Gln Cys1 5 10 15Arg Asn Leu Gln Glu Phe Leu Gly Gly Leu Ser Pro Gly Val Leu Asp 20 25 30Arg Leu Tyr Gly His Pro Ala Thr Cys Leu Ala Val Phe Arg Glu Leu 35 40 45Pro Ser Leu Ala Lys Asn Trp Val Met Arg Met Leu Phe Leu Glu Gln 50 55 60Pro Leu Pro Gln Ala Ala Val Ala Leu Trp Val Lys Lys Glu Phe Ser65 70 75 80Lys39462PRTHomo sapiens 39Met Glu Ser Thr Pro Ser Arg Gly Leu Asn Arg Val His Leu Gln Cys1 5 10 15Arg Asn Leu Gln Glu Phe Leu Gly Gly Leu Ser Pro Gly Val Leu Asp 20 25 30Arg Leu Tyr Gly His Pro Ala Thr Cys Leu Ala Val Phe Arg Glu Leu 35 40 45Pro Ser Leu Ala Lys Asn Trp Val Met Arg Met Leu Phe Leu Glu Gln 50 55 60Pro Leu Pro Gln Ala Ala Val Ala Leu Trp Val Lys Lys Glu Phe Ser65 70 75 80Lys Ala Gln Glu Glu Ser Thr Gly Leu Leu Ser Gly Leu Arg Ile Trp 85 90 95His Thr Gln Leu Leu Pro Gly Gly Leu Gln Gly Leu Ile Leu Asn Pro 100 105 110Ile Phe Arg Gln Asn Leu Arg Ile Ala Leu Leu Gly Gly Gly Lys Ala 115 120 125Trp Ser Asp Asp Thr Ser Gln Leu Gly Pro Asp Lys His Ala Arg Asp 130 135 140Val Pro Ser Leu Asp Lys Tyr Ala Glu Glu Arg Trp Glu Val Val Leu145 150 155 160His Phe Met Val Gly Ser Pro Ser Ala Ala Val Ser Gln Asp Leu Ala 165 170 175Gln Leu Leu Ser Gln Ala Gly Leu Met Lys Ser Thr Glu Pro Gly Glu 180 185 190Pro Pro Cys Ile Thr Ser Ala Gly Phe Gln Phe Leu Leu Leu Asp Thr 195 200 205Pro Ala Gln Leu Trp Tyr Phe Met Leu Gln Tyr Leu Gln Thr Ala Gln 210 215 220Ser Arg Gly Met Asp Leu Val Glu Ile Leu Ser Phe Leu Phe Gln Leu225 230 235 240Ser Phe Ser Thr Leu Gly Lys Asp Tyr Ser Val Glu Gly Met Ser Asp 245 250 255Ser Leu Leu Asn Phe Leu Gln His Leu Arg Glu Phe Gly Leu Val Phe 260 265 270Gln Arg Lys Arg Lys Ser Arg Arg Tyr Tyr Pro Thr Arg Leu Ala Ile 275 280 285Asn Leu Ser Ser Gly Val Ser Gly Ala Gly Gly Thr Val His Gln Pro 290 295 300Gly Phe Ile Val Val Glu Thr Asn Tyr Arg Leu Tyr Ala Tyr Thr Glu305 310 315 320Ser Glu Leu Gln Ile Ala Leu Ile Ala Leu Phe Ser Glu Met Leu Tyr 325 330 335Arg Phe Pro Asn Met Val Val Ala Gln Val Thr Arg Glu Ser Val Gln 340 345 350Gln Ala Ile Ala Ser Gly Ile Thr Ala Gln Gln Ile Ile His Phe Leu 355 360 365Arg Thr Arg Ala His Pro Val Met Leu Lys Gln Thr Pro Val Leu Pro 370 375 380Pro Thr Ile Thr Asp Gln Ile Arg Leu Trp Glu Leu Glu Arg Asp Arg385 390 395 400Leu Arg Phe Thr Glu Gly Val Leu Tyr Asn Gln Phe Leu Ser Gln Val 405 410 415Asp Phe Glu Leu Leu Leu Ala His Ala Arg Glu Leu Gly Val Leu Val 420 425 430Phe Glu Asn Ser Ala Lys Arg Leu Met Val Val Thr Pro Ala Gly His 435 440 445Ser Asp Val Lys Arg Phe Trp Lys Arg Gln Lys His Ser Ser 450 455 4604021DNAArtificial sequencePrimer 40gagactttgg ctccgattaa g 214119DNAArtificial sequencePrimer 41tgagcgagca tccgcatca 1942441PRTHomo sapiens 42Met Glu Ser Thr Pro Ser Arg Gly Leu Asn Arg Val His Leu Gln Cys1 5 10 15Arg Asn Leu Gln Glu Phe Leu Gly Gly Leu Ser Pro Gly Val Leu Asp 20 25 30Arg Leu Tyr Gly His Pro Ala Thr Cys Leu Ala Val Phe Arg Glu Leu 35 40 45Pro Ser Leu Ala Lys Asn Trp Val Met Arg Met Leu Ala Gln Glu Glu 50 55 60Ser Thr Gly Leu Leu Ser Gly Leu Arg Ile Trp His Thr Gln Leu Leu65 70 75 80Pro Gly Gly Leu Gln Gly Leu Ile Leu Asn Pro Ile Phe Arg Gln Asn 85 90 95Leu Arg Ile Ala Leu Leu Gly Gly Gly Lys Ala Trp Ser Asp Asp Thr 100 105 110Ser Gln Leu Gly Pro Asp Lys His Ala Arg Asp Val Pro Ser Leu Asp 115 120 125Lys Tyr Ala Glu Glu Arg Trp Glu Val Val Leu His Phe Met Val Gly 130 135 140Ser Pro Ser Ala Ala Val Ser Gln Asp Leu Ala Gln Leu Leu Ser Gln145 150 155 160Ala Gly Leu Met Lys Ser Thr Glu Pro Gly Glu Pro Pro Cys Ile Thr 165 170 175Ser Ala Gly Phe Gln Phe Leu Leu Leu Asp Thr Pro Ala Gln Leu Trp 180 185 190Tyr Phe Met Leu Gln Tyr Leu Gln Thr Ala Gln Ser Arg Gly Met Asp 195 200 205Leu Val Glu Ile Leu Ser Phe Leu Phe Gln Leu Ser Phe Ser Thr Leu 210 215 220Gly Lys Asp Tyr Ser Val Glu Gly Met Ser Asp Ser Leu Leu Asn Phe225 230 235 240Leu Gln His Leu Arg Glu Phe Gly Leu Val Phe Gln Arg Lys Arg Lys 245 250 255Ser Arg Arg Tyr Tyr Pro Thr Arg Leu Ala Ile Asn Leu Ser Ser Gly 260 265 270Val Ser Gly Ala Gly Gly Thr Val His Gln Pro Gly Phe Ile Val Val 275 280 285Glu Thr Asn Tyr Arg Leu Tyr Ala Tyr Thr Glu Ser Glu Leu Gln Ile 290 295 300Ala Leu Ile Ala Leu Phe Ser Glu Met Leu Tyr Arg Phe Pro Asn Met305 310 315 320Val Val Ala Gln Val Thr Arg Glu Ser Val Gln Gln Ala Ile Ala Ser 325 330 335Gly Ile Thr Ala Gln Gln Ile Ile His Phe Leu Arg Thr Arg Ala His 340 345 350Pro Val Met Leu Lys Gln Thr Pro Val Leu Pro Pro Thr Ile Thr Asp 355 360 365Gln Ile Arg Leu Trp Glu Leu Glu Arg Asp Arg Leu Arg Phe Thr Glu 370 375 380Gly Val Leu Tyr Asn Gln Phe Leu Ser Gln Val Asp Phe Glu Leu Leu385 390 395 400Leu Ala His Ala Arg Glu Leu Gly Val Leu Val Phe Glu Asn Ser Ala 405 410 415Lys Arg Leu Met Val Val Thr Pro Ala Gly His Ser Asp Val Lys Arg 420 425 430Phe Trp Lys Arg Gln Lys His Ser Ser 435 44043462PRTHomo sapiens 43Met Glu Ser Thr Pro Ser Arg Gly Leu Asn Arg Val His Leu Gln Cys1 5 10 15Arg Asn Leu Gln Glu Phe Leu Gly Gly Leu Ser Pro Gly Val Leu Asp 20 25 30Arg Leu Tyr Gly His Pro Ala Thr Cys Leu Ala Val Phe Arg Glu Leu 35 40 45Pro Ser Leu Ala Lys Asn Trp Val Met Arg Met Leu Phe Leu Glu Gln 50 55 60Pro Leu Pro Gln Ala Ala Val Ala Leu Trp Val Lys Lys Glu Phe Ser65 70 75 80Lys Ala Gln Glu Glu Ser Thr Gly Leu Leu Ser Gly Leu Arg Ile Trp 85 90 95His Thr Gln Leu Leu Pro Gly Gly Leu Gln Gly Leu Ile Leu Asn Pro 100 105 110Ile Phe Arg Gln Asn Leu Arg Ile Ala Leu Leu Gly Gly Gly Lys Ala 115 120 125Trp Ser Asp Asp Thr Ser Gln Leu Gly Pro Asp Lys His Ala Arg Asp 130 135 140Val Pro Ser Leu Asp Lys Tyr Ala Glu Glu Arg Trp Glu Val Val Leu145 150 155 160His Phe Met Val Gly Ser Pro Ser Ala Ala Val Ser Gln Asp Leu Ala 165 170 175Gln Leu Leu Ser Gln Ala Gly Leu Met Lys Ser Thr Glu Pro Gly Glu 180 185 190Pro Pro Cys Ile Thr Ser Ala Gly Phe Gln Phe Leu Leu Leu Asp Thr 195 200 205Pro Ala Gln Leu Trp Tyr Phe Met Leu Gln Tyr Leu Gln Thr Ala Gln 210 215 220Ser Arg Gly Met Asp Leu Val Glu Ile Leu Ser Phe Leu Phe Gln Leu225 230 235 240Ser Phe Ser Thr Leu Gly Lys Asp Tyr Ser Val Glu Gly Met Ser Asp 245 250 255Ser Leu Leu Asn Phe Leu Gln His Leu Arg Glu Phe Gly Leu Val Phe 260 265 270Gln Arg Lys Arg Lys Ser Arg Arg Tyr Tyr Pro Thr Arg Leu Ala Ile 275 280 285Asn Leu Ser Ser Gly Val Ser Gly Ala Gly Gly Thr Val His Gln Pro 290 295 300Gly Phe Ile Val Val Glu Thr Asn Tyr Arg Leu Tyr Ala Tyr Thr Glu305 310 315 320Ser Glu Leu Gln Ile Ala Leu Ile Ala Leu Phe Ser Glu Met Leu Tyr 325 330 335Arg Phe Pro Asn Met Val Val Ala Gln Val Thr Arg Glu Ser Val Gln 340 345 350Gln Ala Ile Ala Ser Gly Ile Thr Ala Gln Gln Ile Ile His Phe Leu 355 360 365Arg Thr Arg Ala His Pro Val Met Leu Lys Gln Thr Pro Val Leu Pro 370 375 380Pro Thr Ile Thr Asp Gln Ile Arg Leu Trp Glu Leu Glu Arg Asp Arg385 390 395 400Leu Arg Phe Thr Glu Gly Val Leu Tyr Asn Gln Phe Leu Ser Gln Val

405 410 415Asp Phe Glu Leu Leu Leu Ala His Ala Arg Glu Leu Gly Val Leu Val 420 425 430Phe Glu Asn Ser Ala Lys Arg Leu Met Val Val Thr Pro Ala Gly His 435 440 445Ser Asp Val Lys Arg Phe Trp Lys Arg Gln Lys His Ser Ser 450 455 4604421DNAArtificial sequencePrimer 44tggggtcatc ggctcaacgt g 214523DNAArtificial sequencePrimer 45tcttgagcag tagatgagtt tgg 2346285PRTHomo sapiens 46Met Arg Glu Leu Lys Arg Thr Leu Asp Ala Lys Gly His Gly Val Leu1 5 10 15Glu Met Pro Ser Gly Thr Gly Lys Thr Val Ser Leu Leu Ala Leu Ile 20 25 30Met Ala Tyr Gln Arg Ala Tyr Pro Leu Glu Val Thr Lys Leu Ile Tyr 35 40 45Cys Ser Arg Thr Val Pro Glu Ile Glu Lys Val Ile Glu Glu Leu Arg 50 55 60Lys Leu Leu Asn Phe Tyr Glu Lys Gln Glu Gly Glu Lys Leu Pro Phe65 70 75 80Leu Gly Leu Ala Leu Ser Ser Arg Lys Asn Leu Cys Ile His Pro Glu 85 90 95Val Thr Pro Leu Arg Phe Gly Lys Asp Val Asp Gly Lys Cys His Ser 100 105 110Leu Thr Ala Ser Tyr Val Arg Ala Gln Tyr Gln His Asp Thr Ser Leu 115 120 125Pro His Cys Arg Phe Tyr Glu Glu Phe Asp Ala His Gly Arg Glu Val 130 135 140Pro Leu Pro Ala Gly Ile Tyr Asn Leu Asp Asp Leu Lys Ala Leu Gly145 150 155 160Arg Arg Gln Gly Trp Cys Pro Tyr Phe Leu Ala Arg Tyr Ser Ile Leu 165 170 175His Ala Asn Val Val Val Tyr Ser Tyr His Tyr Leu Leu Asp Pro Lys 180 185 190Ile Ala Asp Leu Val Ser Lys Glu Leu Ala Arg Lys Ala Val Val Val 195 200 205Phe Asp Glu Ala His Asn Ile Asp Asn Val Cys Ile Asp Ser Met Ser 210 215 220Val Asn Leu Thr Arg Arg Thr Leu Asp Arg Cys Gln Gly Asn Leu Glu225 230 235 240Thr Leu Gln Lys Thr Val Leu Arg Ile Lys Glu Thr Asp Glu Gln Arg 245 250 255Leu Arg Asp Glu Tyr Arg Arg Leu Val Glu Gly Leu Arg Glu Ala Ser 260 265 270Ala Ala Arg Glu Thr Asp Ala His Leu Ala Asn Pro Val 275 280 28547300PRTHomo sapiens 47Met Lys Leu Asn Val Asp Gly Leu Leu Val Tyr Phe Pro Tyr Asp Tyr1 5 10 15Ile Tyr Pro Glu Gln Phe Ser Tyr Met Arg Glu Leu Lys Arg Thr Leu 20 25 30Asp Ala Lys Gly His Gly Val Leu Glu Met Pro Ser Gly Thr Gly Lys 35 40 45Thr Val Ser Leu Leu Ala Leu Ile Met Ala Tyr Gln Arg Ala Tyr Pro 50 55 60Leu Glu Val Thr Lys Leu Ile Tyr Cys Ser Arg Thr Val Pro Glu Ile65 70 75 80Glu Lys Val Ile Glu Glu Leu Arg Lys Leu Leu Asn Phe Tyr Glu Lys 85 90 95Gln Glu Gly Glu Lys Leu Pro Phe Leu Gly Leu Ala Leu Ser Ser Arg 100 105 110Lys Asn Leu Cys Ile His Pro Glu Val Thr Pro Leu Arg Phe Gly Lys 115 120 125Asp Val Asp Gly Lys Cys His Ser Leu Thr Ala Ser Tyr Val Arg Ala 130 135 140Gln Tyr Gln His Asp Thr Ser Leu Pro His Cys Arg Phe Tyr Glu Glu145 150 155 160Phe Asp Ala His Gly Arg Glu Val Pro Leu Pro Ala Gly Ile Tyr Asn 165 170 175Leu Asp Asp Leu Lys Ala Leu Gly Arg Arg Gln Gly Trp Cys Pro Tyr 180 185 190Phe Leu Ala Arg Tyr Ser Ile Leu His Ala Asn Val Val Val Tyr Ser 195 200 205Tyr His Tyr Leu Leu Asp Pro Lys Ile Ala Asp Leu Val Ser Lys Glu 210 215 220Leu Ala Arg Lys Ala Val Val Val Phe Asp Glu Ala His Asn Ile Asp225 230 235 240Asn Val Cys Ile Asp Ser Met Ser Val Asn Leu Thr Arg Arg Thr Leu 245 250 255Asp Arg Cys Gln Gly Asn Leu Glu Thr Leu Gln Lys Thr Val Leu Arg 260 265 270Ile Lys Glu Thr Asp Glu Gln Arg Leu Arg Asp Glu Tyr Arg Arg Leu 275 280 285Val Glu Gly Leu Arg Glu Ala Ser Ala Ala Arg Glu 290 295 3004822DNAArtificial sequencePrimer 48ggtcaacata tttcactggc ac 224922DNAArtificial sequencePrimer 49tccatcagat gaggcttatc gt 225069PRTHomo sapiens 50Met Gln Leu Glu Lys Pro Lys Pro Val Lys Pro Val Thr Phe Ser Thr1 5 10 15Gly Ile Lys Met Gly Gln His Ile Ser Leu Ala Pro Ile His Lys Leu 20 25 30Glu Glu Ala Leu Tyr Glu Tyr Gln Pro Leu Gln Ile Glu Thr Tyr Gly 35 40 45Pro His Val Pro Glu Leu Glu Met Leu Gly Arg Leu Gly Gly Phe Asp 50 55 60Thr Ile Ser Leu Ile6551189PRTHomo sapiens 51Lys Met Glu Ile Tyr Gln Lys Glu Asn Lys Asp Val Ile Gln Lys Asn1 5 10 15Lys Leu Lys Leu Thr Arg Glu Gln Glu Glu Leu Glu Glu Ala Leu Glu 20 25 30Val Glu Arg Gln Glu Asn Glu Gln Arg Arg Leu Phe Ile Gln Lys Glu 35 40 45Glu Gln Leu Gln Gln Ile Leu Lys Arg Lys Asn Lys Gln Ala Phe Leu 50 55 60Asp Glu Leu Glu Ser Ser Asp Leu Pro Val Ala Leu Leu Leu Ala Gln65 70 75 80His Lys Asp Arg Ser Thr Gln Leu Glu Met Gln Leu Glu Lys Pro Lys 85 90 95Pro Val Lys Pro Val Thr Phe Ser Thr Gly Ile Lys Met Gly Gln His 100 105 110Ile Ser Leu Ala Pro Ile His Lys Leu Glu Glu Ala Leu Tyr Glu Tyr 115 120 125Gln Pro Leu Gln Ile Glu Thr Tyr Gly Pro His Val Pro Glu Leu Glu 130 135 140Met Leu Gly Arg Leu Gly Tyr Leu Asn His Val Arg Ala Ala Ser Pro145 150 155 160Gln Asp Leu Ala Gly Gly Tyr Thr Ser Ser Leu Ala Cys His Arg Ala 165 170 175Leu Gln Asp Ala Phe Ser Gly Leu Phe Trp Gln Pro Ser 180 1855222DNAArtificial sequencePrimer 52caaggccaga gataagaaca cc 225322DNAArtificial sequencePrimer 53gtaggctttg atgtgtgatg gt 225494PRTHomo sapiens 54Met Ala Leu Asp Val Lys Ser Arg Ala Lys Arg Tyr Glu Lys Leu Asp1 5 10 15Phe Leu Gly Glu Gly Gln Phe Ala Thr Val Tyr Lys Ala Arg Asp Lys 20 25 30Asn Thr Asn Gln Ile Val Ala Ile Lys Lys Ile Lys Leu Gly His Arg 35 40 45Ser Glu Ala Lys Asp Gly Ile Asn Arg Thr Ala Leu Arg Glu Ile Lys 50 55 60 Leu Leu Gln Glu Leu Ser His Pro Asn Ile Ile Gly Val Ile Ile Lys65 70 75 80Asp Asn Ser Leu Val Leu Thr Pro Ser His Ile Lys Ala Tyr 85 9055120PRTHomo sapiens 55Met Ala Leu Asp Val Lys Ser Arg Ala Lys Arg Tyr Glu Lys Leu Asp1 5 10 15Phe Leu Gly Glu Gly Gln Phe Ala Thr Val Tyr Lys Ala Arg Asp Lys 20 25 30Asn Thr Asn Gln Ile Val Ala Ile Lys Lys Ile Lys Leu Gly His Arg 35 40 45Ser Glu Ala Lys Asp Gly Ile Asn Arg Thr Ala Leu Arg Glu Ile Lys 50 55 60Leu Leu Gln Glu Leu Ser His Pro Asn Ile Ile Gly Leu Leu Asp Ala65 70 75 80Phe Gly His Lys Ser Asn Ile Ser Leu Val Phe Asp Phe Met Glu Thr 85 90 95Asp Leu Glu Val Ile Ile Lys Asp Asn Ser Leu Val Leu Thr Pro Ser 100 105 110His Ile Lys Ala Tyr Met Leu Met 115 1205619DNAArtificial sequencePrimer 56cttggacagg agaaggcac 195721DNAArtificial sequencePrimer 57cagtatagtc acaccagaat g 2158255PRTHomo sapiens 58Met Pro Arg Ser Val Val Gly Thr Ala Cys Met Tyr Phe Lys Arg Phe1 5 10 15Tyr Leu Asn Asn Ser Val Met Glu Tyr His Pro Arg Ile Ile Met Leu 20 25 30Thr Cys Ala Phe Leu Ala Cys Lys Val Asp Glu Phe Asn Val Ser Ser 35 40 45Pro Gln Phe Val Gly Asn Leu Arg Glu Ser Pro Leu Gly Gln Glu Lys 50 55 60Ala Leu Glu Gln Ile Leu Glu Tyr Glu Leu Leu Leu Ile Gln Gln Leu65 70 75 80Asn Phe His Leu Ile Val His Asn Pro Tyr Arg Pro Phe Glu Gly Phe 85 90 95Leu Ile Asp Leu Lys Thr Arg Tyr Pro Ile Leu Glu Asn Pro Glu Ile 100 105 110Leu Arg Lys Thr Ala Asp Asp Phe Leu Asn Arg Ile Ala Leu Thr Asp 115 120 125Ala Tyr Leu Leu Tyr Thr Pro Ser Gln Ile Ala Leu Thr Ala Ile Leu 130 135 140Ser Ser Ala Ser Arg Ala Gly Ile Thr Met Glu Ser Tyr Leu Ser Glu145 150 155 160Ser Leu Met Leu Lys Glu Asn Arg Thr Cys Leu Ser Gln Leu Leu Asp 165 170 175Ile Met Lys Ser Met Arg Asn Leu Val Lys Lys Tyr Glu Pro Pro Arg 180 185 190Ser Glu Glu Val Ala Val Leu Lys Gln Lys Leu Glu Arg Cys His Ser 195 200 205Ala Glu Leu Ala Leu Asn Val Ile Thr Lys Lys Arg Lys Gly Tyr Glu 210 215 220Asp Asp Asp Tyr Val Ser Lys Lys Ser Lys His Glu Glu Val Cys Phe225 230 235 240Thr Pro Lys Met Asn Ser Lys Leu Phe Leu Leu Tyr Ile Leu Val 245 250 25559323PRTHomo sapiens 59Met Tyr His Asn Ser Ser Gln Lys Arg His Trp Thr Phe Ser Ser Glu1 5 10 15Glu Gln Leu Ala Arg Leu Arg Ala Asp Ala Asn Arg Lys Phe Arg Cys 20 25 30Lys Ala Val Ala Asn Gly Lys Val Leu Pro Asn Asp Pro Val Phe Leu 35 40 45Glu Pro His Glu Glu Met Thr Leu Cys Lys Tyr Tyr Glu Lys Arg Leu 50 55 60Leu Glu Phe Cys Ser Val Phe Lys Pro Ala Met Pro Arg Ser Val Val65 70 75 80Gly Thr Ala Cys Met Tyr Phe Lys Arg Phe Tyr Leu Asn Asn Ser Val 85 90 95Met Glu Tyr His Pro Arg Ile Ile Met Leu Thr Cys Ala Phe Leu Ala 100 105 110Cys Lys Val Asp Glu Phe Asn Val Ser Ser Pro Gln Phe Val Gly Asn 115 120 125Leu Arg Glu Ser Pro Leu Gly Gln Glu Lys Ala Leu Glu Gln Ile Leu 130 135 140Glu Tyr Glu Leu Leu Leu Ile Gln Gln Leu Asn Phe His Leu Ile Val145 150 155 160His Asn Pro Tyr Arg Pro Phe Glu Gly Phe Leu Ile Asp Leu Lys Thr 165 170 175Arg Tyr Pro Ile Leu Glu Asn Pro Glu Ile Leu Arg Lys Thr Ala Asp 180 185 190Asp Phe Leu Asn Arg Ile Ala Leu Thr Asp Ala Tyr Leu Leu Tyr Thr 195 200 205Pro Ser Gln Ile Ala Leu Thr Ala Ile Leu Ser Ser Ala Ser Arg Ala 210 215 220Gly Ile Thr Met Glu Ser Tyr Leu Ser Glu Ser Leu Met Leu Lys Glu225 230 235 240Asn Arg Thr Cys Leu Ser Gln Leu Leu Asp Ile Met Lys Ser Met Arg 245 250 255Asn Leu Val Lys Lys Tyr Glu Pro Pro Arg Ser Glu Glu Val Ala Val 260 265 270Leu Lys Gln Lys Leu Glu Arg Cys His Ser Ala Glu Leu Ala Leu Asn 275 280 285Val Ile Thr Lys Lys Arg Lys Gly Tyr Glu Asp Asp Asp Tyr Val Ser 290 295 300Lys Lys Ser Lys His Glu Glu Glu Glu Trp Thr Asp Asp Asp Leu Val305 310 315 320Glu Ser Leu6019DNAArtificial sequencePrimer 60gctcggagga agttcaagg 196119DNAArtificial sequencePrimer 61gtcctggtcc tgatccttg 1962199PRTHomo sapiens 62Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Met Pro Glu 50 55 60Ser Gly Ala Gly Ser Glu Phe Asn Arg Lys Leu Arg Glu Glu Ala Arg65 70 75 80Arg Lys Phe Lys Gly Ile Lys Lys Gly Gly Val Thr Glu Asn Thr Ser 85 90 95Tyr Tyr Ile Phe Thr Gln Cys Pro Asp Gly Ala Phe Glu Ala Phe Pro 100 105 110Val His Asn Trp Tyr Asn Phe Thr Pro Leu Ala Arg His Arg Thr Leu 115 120 125Thr Ala Glu Glu Ala Glu Glu Glu Trp Glu Arg Arg Asn Lys Val Leu 130 135 140Asn His Phe Ser Ile Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln145 150 155 160Asp Glu Asp Glu Glu Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser 165 170 175Glu Leu Arg Ile His Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp 180 185 190Ala Ser Asp Ala Ser Gly Glu 19563238PRTHomo sapiens 63Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Met Pro Glu 50 55 60Ser Gly Ala Gly Ser Glu Phe Asn Arg Lys Leu Arg Glu Glu Ala Arg65 70 75 80Arg Lys Lys Tyr Gly Ile Val Leu Lys Glu Phe Arg Pro Glu Asp Gln 85 90 95Pro Trp Leu Leu Arg Val Asn Gly Lys Ser Gly Arg Lys Phe Lys Gly 100 105 110Ile Lys Lys Gly Gly Val Thr Glu Asn Thr Ser Tyr Tyr Ile Phe Thr 115 120 125Gln Cys Pro Asp Gly Ala Phe Glu Ala Phe Pro Val His Asn Trp Tyr 130 135 140Asn Phe Thr Pro Leu Ala Arg His Arg Thr Leu Thr Ala Glu Glu Ala145 150 155 160Glu Glu Glu Trp Glu Arg Arg Asn Lys Val Leu Asn His Phe Ser Ile 165 170 175Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln Asp Glu Asp Glu Glu 180 185 190Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His 195 200 205Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser 210 215 220Gly Glu Glu Gly Gly Arg Val Pro Lys Ala Lys Lys Lys Ala225 230 2356419DNAArtificial sequencePrimer 64aggcctgggc gtctgtttg 196519DNAArtificial sequencePrimer 65gcacggcatc ctcagtcac 1966437PRTHomo sapiens 66Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Met Pro Glu 50 55 60Ser Gly Ala Gly Ser Glu Phe Asn Arg Lys Leu Arg Glu Glu Ala Arg65 70 75 80Arg Lys Lys Tyr Gly Ile Val Leu Lys Glu Phe Arg Pro Glu Asp Gln 85 90 95Pro Trp Leu Leu Arg Val Asn Gly Lys Ser Gly Arg Lys Phe Lys Gly 100 105 110Ile Lys Lys Gly Gly Val Thr Glu Asn Thr Ser Tyr Tyr Ile Phe Thr 115 120 125Gln Cys Pro Asp Gly Ala Phe Glu Ala Phe Pro Val His Asn Trp Tyr 130 135 140Asn Phe Thr Pro Leu

Ala Arg His Arg Thr Leu Thr Ala Glu Glu Ala145 150 155 160Glu Glu Glu Trp Glu Arg Arg Asn Lys Val Leu Asn His Phe Ser Ile 165 170 175Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln Asp Glu Asp Glu Glu 180 185 190Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His 195 200 205Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser 210 215 220Gly Glu Glu Gly Gly Arg Val Pro Lys Ala Lys Lys Lys Ala Pro Leu225 230 235 240Ala Lys Gly Gly Arg Lys Lys Lys Lys Lys Lys Gly Ser Asp Asp Glu 245 250 255Ala Phe Glu Asp Ser Asp Asp Gly Asp Phe Glu Gly Gln Glu Val Asp 260 265 270Tyr Met Ser Asp Gly Ser Ser Ser Ser Gln Glu Glu Pro Glu Ser Lys 275 280 285Ala Lys Ala Pro Gln Gln Glu Glu Gly Pro Lys Gly Val Asp Glu Gln 290 295 300Ser Asp Ser Ser Glu Glu Ser Glu Glu Glu Lys Pro Pro Glu Glu Asp305 310 315 320Lys Glu Glu Glu Glu Glu Lys Lys Ala Pro Thr Pro Gln Glu Lys Lys 325 330 335Arg Arg Lys Asp Ser Ser Glu Glu Ser Asp Ser Ser Glu Glu Ser Asp 340 345 350Ile Asp Ser Glu Ala Ser Ser Ala Leu Phe Met Ala Val Arg Pro Ser 355 360 365Pro Val Ala Gly Glu Ala Trp Ala Ser Val Cys Arg Leu Thr His Leu 370 375 380Pro Thr Leu Thr Ser Ala Glu Glu Glu Asp Ala Thr Gln Glu Arg Ala385 390 395 400Glu Ala Val Gly Arg Glu Leu Lys Gly Gln Gln Pro Pro Arg His Ala 405 410 415Gln Arg Arg Gly Trp Gln His Leu Leu His Pro Ala Gly Gly Cys Gln 420 425 430Gln Thr Arg Ala Arg 43567480PRTHomo sapiens 67Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Met Pro Glu 50 55 60Ser Gly Ala Gly Ser Glu Phe Asn Arg Lys Leu Arg Glu Glu Ala Arg65 70 75 80Arg Lys Lys Tyr Gly Ile Val Leu Lys Glu Phe Arg Pro Glu Asp Gln 85 90 95Pro Trp Leu Leu Arg Val Asn Gly Lys Ser Gly Arg Lys Phe Lys Gly 100 105 110Ile Lys Lys Gly Gly Val Thr Glu Asn Thr Ser Tyr Tyr Ile Phe Thr 115 120 125Gln Cys Pro Asp Gly Ala Phe Glu Ala Phe Pro Val His Asn Trp Tyr 130 135 140Asn Phe Thr Pro Leu Ala Arg His Arg Thr Leu Thr Ala Glu Glu Ala145 150 155 160Glu Glu Glu Trp Glu Arg Arg Asn Lys Val Leu Asn His Phe Ser Ile 165 170 175Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln Asp Glu Asp Glu Glu 180 185 190Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His 195 200 205Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser 210 215 220Gly Glu Glu Gly Gly Arg Val Pro Lys Ala Lys Lys Lys Ala Pro Leu225 230 235 240Ala Lys Gly Gly Arg Lys Lys Lys Lys Lys Lys Gly Ser Asp Asp Glu 245 250 255Ala Phe Glu Asp Ser Asp Asp Gly Asp Phe Glu Gly Gln Glu Val Asp 260 265 270Tyr Met Ser Asp Gly Ser Ser Ser Ser Gln Glu Glu Pro Glu Ser Lys 275 280 285Ala Lys Ala Pro Gln Gln Glu Glu Gly Pro Lys Gly Val Asp Glu Gln 290 295 300Ser Asp Ser Ser Glu Glu Ser Glu Glu Glu Lys Pro Pro Glu Glu Asp305 310 315 320Lys Glu Glu Glu Glu Glu Lys Lys Ala Pro Thr Pro Gln Glu Lys Lys 325 330 335Arg Arg Lys Asp Ser Ser Glu Glu Ser Asp Ser Ser Glu Glu Ser Asp 340 345 350Ile Asp Ser Glu Ala Ser Ser Ala Leu Phe Met Ala Lys Lys Lys Thr 355 360 365Pro Pro Lys Arg Glu Arg Lys Pro Ser Gly Gly Ser Ser Arg Gly Asn 370 375 380Ser Arg Pro Gly Thr Pro Ser Ala Glu Gly Gly Ser Thr Ser Ser Thr385 390 395 400Leu Arg Ala Ala Ala Ser Lys Leu Glu Gln Gly Lys Arg Val Ser Glu 405 410 415Met Pro Ala Ala Lys Arg Leu Arg Leu Asp Thr Gly Pro Gln Ser Leu 420 425 430Ser Gly Lys Ser Thr Pro Gln Pro Pro Ser Gly Lys Thr Thr Pro Asn 435 440 445Ser Gly Asp Val Gln Val Thr Glu Asp Ala Val Arg Arg Tyr Leu Thr 450 455 460Arg Lys Pro Met Thr Thr Lys Asp Leu Leu Lys Lys Phe Gln Thr Lys465 470 475 48068481PRTHomo sapiens 68Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Met Pro Glu 50 55 60Ser Gly Ala Gly Ser Glu Phe Asn Arg Lys Leu Arg Glu Glu Ala Arg65 70 75 80Arg Lys Lys Tyr Gly Ile Val Leu Lys Glu Phe Arg Pro Glu Asp Gln 85 90 95Pro Trp Leu Leu Arg Val Asn Gly Lys Ser Gly Arg Lys Phe Lys Gly 100 105 110Ile Lys Lys Gly Gly Val Thr Glu Asn Thr Ser Tyr Tyr Ile Phe Thr 115 120 125Gln Cys Pro Asp Gly Ala Phe Glu Ala Phe Pro Val His Asn Trp Tyr 130 135 140Asn Phe Thr Pro Leu Ala Arg His Arg Thr Leu Thr Ala Glu Glu Ala145 150 155 160Glu Glu Glu Trp Glu Arg Arg Asn Lys Val Leu Asn His Phe Ser Ile 165 170 175Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln Asp Glu Asp Glu Glu 180 185 190Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His 195 200 205Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser 210 215 220Gly Glu Glu Gly Gly Arg Val Pro Lys Ala Lys Lys Lys Ala Pro Leu225 230 235 240Ala Lys Gly Gly Arg Lys Lys Lys Lys Lys Lys Gly Ser Asp Asp Glu 245 250 255Ala Phe Glu Asp Ser Asp Asp Gly Asp Phe Glu Gly Gln Glu Val Asp 260 265 270Tyr Met Ser Asp Gly Ser Ser Ser Ser Gln Glu Glu Pro Glu Ser Lys 275 280 285Ala Lys Ala Pro Gln Gln Glu Glu Gly Pro Lys Gly Val Asp Glu Gln 290 295 300Ser Asp Ser Ser Glu Glu Ser Glu Glu Glu Lys Pro Pro Glu Glu Asp305 310 315 320Lys Glu Glu Glu Glu Glu Lys Lys Ala Pro Thr Pro Gln Glu Lys Lys 325 330 335Arg Arg Lys Asp Ser Ser Glu Glu Ser Asp Ser Ser Glu Glu Ser Asp 340 345 350Ile Asp Ser Glu Ala Ser Ser Ala Phe Phe Met Ala Val Arg Pro Ser 355 360 365Pro Val Ala Gly Glu Ala Trp Ala Ser Val Cys Arg Leu Thr His Leu 370 375 380Pro Thr Leu Thr Ser Ala Glu Glu Glu Asp Ala Thr Gln Glu Arg Ala385 390 395 400Glu Ala Val Gly Arg Glu Leu Lys Gly Gln Gln Pro Pro Arg His Ala 405 410 415Gln Arg Arg Gly Trp Gln His Leu Leu His Pro Ala Gly Gly Cys Gln 420 425 430Gln Thr Arg Ala Arg Glu Ala Gly Glu Arg Asp Ala Cys Ser Gln Ala 435 440 445Val Ala Ala Gly His Gly Thr Pro Glu Pro Val Trp Glu Val Asp Thr 450 455 460Pro Ala Thr Ile Arg Gln Asp Asn Thr Gln Gln Arg Arg Arg Ala Gly465 470 475 480Asp69217PRTHomo sapiens 69Val Asp Glu Gln Ser Asp Ser Ser Glu Glu Ser Glu Glu Glu Lys Pro1 5 10 15Pro Glu Glu Asp Lys Glu Glu Glu Glu Glu Lys Lys Ala Pro Thr Pro 20 25 30Gln Glu Lys Lys Arg Arg Lys Asp Ser Ser Glu Glu Ser Asp Ser Ser 35 40 45Glu Glu Ser Asp Ile Asp Ser Glu Ala Ser Ser Ala Leu Phe Met Ala 50 55 60Lys Lys Lys Thr Pro Pro Lys Arg Glu Arg Lys Pro Ser Gly Gly Ser65 70 75 80Ser Arg Gly Asn Ser Arg Pro Gly Thr Pro Ser Ala Glu Gly Gly Ser 85 90 95Thr Ser Ser Thr Leu Arg Ala Ala Ala Ser Lys Leu Glu Gln Gly Lys 100 105 110Arg Val Ser Glu Met Pro Ala Ala Lys Arg Leu Arg Leu Asp Thr Gly 115 120 125Pro Gln Ser Leu Ser Gly Lys Ser Thr Pro Gln Pro Pro Ser Gly Lys 130 135 140Thr Thr Pro Asn Ser Gly Asp Val Gln Val Thr Glu Asp Ala Val Arg145 150 155 160Arg Tyr Leu Thr Arg Lys Pro Met Thr Thr Lys Asp Leu Leu Lys Lys 165 170 175Phe Gln Thr Lys Lys Thr Gly Leu Ser Ser Glu Gln Thr Val Asn Val 180 185 190Leu Ala Gln Ile Leu Lys Arg Leu Asn Pro Glu Arg Lys Met Ile Asn 195 200 205Asp Lys Met His Phe Ser Leu Lys Glu 210 2157021DNAArtificial sequencePrimer 70taccaagagg aggagaagga g 217120DNAArtificial sequencePrimer 71tcctctgagc tgtccgactc 2072178PRTHomo sapiens 72Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Lys Glu Lys 50 55 60Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His Asp Leu Glu Asp65 70 75 80Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser Gly Glu Glu Gly 85 90 95Gly Arg Val Pro Lys Ala Lys Lys Lys Ala Pro Leu Ala Lys Gly Gly 100 105 110Arg Lys Lys Lys Lys Lys Lys Gly Ser Asp Asp Glu Ala Phe Glu Asp 115 120 125Ser Asp Asp Gly Asp Phe Glu Gly Gln Glu Val Asp Tyr Met Ser Asp 130 135 140Gly Ser Ser Ser Ser Gln Glu Glu Pro Glu Ser Lys Ala Lys Ala Pro145 150 155 160Gln Gln Glu Glu Gly Pro Lys Gly Val Asp Glu Gln Ser Asp Ser Ser 165 170 175Glu Glu73358PRTHomo sapiens 73Met Ala Ala Leu Gly Pro Ser Ser Gln Asn Val Thr Glu Tyr Val Val1 5 10 15Arg Val Pro Lys Asn Thr Thr Lys Lys Tyr Asn Ile Met Ala Phe Asn 20 25 30Ala Ala Asp Lys Val Asn Phe Ala Thr Trp Asn Gln Ala Arg Leu Glu 35 40 45Arg Asp Leu Ser Asn Lys Lys Ile Tyr Gln Glu Glu Glu Met Pro Glu 50 55 60Ser Gly Ala Gly Ser Glu Phe Asn Arg Lys Leu Arg Glu Glu Ala Arg65 70 75 80Arg Lys Lys Tyr Gly Ile Val Leu Lys Glu Phe Arg Pro Glu Asp Gln 85 90 95Pro Trp Leu Leu Arg Val Asn Gly Lys Ser Gly Arg Lys Phe Lys Gly 100 105 110Ile Lys Lys Gly Gly Val Thr Glu Asn Thr Ser Tyr Tyr Ile Phe Thr 115 120 125Gln Cys Pro Asp Gly Ala Phe Glu Ala Phe Pro Val His Asn Trp Tyr 130 135 140Asn Phe Thr Pro Leu Ala Arg His Arg Thr Leu Thr Ala Glu Glu Ala145 150 155 160Glu Glu Glu Trp Glu Arg Arg Asn Lys Val Leu Asn His Phe Ser Ile 165 170 175Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln Asp Glu Asp Glu Glu 180 185 190Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His 195 200 205Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser 210 215 220Gly Glu Glu Gly Gly Arg Val Pro Lys Ala Lys Lys Lys Ala Pro Leu225 230 235 240Ala Lys Gly Gly Arg Lys Lys Lys Lys Lys Lys Gly Ser Asp Asp Glu 245 250 255Ala Phe Glu Asp Ser Asp Asp Gly Asp Phe Glu Gly Gln Glu Val Asp 260 265 270Tyr Met Ser Asp Gly Ser Ser Ser Ser Gln Glu Glu Pro Glu Ser Lys 275 280 285Ala Lys Ala Pro Gln Gln Glu Glu Gly Pro Lys Gly Val Asp Glu Gln 290 295 300Ser Asp Ser Ser Glu Glu Ser Glu Glu Glu Lys Pro Pro Glu Glu Asp305 310 315 320Lys Glu Glu Glu Glu Glu Lys Lys Ala Pro Thr Pro Gln Glu Lys Lys 325 330 335Arg Arg Lys Asp Ser Ser Glu Glu Ser Asp Ser Ser Glu Glu Ser Asp 340 345 350Ile Asp Ser Glu Ala Ser 3557420DNAArtificial sequencePrimer 74cagagaacac gtcctactac 207519DNAArtificial sequencePrimer 75cagagaacac gtcctacta 1976183PRTHomo sapiens 76Met Gln Gln Arg Arg Leu Lys Asp Gln Asp Gln Asp Glu Asp Glu Glu1 5 10 15Glu Lys Glu Lys Arg Gly Arg Arg Lys Ala Ser Glu Leu Arg Ile His 20 25 30Asp Leu Glu Asp Asp Leu Glu Met Ser Ser Asp Ala Ser Asp Ala Ser 35 40 45Gly Glu Glu Gly Gly Arg Val Pro Lys Ala Lys Lys Lys Ala Pro Leu 50 55 60Ala Lys Gly Gly Arg Lys Lys Lys Lys Lys Lys Gly Ser Asp Asp Glu65 70 75 80Ala Phe Glu Asp Ser Asp Asp Gly Asp Phe Glu Gly Gln Glu Val Asp 85 90 95Tyr Met Ser Asp Gly Ser Ser Ser Ser Gln Glu Glu Pro Glu Ser Lys 100 105 110Ala Lys Ala Pro Gln Gln Glu Glu Gly Pro Lys Gly Val Asp Glu Gln 115 120 125Ser Asp Ser Ser Glu Glu Ser Glu Glu Glu Lys Pro Pro Glu Lys Pro 130 135 140Pro Pro Gly Ser Ala Ser Leu Thr Leu Thr Lys Gly Leu Cys Cys Pro145 150 155 160Leu Gly Asn Phe Tyr Ser Ser Pro Phe His Phe Pro Lys Ser Leu Phe 165 170 175Ser Cys Asp Leu Ser Thr Thr 18077240PRTHomo sapiens 77Asn Thr Ser Tyr Tyr Ile Phe Thr Gln Cys Pro Asp Gly Ala Phe Glu1 5 10 15Ala Phe Pro Val His Asn Trp Tyr Asn Phe Thr Pro Leu Ala Arg His 20 25 30Arg Thr Leu Thr Ala Glu Glu Ala Glu Glu Glu Trp Glu Arg Arg Asn 35 40 45Lys Val Leu Asn His Phe Ser Ile Met Gln Gln Arg Arg Leu Lys Asp 50 55 60Gln Asp Gln Asp Glu Asp Glu Glu Glu Lys Glu Lys Arg Gly Arg Arg65 70 75 80Lys Ala Ser Glu Leu Arg Ile His Asp Leu Glu Asp Asp Leu Glu Met 85 90 95Ser Ser Asp Ala Ser Asp Ala Ser Gly Glu Glu Gly Gly Arg Val Pro 100 105 110Lys Ala Lys Lys Lys Ala Pro Leu Ala Lys Gly Gly Arg Lys Lys Lys 115 120 125Lys Lys Lys Gly Ser Asp Asp Glu Ala Phe Glu Asp Ser Asp Asp Gly 130 135 140Asp Phe Glu Gly Gln Glu Val Asp Tyr Met Ser Asp Gly Ser Ser Ser145 150 155 160Ser Gln Glu Glu Pro Glu Ser Lys Ala Lys Ala Pro Gln Gln Glu Glu 165 170 175Gly Pro Lys Gly Val Asp Glu Gln Ser Asp Ser Ser Glu Glu Ser Glu 180 185 190Glu Glu Lys Pro Pro Glu Glu Asp Lys Glu Glu Glu Glu Glu Lys Lys 195 200 205Ala Pro Thr Pro Gln Glu Lys Lys Arg

Arg Lys Asp Ser Ser Glu Glu 210 215 220Ser Asp Ser Ser Glu Glu Ser Asp Ile Asp Ser Glu Ala Ser Ser Ala225 230 235 2407819DNAArtificial sequencePrimer 78agacacggac agcgacgaa 197919DNAArtificial sequencePrimer 79accacctgaa gcttgcctc 1980153PRTHomo sapiens 80Met Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys His Leu Ala1 5 10 15Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu Leu Thr Ala 20 25 30Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn Asp Glu Gly 35 40 45Trp Val Arg Ser Thr Glu Val Lys Asp Pro Trp Asn Leu Ser Asn Asp 50 55 60Glu Tyr Tyr Tyr Pro Lys Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly65 70 75 80Asn Ile Ile Gln His Ser Ile Pro Ala Val Glu Leu Arg Gln Pro Phe 85 90 95Phe Pro Thr His Met Gly Pro Ile Lys Leu Arg Gln Phe His Arg Pro 100 105 110Pro Leu Lys Lys Tyr Ser Phe Gly Ala Leu Ser Gln Pro Gly Pro His 115 120 125Ser Val Gln Pro Leu Leu Lys His Ile Lys Lys Lys Ala Glu Met Arg 130 135 140Glu Gln Glu Arg Gln Ala Ser Gly Gly145 15081660PRTHomo sapiens 81Met Gly Pro Gly Cys Asp Leu Leu Leu Arg Thr Ala Ala Thr Ile Thr1 5 10 15Ala Ala Ala Ile Met Ser Asp Thr Asp Ser Asp Glu Asp Ser Ala Gly 20 25 30Gly Gly Pro Phe Ser Leu Ala Gly Phe Leu Phe Gly Asn Ile Asn Gly 35 40 45Ala Gly Gln Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys 50 55 60His Leu Ala Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu65 70 75 80Leu Thr Ala Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn 85 90 95Asp Glu Gly Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp 100 105 110Ile Asn Glu Val Ala Glu Asp Glu Ser Arg Arg Tyr Gln Gln Thr Met 115 120 125Gly Ser Leu Gln Pro Leu Cys His Ser Asp Tyr Asp Glu Asp Asp Tyr 130 135 140Asp Ala Asp Cys Glu Asp Ile Asp Cys Lys Leu Met Pro Pro Pro Pro145 150 155 160Pro Pro Pro Gly Pro Met Lys Lys Asp Lys Asp Gln Asp Ser Ile Thr 165 170 175Gly Glu Lys Val Asp Phe Ser Ser Ser Ser Asp Ser Glu Ser Glu Met 180 185 190Gly Pro Gln Glu Ala Thr Gln Ala Glu Ser Glu Asp Gly Lys Leu Thr 195 200 205Leu Pro Leu Ala Gly Ile Met Gln His Asp Ala Thr Lys Leu Leu Pro 210 215 220Ser Val Thr Glu Leu Phe Pro Glu Phe Arg Pro Gly Lys Val Leu Arg225 230 235 240Phe Leu Arg Leu Phe Gly Pro Gly Lys Asn Val Pro Ser Val Trp Arg 245 250 255Ser Ala Arg Arg Lys Arg Lys Lys Lys His Arg Glu Leu Ile Gln Glu 260 265 270Glu Gln Ile Gln Glu Val Glu Cys Ser Val Glu Ser Glu Val Ser Gln 275 280 285Lys Ser Leu Trp Asn Tyr Asp Tyr Ala Pro Pro Pro Pro Pro Glu Gln 290 295 300Cys Leu Ser Asp Asp Glu Ile Thr Met Met Ala Pro Val Glu Ser Lys305 310 315 320Phe Ser Gln Ser Thr Gly Asp Ile Asp Lys Val Thr Asp Thr Lys Pro 325 330 335Arg Val Ala Glu Trp Arg Tyr Gly Pro Ala Arg Leu Trp Tyr Asp Met 340 345 350Leu Gly Val Pro Glu Asp Gly Ser Gly Phe Asp Tyr Gly Phe Lys Leu 355 360 365Arg Lys Thr Glu His Glu Pro Val Ile Lys Ser Arg Met Ile Glu Glu 370 375 380Phe Arg Lys Leu Glu Glu Asn Asn Gly Thr Asp Leu Leu Ala Asp Glu385 390 395 400Asn Phe Leu Met Val Thr Gln Leu His Trp Glu Asp Asp Ile Ile Trp 405 410 415Asp Gly Glu Asp Val Lys His Lys Gly Thr Lys Pro Gln Arg Ala Ser 420 425 430Leu Ala Gly Trp Leu Pro Ser Ser Met Thr Arg Asn Ala Met Ala Tyr 435 440 445Asn Val Gln Gln Gly Phe Ala Ala Thr Leu Asp Asp Asp Lys Pro Trp 450 455 460Tyr Ser Ile Phe Pro Ile Asp Asn Glu Asp Leu Val Tyr Gly Arg Trp465 470 475 480Glu Asp Asn Ile Ile Trp Asp Ala Gln Ala Met Pro Arg Leu Leu Glu 485 490 495Pro Pro Val Leu Thr Leu Asp Pro Asn Asp Glu Asn Leu Ile Leu Glu 500 505 510Ile Pro Asp Glu Lys Glu Glu Ala Thr Ser Asn Ser Pro Ser Lys Glu 515 520 525Ser Lys Lys Glu Ser Ser Leu Lys Lys Ser Arg Ile Leu Leu Gly Lys 530 535 540Thr Gly Val Ile Lys Glu Glu Pro Gln Gln Asn Met Ser Gln Pro Glu545 550 555 560Val Lys Asp Pro Trp Asn Leu Ser Asn Asp Glu Tyr Tyr Tyr Pro Lys 565 570 575Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly Asn Ile Ile Gln His Ser 580 585 590Ile Pro Ala Val Glu Leu Arg Gln Pro Phe Phe Pro Thr His Met Gly 595 600 605Pro Ile Lys Leu Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser 610 615 620Phe Gly Ala Leu Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu625 630 635 640Lys His Ile Lys Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala 645 650 655Ser Gly Gly Gly 66082153PRTHomo sapiens 82Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys His Leu Ala1 5 10 15Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu Leu Thr Ala 20 25 30Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn Asp Glu Gly 35 40 45Trp Val Arg Ser Thr Glu Val Lys Asp Pro Trp Asn Leu Ser Asn Asp 50 55 60Glu Tyr Tyr Tyr Pro Lys Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly65 70 75 80Asn Ile Ile Gln His Ser Ile Pro Ala Val Glu Leu Arg Gln Pro Phe 85 90 95Phe Pro Thr His Met Gly Pro Ile Lys Leu Arg Gln Phe His Arg Pro 100 105 110Pro Leu Lys Lys Tyr Ser Phe Gly Ala Leu Ser Gln Pro Gly Pro His 115 120 125Ser Val Gln Pro Leu Leu Lys His Ile Lys Lys Lys Ala Glu Met Arg 130 135 140Glu Gln Glu Arg Gln Ala Ser Gly Gly145 15083111PRTHomo sapiens 83Met Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys His Leu Ala1 5 10 15Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu Leu Thr Ala 20 25 30Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn Asp Glu Gly 35 40 45Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp Ile Lys Leu 50 55 60Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser Phe Gly Ala Leu65 70 75 80Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu Lys His Ile Lys 85 90 95Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala Ser Gly Gly 100 105 1108477PRTHomo sapiens 84Met Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys His Leu Ala1 5 10 15Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu Leu Arg Gln 20 25 30Phe His Arg Pro Pro Leu Lys Lys Tyr Ser Phe Gly Ala Leu Ser Gln 35 40 45Pro Gly Pro His Ser Val Gln Pro Leu Leu Lys His Ile Lys Lys Lys 50 55 60Ala Lys Met Arg Glu Gln Glu Arg Gln Ala Ser Gly Gly65 70 758522DNAArtificial sequencePrimer 85gagctttctg gatgatgtaa ac 228621DNAArtificial sequencePrimer 86ctcctcatca tcataccctt c 2187205PRTHomo sapiens 87Met Asp Asp Val Asn Leu Ile Leu Ala Asn Ser Val Lys Tyr Asn Gly1 5 10 15Pro Glu Ser Gln Tyr Thr Lys Thr Ala Gln Glu Ile Val Asn Val Cys 20 25 30Tyr Gln Thr Leu Thr Glu Tyr Asp Glu His Leu Thr Gln Leu Glu Lys 35 40 45Asp Ile Cys Thr Ala Lys Glu Ala Ala Leu Glu Glu Ala Glu Leu Glu 50 55 60Ser Leu Asp Pro Met Thr Pro Gly Pro Tyr Thr Pro Gln Pro Pro Asp65 70 75 80Leu Tyr Asp Thr Asn Thr Ser Leu Ser Met Ser Arg Asp Ala Ser Val 85 90 95Phe Gln Asp Glu Ser Asn Met Ser Val Leu Asp Ile Pro Ser Ala Thr 100 105 110Pro Glu Lys Gln Val Thr Gln Met Arg Gln Gly Arg Gly Arg Leu Gly 115 120 125Glu Glu Asp Ser Asp Val Asp Ile Glu Gly Tyr Asp Asp Glu Glu Glu 130 135 140Asp Gly Lys Pro Lys Thr Pro Ala Pro Glu Gly Glu Asp Gly Asp Gly145 150 155 160Asp Leu Ala Asp Glu Glu Glu Gly Thr Val Gln Gln Pro Gln Ala Ser 165 170 175Val Leu Tyr Glu Asp Leu Leu Met Ser Glu Gly Glu Asp Asp Glu Glu 180 185 190Asp Ala Gly Ser Asp Glu Glu Gly Asp Asn Pro Phe Ser 195 200 20588206PRTHomo sapiens 88Lys Tyr Gln Ser Arg Glu Ser Phe Leu Asp Asp Val Asn Leu Ile Leu1 5 10 15Ala Asn Ser Val Lys Tyr Asn Gly Pro Glu Ser Gln Tyr Thr Lys Thr 20 25 30Ala Gln Glu Ile Val Asn Val Cys Tyr Gln Thr Leu Thr Glu Tyr Asp 35 40 45Glu His Leu Thr Gln Leu Glu Lys Asp Ile Cys Thr Ala Lys Glu Ala 50 55 60Ala Leu Glu Glu Ala Glu Leu Glu Ser Leu Asp Pro Met Thr Pro Gly65 70 75 80Pro Tyr Thr Pro Gln Pro Pro Asp Leu Tyr Asp Thr Asn Thr Ser Leu 85 90 95Ser Met Ser Arg Asp Ala Ser Val Phe Gln Asp Glu Ser Asn Met Ser 100 105 110Val Leu Asp Ile Pro Ser Ala Thr Pro Glu Lys Gln Val Thr Gln Glu 115 120 125Gly Glu Asp Gly Asp Gly Asp Leu Ala Asp Glu Glu Glu Gly Thr Val 130 135 140Gln Gln Pro Gln Ala Ser Val Leu Tyr Glu Asp Leu Leu Met Ser Glu145 150 155 160Gly Glu Asp Asp Glu Glu Asp Ala Gly Ser Asp Glu Glu Gly Asp Asn 165 170 175Pro Phe Ser Ala Ile Gln Leu Ser Glu Ser Gly Ser Asp Ser Asp Val 180 185 190Gly Ser Gly Gly Ile Arg Pro Lys Gln Pro Arg Met Leu Gln 195 200 2058922DNAArtificial sequencePrimer 89gagctttctg gatgatgtaa ac 229021DNAArtificial sequencePrimer 90ctcctcatca tcataccctt c 21911466PRTHomo sapiens 91Met Gly Pro Gly Cys Asp Leu Leu Leu Arg Thr Ala Ala Thr Ile Thr1 5 10 15Ala Ala Ala Ile Met Ser Asp Thr Asp Ser Asp Glu Asp Ser Ala Gly 20 25 30Gly Gly Pro Phe Ser Leu Ala Gly Phe Leu Phe Gly Asn Ile Asn Gly 35 40 45Ala Gly Gln Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys 50 55 60His Leu Ala Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu65 70 75 80Leu Thr Ala Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn 85 90 95Asp Glu Gly Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp 100 105 110Ile Asn Glu Val Ala Glu Asp Glu Ser Arg Arg Tyr Gln Gln Thr Met 115 120 125Gly Ser Leu Gln Pro Leu Cys His Ser Asp Tyr Asp Glu Asp Asp Tyr 130 135 140Asp Ala Asp Cys Glu Asp Ile Asp Cys Lys Leu Met Pro Pro Pro Pro145 150 155 160Pro Pro Pro Gly Pro Met Lys Lys Asp Lys Asp Gln Asp Ser Ile Thr 165 170 175Gly Glu Lys Val Asp Phe Ser Ser Ser Ser Asp Ser Glu Ser Glu Met 180 185 190Gly Pro Gln Glu Ala Thr Gln Ala Glu Ser Glu Asp Gly Lys Leu Thr 195 200 205Leu Pro Leu Ala Gly Ile Met Gln His Asp Ala Thr Lys Leu Leu Pro 210 215 220Ser Val Thr Glu Leu Phe Pro Glu Phe Arg Pro Gly Lys Val Leu Arg225 230 235 240Phe Leu Arg Leu Phe Gly Pro Gly Lys Asn Val Pro Ser Val Trp Arg 245 250 255Ser Ala Arg Arg Lys Arg Lys Lys Lys His Arg Glu Leu Ile Gln Glu 260 265 270Glu Gln Ile Gln Glu Val Glu Cys Ser Val Glu Ser Glu Val Ser Gln 275 280 285Lys Ser Leu Trp Asn Tyr Asp Tyr Ala Pro Pro Pro Pro Pro Glu Gln 290 295 300Cys Leu Ser Asp Asp Glu Ile Thr Met Met Ala Pro Val Glu Ser Lys305 310 315 320Phe Ser Gln Ser Thr Gly Asp Ile Asp Lys Val Thr Asp Thr Lys Pro 325 330 335Arg Val Ala Glu Trp Arg Tyr Gly Pro Ala Arg Leu Trp Tyr Asp Met 340 345 350Leu Gly Val Pro Glu Asp Gly Ser Gly Phe Asp Tyr Gly Phe Lys Leu 355 360 365Arg Lys Thr Glu His Glu Pro Val Ile Lys Ser Arg Met Ile Glu Glu 370 375 380Phe Arg Lys Leu Glu Glu Asn Asn Gly Thr Asp Leu Leu Ala Asp Glu385 390 395 400Asn Phe Leu Met Val Thr Gln Leu His Trp Glu Asp Asp Ile Ile Trp 405 410 415Asp Gly Glu Asp Val Lys His Lys Gly Thr Lys Pro Gln Arg Ala Ser 420 425 430Leu Ala Gly Trp Leu Pro Ser Ser Met Thr Arg Asn Ala Met Ala Tyr 435 440 445Asn Val Gln Gln Gly Phe Ala Ala Thr Leu Asp Asp Asp Lys Pro Trp 450 455 460Tyr Ser Ile Phe Pro Ile Asp Asn Glu Asp Leu Val Tyr Gly Arg Trp465 470 475 480Glu Asp Asn Ile Ile Trp Asp Ala Gln Ala Met Pro Arg Leu Leu Glu 485 490 495Pro Pro Val Leu Thr Leu Asp Pro Asn Asp Glu Asn Leu Ile Leu Glu 500 505 510Ile Pro Asp Glu Lys Glu Glu Ala Thr Ser Asn Ser Pro Ser Lys Glu 515 520 525Ser Lys Lys Glu Ser Ser Leu Lys Lys Ser Arg Ile Leu Leu Gly Lys 530 535 540Thr Gly Val Ile Lys Glu Glu Pro Gln Gln Asn Met Ser Gln Pro Glu545 550 555 560Val Lys Asp Pro Trp Asn Leu Ser Asn Asp Glu Tyr Tyr Tyr Pro Lys 565 570 575Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly Asn Ile Ile Gln His Ser 580 585 590Ile Pro Ala Val Glu Leu Arg Gln Pro Phe Phe Pro Thr His Met Gly 595 600 605Pro Ile Lys Leu Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser 610 615 620Phe Gly Ala Leu Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu625 630 635 640Lys His Ile Lys Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala 645 650 655Ser Gly Gly Gly Glu Met Phe Phe Met Arg Thr Pro Gln Asp Leu Thr 660 665 670Gly Lys Asp Gly Asp Leu Ile Leu Ala Glu Tyr Ser Glu Glu Asn Gly 675 680 685Pro Leu Met Met Gln Val Gly Met Ala Thr Lys Ile Lys Asn Tyr Tyr 690 695 700Lys Arg Lys Pro Gly Lys Asp Pro Gly Ala Pro Asp Cys Lys Tyr Gly705 710 715 720Glu Thr Val Tyr Cys His Thr Ser Pro Phe Leu Gly Ser Leu His Pro 725 730 735Gly Gln Leu Leu Gln Ala Phe Glu Asn Asn Leu Phe Arg Ala Pro Ile 740 745 750Tyr Leu His Lys Met Pro Glu Thr Asp Phe Leu Ile Ile Arg Thr Arg 755 760 765Gln Gly Tyr Tyr Ile Arg Glu Leu Val Asp Ile Phe Val Val

Gly Gln 770 775 780Gln Cys Pro Leu Phe Glu Val Pro Gly Pro Asn Ser Lys Arg Ala Asn785 790 795 800Thr His Ile Arg Asp Phe Leu Gln Val Phe Ile Tyr Arg Leu Phe Trp 805 810 815Lys Ser Lys Asp Arg Pro Arg Arg Ile Arg Met Glu Asp Ile Lys Lys 820 825 830Ala Phe Pro Ser His Ser Glu Ser Ser Ile Arg Lys Arg Leu Lys Leu 835 840 845Cys Ala Asp Phe Lys Arg Thr Gly Met Asp Ser Asn Trp Trp Val Leu 850 855 860Lys Ser Asp Phe Arg Leu Pro Thr Glu Glu Glu Ile Arg Ala Met Val865 870 875 880Ser Pro Glu Gln Cys Cys Ala Tyr Tyr Ser Met Ile Ala Ala Glu Gln 885 890 895Arg Leu Lys Asp Ala Gly Tyr Gly Glu Lys Ser Phe Phe Ala Pro Glu 900 905 910Glu Glu Asn Glu Glu Asp Phe Gln Met Lys Ile Asp Asp Glu Val Arg 915 920 925Thr Ala Pro Trp Asn Thr Thr Arg Ala Phe Ile Ala Ala Met Lys Gly 930 935 940Lys Cys Leu Leu Glu Val Thr Gly Val Ala Asp Pro Thr Gly Cys Gly945 950 955 960Glu Gly Phe Ser Tyr Val Lys Ile Pro Asn Lys Pro Thr Gln Gln Lys 965 970 975Asp Asp Lys Glu Pro Gln Pro Val Lys Lys Thr Val Thr Gly Thr Asp 980 985 990Ala Asp Leu Arg Arg Leu Ser Leu Lys Asn Ala Lys Gln Leu Leu Arg 995 1000 1005Lys Phe Gly Val Pro Glu Glu Glu Ile Lys Lys Leu Ser Arg Trp 1010 1015 1020Glu Val Ile Asp Val Val Arg Thr Met Ser Thr Glu Gln Ala Arg 1025 1030 1035Ser Gly Glu Gly Pro Met Ser Lys Phe Ala Arg Gly Ser Arg Phe 1040 1045 1050Ser Val Ala Glu His Gln Glu Arg Tyr Lys Glu Glu Cys Gln Arg 1055 1060 1065Ile Phe Asp Leu Gln Asn Lys Val Leu Ser Ser Thr Glu Val Leu 1070 1075 1080Ser Thr Asp Thr Asp Ser Ser Ser Ala Glu Asp Ser Asp Phe Glu 1085 1090 1095Glu Met Gly Lys Asn Ile Glu Asn Met Leu Gln Asn Lys Lys Thr 1100 1105 1110Ser Ser Gln Leu Ser Arg Glu Arg Glu Glu Gln Glu Arg Lys Glu 1115 1120 1125Leu Gln Arg Met Leu Leu Ala Ala Gly Ser Ala Ala Ser Gly Asn 1130 1135 1140Asn His Arg Asp Asp Asp Thr Ala Ser Val Thr Ser Leu Asn Ser 1145 1150 1155Ser Ala Thr Gly Arg Cys Leu Lys Ile Tyr Arg Thr Phe Arg Asp 1160 1165 1170Glu Glu Gly Lys Glu Tyr Val Arg Cys Glu Thr Val Arg Lys Pro 1175 1180 1185Ala Val Ile Asp Ala Tyr Val Arg Ile Arg Thr Thr Lys Asp Glu 1190 1195 1200Glu Phe Ile Arg Lys Phe Ala Leu Phe Asp Glu Gln His Arg Glu 1205 1210 1215Glu Met Arg Lys Glu Arg Arg Arg Ile Gln Glu Gln Leu Arg Arg 1220 1225 1230Leu Lys Arg Asn Gln Glu Lys Glu Lys Leu Lys Gly Pro Pro Glu 1235 1240 1245Lys Lys Pro Lys Lys Met Lys Glu Arg Pro Asp Leu Lys Leu Lys 1250 1255 1260Cys Gly Ala Cys Gly Ala Ile Gly His Met Arg Thr Asn Lys Phe 1265 1270 1275Cys Pro Leu Tyr Tyr Gln Thr Asn Ala Pro Pro Ser Asn Pro Val 1280 1285 1290Ala Met Thr Glu Glu Gln Glu Glu Glu Leu Glu Lys Thr Val Ile 1295 1300 1305His Asn Asp Asn Glu Glu Leu Ile Lys Val Glu Gly Thr Lys Ile 1310 1315 1320Val Leu Gly Lys Gln Leu Ile Glu Ser Ala Asp Glu Val Arg Arg 1325 1330 1335Lys Ser Leu Val Leu Lys Phe Pro Lys Gln Gln Leu Pro Pro Lys 1340 1345 1350Lys Lys Arg Arg Val Gly Thr Thr Val His Cys Asp Tyr Leu Asn 1355 1360 1365Arg Pro His Lys Ser Ile His Arg Arg Arg Thr Asp Pro Met Val 1370 1375 1380Thr Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg Asp 1385 1390 1395Leu Pro Asn Thr Tyr Pro Phe His Thr Pro Val Asn Ala Lys Val 1400 1405 1410Val Lys Asp Tyr Tyr Lys Ile Ile Thr Arg Pro Met Asp Leu Gln 1415 1420 1425Thr Leu Arg Glu Asn Val Arg Lys Arg Leu Tyr Pro Ser Arg Glu 1430 1435 1440Glu Phe Arg Glu His Leu Glu Leu Ile Val Lys Asn Ser Ala Thr 1445 1450 1455Tyr Asn Ala Gly Ser Phe Ser Ile 1460 1465921872PRTHomo sapiens 92Met Gly Pro Gly Cys Asp Leu Leu Leu Arg Thr Ala Ala Thr Ile Thr1 5 10 15Ala Ala Ala Ile Met Ser Asp Thr Asp Ser Asp Glu Asp Ser Ala Gly 20 25 30Gly Gly Pro Phe Ser Leu Ala Gly Phe Leu Phe Gly Asn Ile Asn Gly 35 40 45Ala Gly Gln Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys 50 55 60His Leu Ala Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu65 70 75 80Leu Thr Ala Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn 85 90 95Asp Glu Gly Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp 100 105 110Ile Asn Glu Val Ala Glu Asp Glu Ser Arg Arg Tyr Gln Gln Thr Met 115 120 125Gly Ser Leu Gln Pro Leu Cys His Ser Asp Tyr Asp Glu Asp Asp Tyr 130 135 140Asp Ala Asp Cys Glu Asp Ile Asp Cys Lys Leu Met Pro Pro Pro Pro145 150 155 160Pro Pro Pro Gly Pro Met Lys Lys Asp Lys Asp Gln Asp Ser Ile Thr 165 170 175Gly Glu Lys Val Asp Phe Ser Ser Ser Ser Asp Ser Glu Ser Glu Met 180 185 190Gly Pro Gln Glu Ala Thr Gln Ala Glu Ser Glu Asp Gly Lys Leu Thr 195 200 205Leu Pro Leu Ala Gly Ile Met Gln His Asp Ala Thr Lys Leu Leu Pro 210 215 220Ser Val Thr Glu Leu Phe Pro Glu Phe Arg Pro Gly Lys Val Leu Arg225 230 235 240Phe Leu Arg Leu Phe Gly Pro Gly Lys Asn Val Pro Ser Val Trp Arg 245 250 255Ser Ala Arg Arg Lys Arg Lys Lys Lys His Arg Glu Leu Ile Gln Glu 260 265 270Glu Gln Ile Gln Glu Val Glu Cys Ser Val Glu Ser Glu Val Ser Gln 275 280 285Lys Ser Leu Trp Asn Tyr Asp Tyr Ala Pro Pro Pro Pro Pro Glu Gln 290 295 300Cys Leu Ser Asp Asp Glu Ile Thr Met Met Ala Pro Val Glu Ser Lys305 310 315 320Phe Ser Gln Ser Thr Gly Asp Ile Asp Lys Val Thr Asp Thr Lys Pro 325 330 335Arg Val Ala Glu Trp Arg Tyr Gly Pro Ala Arg Leu Trp Tyr Asp Met 340 345 350Leu Gly Val Pro Glu Asp Gly Ser Gly Phe Asp Tyr Gly Phe Lys Leu 355 360 365Arg Lys Thr Glu His Glu Pro Val Ile Lys Ser Arg Met Ile Glu Glu 370 375 380Phe Arg Lys Leu Glu Glu Asn Asn Gly Thr Asp Leu Leu Ala Asp Glu385 390 395 400Asn Phe Leu Met Val Thr Gln Leu His Trp Glu Asp Asp Ile Ile Trp 405 410 415Asp Gly Glu Asp Val Lys His Lys Gly Thr Lys Pro Gln Arg Ala Ser 420 425 430Leu Ala Gly Trp Leu Pro Ser Ser Met Thr Arg Asn Ala Met Ala Tyr 435 440 445Asn Val Gln Gln Gly Phe Ala Ala Thr Leu Asp Asp Asp Lys Pro Trp 450 455 460Tyr Ser Ile Phe Pro Ile Asp Asn Glu Asp Leu Val Tyr Gly Arg Trp465 470 475 480Glu Asp Asn Ile Ile Trp Asp Ala Gln Ala Met Pro Arg Leu Leu Glu 485 490 495Pro Pro Val Leu Thr Leu Asp Pro Asn Asp Glu Asn Leu Ile Leu Glu 500 505 510Ile Pro Asp Glu Lys Glu Glu Ala Thr Ser Asn Ser Pro Ser Lys Glu 515 520 525Ser Lys Lys Glu Ser Ser Leu Lys Lys Ser Arg Ile Leu Leu Gly Lys 530 535 540Thr Gly Val Ile Lys Glu Glu Pro Gln Gln Asn Met Ser Gln Pro Glu545 550 555 560Val Lys Asp Pro Trp Asn Leu Ser Asn Asp Glu Tyr Tyr Tyr Pro Lys 565 570 575Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly Asn Ile Ile Gln His Ser 580 585 590Ile Pro Ala Val Glu Leu Arg Gln Pro Phe Phe Pro Thr His Met Gly 595 600 605Pro Ile Lys Leu Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser 610 615 620Phe Gly Ala Leu Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu625 630 635 640Lys His Ile Lys Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala 645 650 655Ser Gly Gly Gly Glu Met Phe Phe Met Arg Thr Pro Gln Asp Leu Thr 660 665 670Gly Lys Asp Gly Asp Leu Ile Leu Ala Glu Tyr Ser Glu Glu Asn Gly 675 680 685Pro Leu Met Met Gln Val Gly Met Ala Thr Lys Ile Lys Asn Tyr Tyr 690 695 700Lys Arg Lys Pro Gly Lys Asp Pro Gly Ala Pro Asp Cys Lys Tyr Gly705 710 715 720Glu Thr Val Tyr Cys His Thr Ser Pro Phe Leu Gly Ser Leu His Pro 725 730 735Gly Gln Leu Leu Gln Ala Phe Glu Asn Asn Leu Phe Arg Ala Pro Ile 740 745 750Tyr Leu His Lys Met Pro Glu Thr Asp Phe Leu Ile Ile Arg Thr Arg 755 760 765Gln Gly Tyr Tyr Ile Arg Glu Leu Val Asp Ile Phe Val Val Gly Gln 770 775 780Gln Cys Pro Leu Phe Glu Val Pro Gly Pro Asn Ser Lys Arg Ala Asn785 790 795 800Thr His Ile Arg Asp Phe Leu Gln Val Phe Ile Tyr Arg Leu Phe Trp 805 810 815Lys Ser Lys Asp Arg Pro Arg Arg Ile Arg Met Glu Asp Ile Lys Lys 820 825 830Ala Phe Pro Ser His Ser Glu Ser Ser Ile Arg Lys Arg Leu Lys Leu 835 840 845Cys Ala Asp Phe Lys Arg Thr Gly Met Asp Ser Asn Trp Trp Val Leu 850 855 860Lys Ser Asp Phe Arg Leu Pro Thr Glu Glu Glu Ile Arg Ala Met Val865 870 875 880Ser Pro Glu Gln Cys Cys Ala Tyr Tyr Ser Met Ile Ala Ala Glu Gln 885 890 895Arg Leu Lys Asp Ala Gly Tyr Gly Glu Lys Ser Phe Phe Ala Pro Glu 900 905 910Glu Glu Asn Glu Glu Asp Phe Gln Met Lys Ile Asp Asp Glu Val Arg 915 920 925Thr Ala Pro Trp Asn Thr Thr Arg Ala Phe Ile Ala Ala Met Lys Gly 930 935 940Lys Cys Leu Leu Glu Val Thr Gly Val Ala Asp Pro Thr Gly Cys Gly945 950 955 960Glu Gly Phe Ser Tyr Val Lys Ile Pro Asn Lys Pro Thr Gln Gln Lys 965 970 975Asp Asp Lys Glu Pro Gln Pro Val Lys Lys Thr Val Thr Gly Thr Asp 980 985 990Ala Asp Leu Arg Arg Leu Ser Leu Lys Asn Ala Lys Gln Leu Leu Arg 995 1000 1005Lys Phe Gly Val Pro Glu Glu Glu Ile Lys Lys Leu Ser Arg Trp 1010 1015 1020Glu Val Ile Asp Val Val Arg Thr Met Ser Thr Glu Gln Ala Arg 1025 1030 1035Ser Gly Glu Gly Pro Met Ser Lys Phe Ala Arg Gly Ser Arg Phe 1040 1045 1050Ser Val Ala Glu His Gln Glu Arg Tyr Lys Glu Glu Cys Gln Arg 1055 1060 1065Ile Phe Asp Leu Gln Asn Lys Val Leu Ser Ser Thr Glu Val Leu 1070 1075 1080Ser Thr Asp Thr Asp Ser Ser Ser Ala Glu Asp Ser Asp Phe Glu 1085 1090 1095Glu Met Gly Lys Asn Ile Glu Asn Met Leu Gln Asn Lys Lys Thr 1100 1105 1110Ser Ser Gln Leu Ser Arg Glu Arg Glu Glu Gln Glu Arg Lys Glu 1115 1120 1125Leu Gln Arg Met Leu Leu Ala Ala Gly Ser Ala Ala Ser Gly Asn 1130 1135 1140Asn His Arg Asp Asp Asp Thr Ala Ser Val Thr Ser Leu Asn Ser 1145 1150 1155Ser Ala Thr Gly Arg Cys Leu Lys Ile Tyr Arg Thr Phe Arg Asp 1160 1165 1170Glu Glu Gly Lys Glu Tyr Val Arg Cys Glu Thr Val Arg Lys Pro 1175 1180 1185Ala Val Ile Asp Ala Tyr Val Arg Ile Arg Thr Thr Lys Asp Glu 1190 1195 1200Glu Phe Ile Arg Lys Phe Ala Leu Phe Asp Glu Gln His Arg Glu 1205 1210 1215Glu Met Arg Lys Glu Arg Arg Arg Ile Gln Glu Gln Leu Arg Arg 1220 1225 1230Leu Lys Arg Asn Gln Glu Lys Glu Lys Leu Lys Gly Pro Pro Glu 1235 1240 1245Lys Lys Pro Lys Lys Met Lys Glu Arg Pro Asp Leu Lys Leu Lys 1250 1255 1260Cys Gly Ala Cys Gly Ala Ile Gly His Met Arg Thr Asn Lys Phe 1265 1270 1275Cys Pro Leu Tyr Tyr Gln Thr Asn Ala Pro Pro Ser Asn Pro Val 1280 1285 1290Ala Met Thr Glu Glu Gln Glu Glu Glu Leu Glu Lys Thr Val Ile 1295 1300 1305His Asn Asp Asn Glu Glu Leu Ile Lys Val Glu Gly Thr Lys Ile 1310 1315 1320Val Leu Gly Lys Gln Leu Ile Glu Ser Ala Asp Glu Val Arg Arg 1325 1330 1335Lys Ser Leu Val Leu Lys Phe Pro Lys Gln Gln Leu Pro Pro Lys 1340 1345 1350Lys Lys Arg Arg Val Gly Thr Thr Val His Cys Asp Tyr Leu Asn 1355 1360 1365Arg Pro His Lys Ser Ile His Arg Arg Arg Thr Asp Pro Met Val 1370 1375 1380Thr Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg Asp 1385 1390 1395Leu Pro Asn Thr Tyr Pro Phe His Thr Pro Val Asn Ala Lys Val 1400 1405 1410Val Lys Asp Tyr Tyr Lys Ile Ile Thr Arg Pro Met Asp Leu Gln 1415 1420 1425Thr Leu Arg Glu Asn Val Arg Lys Arg Leu Tyr Pro Ser Arg Glu 1430 1435 1440Glu Phe Arg Glu His Leu Glu Leu Ile Val Lys Asn Ser Ala Thr 1445 1450 1455Tyr Asn Gly Pro Lys His Ser Leu Thr Gln Ile Ser Gln Ser Met 1460 1465 1470Leu Asp Leu Cys Asp Glu Lys Leu Lys Glu Lys Glu Asp Lys Leu 1475 1480 1485Ala Arg Leu Glu Lys Ala Ile Asn Pro Leu Leu Asp Asp Asp Asp 1490 1495 1500Gln Val Ala Phe Ser Phe Ile Leu Asp Asn Ile Val Thr Gln Lys 1505 1510 1515Met Met Ala Val Pro Asp Ser Trp Pro Phe His His Pro Val Asn 1520 1525 1530Lys Lys Phe Val Pro Asp Tyr Tyr Lys Val Ile Val Asn Pro Met 1535 1540 1545Asp Leu Glu Thr Ile Arg Lys Asn Ile Ser Lys His Lys Tyr Gln 1550 1555 1560Ser Arg Glu Ser Phe Leu Asp Asp Val Asn Leu Ile Leu Ala Asn 1565 1570 1575Ser Val Lys Tyr Asn Gly Pro Glu Ser Gln Tyr Thr Lys Thr Ala 1580 1585 1590Gln Glu Ile Val Asn Val Cys Tyr Gln Thr Leu Thr Glu Tyr Asp 1595 1600 1605Glu His Leu Thr Gln Leu Glu Lys Asp Ile Cys Thr Ala Lys Glu 1610 1615 1620Ala Ala Leu Glu Glu Ala Glu Leu Glu Ser Leu Asp Pro Met Thr 1625 1630 1635Pro Gly Pro Tyr Thr Pro Gln Pro Pro Asp Leu Tyr Asp Thr Asn 1640 1645 1650Thr Ser Leu Ser Met Ser Arg Asp Ala Ser Val Phe Gln Asp Glu 1655 1660 1665Ser Asn Met Ser Val Leu Asp Ile Pro Ser Ala Thr Pro Glu Lys 1670 1675 1680Gln Val Thr Gln Glu Gly Glu Asp Gly Asp Gly Asp Leu Ala Asp 1685 1690 1695Glu Glu Glu Gly Thr Val Gln Gln Pro Gln Ala Ser Val Leu Tyr 1700 1705 1710Glu Asp Leu Leu Met Ser Glu Gly Glu Asp Asp Glu Glu Asp Ala 1715 1720 1725Gly Ser Asp Glu Glu Gly Asp Asn Pro Phe Ser Ala Ile Gln Leu 1730 1735 1740Ser Glu Ser Gly Ser Asp Ser Asp Val Gly Ser Gly Gly Ile Arg 1745 1750 1755Pro Lys Gln Pro

Arg Met Leu Gln Glu Asn Thr Arg Met Asp Met 1760 1765 1770Glu Asn Glu Glu Ser Met Met Ser Tyr Glu Gly Asp Gly Gly Glu 1775 1780 1785Ala Ser His Gly Leu Glu Asp Ser Asn Ile Ser Tyr Gly Ser Tyr 1790 1795 1800Glu Glu Pro Asp Pro Lys Ser Asn Thr Gln Asp Thr Ser Phe Ser 1805 1810 1815Ser Ile Gly Gly Tyr Glu Val Ser Glu Glu Glu Glu Asp Glu Glu 1820 1825 1830Glu Glu Glu Gln Arg Ser Gly Pro Ser Val Leu Ser Gln Val His 1835 1840 1845Leu Ser Glu Asp Glu Glu Asp Ser Glu Asp Phe His Ser Ile Ala 1850 1855 1860Gly Asp Ser Asp Leu Asp Ser Asp Glu 1865 1870931488PRTHomo sapiens 93Met Gly Pro Gly Cys Asp Leu Leu Leu Arg Thr Ala Ala Thr Ile Thr1 5 10 15Ala Ala Ala Ile Met Ser Asp Thr Asp Ser Asp Glu Asp Ser Ala Gly 20 25 30Gly Gly Pro Phe Ser Leu Ala Gly Phe Leu Phe Gly Asn Ile Asn Gly 35 40 45Ala Gly Gln Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys 50 55 60His Leu Ala Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu65 70 75 80Leu Thr Ala Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn 85 90 95Asp Glu Gly Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp 100 105 110Ile Asn Glu Val Ala Glu Asp Glu Ser Arg Arg Tyr Gln Gln Thr Met 115 120 125Gly Ser Leu Gln Pro Leu Cys His Ser Asp Tyr Asp Glu Asp Asp Tyr 130 135 140Asp Ala Asp Cys Glu Asp Ile Asp Cys Lys Leu Met Pro Pro Pro Pro145 150 155 160Pro Pro Pro Gly Pro Met Lys Lys Asp Lys Asp Gln Asp Ser Ile Thr 165 170 175Gly Glu Lys Val Asp Phe Ser Ser Ser Ser Asp Ser Glu Ser Glu Met 180 185 190Gly Pro Gln Glu Ala Thr Gln Ala Glu Ser Glu Asp Gly Lys Leu Thr 195 200 205Leu Pro Leu Ala Gly Ile Met Gln His Asp Ala Thr Lys Leu Leu Pro 210 215 220Ser Val Thr Glu Leu Phe Pro Glu Phe Arg Pro Gly Lys Val Leu Arg225 230 235 240Phe Leu Arg Leu Phe Gly Pro Gly Lys Asn Val Pro Ser Val Trp Arg 245 250 255Ser Ala Arg Arg Lys Arg Lys Lys Lys His Arg Glu Leu Ile Gln Glu 260 265 270Glu Gln Ile Gln Glu Val Glu Cys Ser Val Glu Ser Glu Val Ser Gln 275 280 285Lys Ser Leu Trp Asn Tyr Asp Tyr Ala Pro Pro Pro Pro Pro Glu Gln 290 295 300Cys Leu Ser Asp Asp Glu Ile Thr Met Met Ala Pro Val Glu Ser Lys305 310 315 320Phe Ser Gln Ser Thr Gly Asp Ile Asp Lys Val Thr Asp Thr Lys Pro 325 330 335Arg Val Ala Glu Trp Arg Tyr Gly Pro Ala Arg Leu Trp Tyr Asp Met 340 345 350Leu Gly Val Pro Glu Asp Gly Ser Gly Phe Asp Tyr Gly Phe Lys Leu 355 360 365Arg Lys Thr Glu His Glu Pro Val Ile Lys Ser Arg Met Ile Glu Glu 370 375 380Phe Arg Lys Leu Glu Glu Asn Asn Gly Thr Asp Leu Leu Ala Asp Glu385 390 395 400Asn Phe Leu Met Val Thr Gln Leu His Trp Glu Asp Asp Ile Ile Trp 405 410 415Asp Gly Glu Asp Val Lys His Lys Gly Thr Lys Pro Gln Arg Ala Ser 420 425 430Leu Ala Gly Trp Leu Pro Ser Ser Met Thr Arg Asn Ala Met Ala Tyr 435 440 445Asn Val Gln Gln Gly Phe Ala Ala Thr Leu Asp Asp Asp Lys Pro Trp 450 455 460Tyr Ser Ile Phe Pro Ile Asp Asn Glu Asp Leu Val Tyr Gly Arg Trp465 470 475 480Glu Asp Asn Ile Ile Trp Asp Ala Gln Ala Met Pro Arg Leu Leu Glu 485 490 495Pro Pro Val Leu Thr Leu Asp Pro Asn Asp Glu Asn Leu Ile Leu Glu 500 505 510Ile Pro Asp Glu Lys Glu Glu Ala Thr Ser Asn Ser Pro Ser Lys Glu 515 520 525Ser Lys Lys Glu Ser Ser Leu Lys Lys Ser Arg Ile Leu Leu Gly Lys 530 535 540Thr Gly Val Ile Lys Glu Glu Pro Gln Gln Asn Met Ser Gln Pro Glu545 550 555 560Val Lys Asp Pro Trp Asn Leu Ser Asn Asp Glu Tyr Tyr Tyr Pro Lys 565 570 575Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly Asn Ile Ile Gln His Ser 580 585 590Ile Pro Ala Val Glu Leu Arg Gln Pro Phe Phe Pro Thr His Met Gly 595 600 605Pro Ile Lys Leu Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser 610 615 620Phe Gly Ala Leu Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu625 630 635 640Lys His Ile Lys Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala 645 650 655Ser Gly Gly Gly Glu Met Phe Phe Met Arg Thr Pro Gln Asp Leu Thr 660 665 670Gly Lys Asp Gly Asp Leu Ile Leu Ala Glu Tyr Ser Glu Glu Asn Gly 675 680 685Pro Leu Met Met Gln Val Gly Met Ala Thr Lys Ile Lys Asn Tyr Tyr 690 695 700Lys Arg Lys Pro Gly Lys Asp Pro Gly Ala Pro Asp Cys Lys Tyr Gly705 710 715 720Glu Thr Val Tyr Cys His Thr Ser Pro Phe Leu Gly Ser Leu His Pro 725 730 735Gly Gln Leu Leu Gln Ala Phe Glu Asn Asn Leu Phe Arg Ala Pro Ile 740 745 750Tyr Leu His Lys Met Pro Glu Thr Asp Phe Leu Ile Ile Arg Thr Arg 755 760 765Gln Gly Tyr Tyr Ile Arg Glu Leu Val Asp Ile Phe Val Val Gly Gln 770 775 780Gln Cys Pro Leu Phe Glu Val Pro Gly Pro Asn Ser Lys Arg Ala Asn785 790 795 800Thr His Ile Arg Asp Phe Leu Gln Val Phe Ile Tyr Arg Leu Phe Trp 805 810 815Lys Ser Lys Asp Arg Pro Arg Arg Ile Arg Met Glu Asp Ile Lys Lys 820 825 830Ala Phe Pro Ser His Ser Glu Ser Ser Ile Arg Lys Arg Leu Lys Leu 835 840 845Cys Ala Asp Phe Lys Arg Thr Gly Met Asp Ser Asn Trp Trp Val Leu 850 855 860Lys Ser Asp Phe Arg Leu Pro Thr Glu Glu Glu Ile Arg Ala Met Val865 870 875 880Ser Pro Glu Gln Cys Cys Ala Tyr Tyr Ser Met Ile Ala Ala Glu Gln 885 890 895Arg Leu Lys Asp Ala Gly Tyr Gly Glu Lys Ser Phe Phe Ala Pro Glu 900 905 910Glu Glu Asn Glu Glu Asp Phe Gln Met Lys Ile Asp Asp Glu Val Arg 915 920 925Thr Ala Pro Trp Asn Thr Thr Arg Ala Phe Ile Ala Ala Met Lys Gly 930 935 940Lys Cys Leu Leu Glu Val Thr Gly Val Ala Asp Pro Thr Gly Cys Gly945 950 955 960Glu Gly Phe Ser Tyr Val Lys Ile Pro Asn Lys Pro Thr Gln Gln Lys 965 970 975Asp Asp Lys Glu Pro Gln Pro Val Lys Lys Thr Val Thr Gly Thr Asp 980 985 990Ala Asp Leu Arg Arg Leu Ser Leu Lys Asn Ala Lys Gln Leu Leu Arg 995 1000 1005Lys Phe Gly Val Pro Glu Glu Glu Ile Lys Lys Leu Ser Arg Trp 1010 1015 1020Glu Val Ile Asp Val Val Arg Thr Met Ser Thr Glu Gln Ala Arg 1025 1030 1035Ser Gly Glu Gly Pro Met Ser Lys Phe Ala Arg Gly Ser Arg Phe 1040 1045 1050Ser Val Ala Glu His Gln Glu Arg Tyr Lys Glu Glu Cys Gln Arg 1055 1060 1065Ile Phe Asp Leu Gln Asn Lys Val Leu Ser Ser Thr Glu Val Leu 1070 1075 1080Ser Thr Asp Thr Asp Ser Ser Ser Ala Glu Asp Ser Asp Phe Glu 1085 1090 1095Glu Met Gly Lys Asn Ile Glu Asn Met Leu Gln Asn Lys Lys Thr 1100 1105 1110Ser Ser Gln Leu Ser Arg Glu Arg Glu Glu Gln Glu Arg Lys Glu 1115 1120 1125Leu Gln Arg Met Leu Leu Ala Ala Gly Ser Ala Ala Ser Gly Asn 1130 1135 1140Asn His Arg Asp Asp Asp Thr Ala Ser Val Thr Ser Leu Asn Ser 1145 1150 1155Ser Ala Thr Gly Arg Cys Leu Lys Ile Tyr Arg Thr Phe Arg Asp 1160 1165 1170Glu Glu Gly Lys Glu Tyr Val Arg Cys Glu Thr Val Arg Lys Pro 1175 1180 1185Ala Val Ile Asp Ala Tyr Val Arg Ile Arg Thr Thr Lys Asp Glu 1190 1195 1200Glu Phe Ile Arg Lys Phe Ala Leu Phe Asp Glu Gln His Arg Glu 1205 1210 1215Glu Met Arg Lys Glu Arg Arg Arg Ile Gln Glu Gln Leu Arg Arg 1220 1225 1230Leu Lys Arg Asn Gln Glu Lys Glu Lys Leu Lys Gly Pro Pro Glu 1235 1240 1245Lys Lys Pro Lys Lys Met Lys Glu Arg Pro Asp Leu Lys Leu Lys 1250 1255 1260Cys Gly Ala Cys Gly Ala Ile Gly His Met Arg Thr Asn Lys Phe 1265 1270 1275Cys Pro Leu Tyr Tyr Gln Thr Asn Ala Pro Pro Ser Asn Pro Val 1280 1285 1290Ala Met Thr Glu Glu Gln Glu Glu Glu Leu Glu Lys Thr Val Ile 1295 1300 1305His Asn Asp Asn Glu Glu Leu Ile Lys Val Glu Gly Thr Lys Ile 1310 1315 1320Val Leu Gly Lys Gln Leu Ile Glu Ser Ala Asp Glu Val Arg Arg 1325 1330 1335Lys Ser Leu Val Leu Lys Phe Pro Lys Gln Gln Leu Pro Pro Lys 1340 1345 1350Lys Lys Arg Arg Val Gly Thr Thr Val His Cys Asp Tyr Leu Asn 1355 1360 1365Arg Pro His Lys Ser Ile His Arg Arg Arg Thr Asp Pro Met Val 1370 1375 1380Thr Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg Asp 1385 1390 1395Leu Pro Asn Thr Tyr Pro Phe His Thr Pro Val Asn Ala Lys Val 1400 1405 1410Val Lys Asp Tyr Tyr Lys Ile Ile Thr Arg Pro Met Asp Leu Gln 1415 1420 1425Thr Leu Arg Glu Asn Val Arg Lys Arg Leu Tyr Pro Ser Arg Glu 1430 1435 1440Glu Phe Arg Glu His Leu Asp Asp Arg Trp Arg Pro Cys Leu Lys 1445 1450 1455Lys Lys Lys Lys Glu Glu Glu Thr Trp Leu Ser Glu Tyr Ala Phe 1460 1465 1470His Lys Pro Thr Arg Gly Cys Ser Leu Pro Thr Gln Ser Gln Phe 1475 1480 148594104PRTHomo sapiens 94Met Val Thr Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg1 5 10 15Asp Leu Pro Asn Thr Tyr Pro Phe His Thr Pro Val Asn Ala Lys Val 20 25 30Val Lys Asp Tyr Tyr Lys Ile Ile Thr Arg Pro Met Asp Leu Gln Thr 35 40 45Leu Arg Glu Asn Val Arg Lys Arg Leu Tyr Pro Ser Arg Glu Glu Phe 50 55 60Arg Glu His Leu Glu Leu Ile Val Lys Asn Ser Ala Thr Tyr Asn Gly65 70 75 80Lys Asn Gln Met Phe Arg Asp Cys Lys Gly His Cys Ser Asp Pro Tyr 85 90 95Ser Leu Leu Ala Leu Asn Ser Asp 10095552PRTHomo sapiens 95Thr Lys Ile Val Leu Gly Lys Gln Leu Ile Glu Ser Ala Asp Glu Val1 5 10 15Arg Arg Lys Ser Leu Val Leu Lys Phe Pro Lys Gln Gln Leu Pro Pro 20 25 30Lys Lys Lys Arg Arg Val Gly Thr Thr Val His Cys Asp Tyr Leu Asn 35 40 45Arg Pro His Lys Ser Ile His Arg Arg Arg Thr Asp Pro Met Val Thr 50 55 60Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg Asp Leu Pro65 70 75 80Asn Thr Tyr Pro Phe His Thr Pro Val Asn Ala Lys Val Val Lys Asp 85 90 95Tyr Tyr Lys Ile Ile Thr Arg Pro Met Asp Leu Gln Thr Leu Arg Glu 100 105 110Asn Val Arg Lys Arg Leu Tyr Pro Ser Arg Glu Glu Phe Arg Glu His 115 120 125Leu Glu Leu Ile Val Lys Asn Ser Ala Thr Tyr Asn Gly Pro Lys His 130 135 140Ser Leu Thr Gln Ile Ser Gln Ser Met Leu Asp Leu Cys Asp Glu Lys145 150 155 160Leu Lys Glu Lys Glu Asp Lys Leu Ala Arg Leu Glu Lys Ala Ile Asn 165 170 175Pro Leu Leu Asp Asp Asp Asp Gln Val Ala Phe Ser Phe Ile Leu Asp 180 185 190Asn Ile Val Thr Gln Lys Met Met Ala Val Pro Asp Ser Trp Pro Phe 195 200 205His His Pro Val Asn Lys Lys Phe Val Pro Asp Tyr Tyr Lys Val Ile 210 215 220Val Asn Pro Met Asp Leu Glu Thr Ile Arg Lys Asn Ile Ser Lys His225 230 235 240Lys Tyr Gln Ser Arg Glu Ser Phe Leu Asp Asp Val Asn Leu Ile Leu 245 250 255Ala Asn Ser Val Lys Tyr Asn Gly Pro Glu Ser Gln Tyr Thr Lys Thr 260 265 270Ala Gln Glu Ile Val Asn Val Cys Tyr Gln Thr Leu Thr Glu Tyr Asp 275 280 285Glu His Leu Thr Gln Leu Glu Lys Asp Ile Cys Thr Ala Lys Glu Ala 290 295 300Ala Leu Glu Glu Ala Glu Leu Glu Ser Leu Asp Pro Met Thr Pro Gly305 310 315 320Pro Tyr Thr Pro Gln Pro Pro Asp Leu Tyr Asp Thr Asn Thr Ser Leu 325 330 335Ser Met Ser Arg Asp Ala Ser Val Phe Gln Asp Glu Ser Asn Met Ser 340 345 350Val Leu Asp Ile Pro Ser Ala Thr Pro Glu Lys Gln Val Thr Gln Glu 355 360 365Gly Glu Asp Gly Asp Gly Asp Leu Ala Asp Glu Glu Glu Gly Thr Val 370 375 380Gln Gln Pro Gln Ala Ser Val Leu Tyr Glu Asp Leu Leu Met Ser Glu385 390 395 400Gly Glu Asp Asp Glu Glu Asp Ala Gly Ser Asp Glu Glu Gly Asp Asn 405 410 415Pro Phe Ser Ala Ile Gln Leu Ser Glu Ser Gly Ser Asp Ser Asp Val 420 425 430Gly Ser Gly Gly Ile Arg Pro Lys Gln Pro Arg Met Leu Gln Glu Asn 435 440 445Thr Arg Met Asp Met Glu Asn Glu Glu Ser Met Met Ser Tyr Glu Gly 450 455 460Asp Gly Gly Glu Ala Ser His Gly Leu Glu Asp Ser Asn Ile Ser Tyr465 470 475 480Gly Ser Tyr Glu Glu Pro Asp Pro Lys Ser Asn Thr Gln Asp Thr Ser 485 490 495Phe Ser Ser Ile Gly Gly Tyr Glu Val Ser Glu Glu Glu Glu Asp Glu 500 505 510Glu Glu Glu Glu Gln Arg Ser Gly Pro Ser Val Leu Ser Gln Val His 515 520 525Leu Ser Glu Asp Glu Glu Asp Ser Glu Asp Phe His Ser Ile Ala Gly 530 535 540Asp Ser Asp Leu Asp Ser Asp Glu545 550961460PRTHomo sapiens 96Met Gly Pro Gly Cys Asp Leu Leu Leu Arg Thr Ala Ala Thr Ile Thr1 5 10 15Ala Ala Ala Ile Met Ser Asp Thr Asp Ser Asp Glu Asp Ser Ala Gly 20 25 30Gly Gly Pro Phe Ser Leu Ala Gly Phe Leu Phe Gly Asn Ile Asn Gly 35 40 45Ala Gly Gln Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys 50 55 60His Leu Ala Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu65 70 75 80Leu Thr Ala Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn 85 90 95Asp Glu Gly Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp 100 105 110Ile Asn Glu Val Ala Glu Asp Glu Ser Arg Arg Tyr Gln Gln Thr Met 115 120 125Gly Ser Leu Gln Pro Leu Cys His Ser Asp Tyr Asp Glu Asp Asp Tyr 130 135 140Asp Ala Asp Cys Glu Asp Ile Asp Cys Lys Leu Met Pro Pro Pro Pro145 150 155 160Pro Pro Pro Gly Pro Met Lys Lys Asp Lys Asp Gln Asp Ser Ile Thr 165 170 175Gly Glu Lys Val Asp Phe Ser Ser Ser Ser Asp Ser Glu Ser Glu Met 180 185 190Gly Pro Gln Glu Ala Thr Gln Ala Glu Ser Glu Asp Gly Lys Leu Thr 195

200 205Leu Pro Leu Ala Gly Ile Met Gln His Asp Ala Thr Lys Leu Leu Pro 210 215 220Ser Val Thr Glu Leu Phe Pro Glu Phe Arg Pro Gly Lys Val Leu Arg225 230 235 240Phe Leu Arg Leu Phe Gly Pro Gly Lys Asn Val Pro Ser Val Trp Arg 245 250 255Ser Ala Arg Arg Lys Arg Lys Lys Lys His Arg Glu Leu Ile Gln Glu 260 265 270Glu Gln Ile Gln Glu Val Glu Cys Ser Val Glu Ser Glu Val Ser Gln 275 280 285Lys Ser Leu Trp Asn Tyr Asp Tyr Ala Pro Pro Pro Pro Pro Glu Gln 290 295 300Cys Leu Ser Asp Asp Glu Ile Thr Met Met Ala Pro Val Glu Ser Lys305 310 315 320Phe Ser Gln Ser Thr Gly Asp Ile Asp Lys Val Thr Asp Thr Lys Pro 325 330 335Arg Val Ala Glu Trp Arg Tyr Gly Pro Ala Arg Leu Trp Tyr Asp Met 340 345 350Leu Gly Val Pro Glu Asp Gly Ser Gly Phe Asp Tyr Gly Phe Lys Leu 355 360 365Arg Lys Thr Glu His Glu Pro Val Ile Lys Ser Arg Met Ile Glu Glu 370 375 380Phe Arg Lys Leu Glu Glu Asn Asn Gly Thr Asp Leu Leu Ala Asp Glu385 390 395 400Asn Phe Leu Met Val Thr Gln Leu His Trp Glu Asp Asp Ile Ile Trp 405 410 415Asp Gly Glu Asp Val Lys His Lys Gly Thr Lys Pro Gln Arg Ala Ser 420 425 430Leu Ala Gly Trp Leu Pro Ser Ser Met Thr Arg Asn Ala Met Ala Tyr 435 440 445Asn Val Gln Gln Gly Phe Ala Ala Thr Leu Asp Asp Asp Lys Pro Trp 450 455 460Tyr Ser Ile Phe Pro Ile Asp Asn Glu Asp Leu Val Tyr Gly Arg Trp465 470 475 480Glu Asp Asn Ile Ile Trp Asp Ala Gln Ala Met Pro Arg Leu Leu Glu 485 490 495Pro Pro Val Leu Thr Leu Asp Pro Asn Asp Glu Asn Leu Ile Leu Glu 500 505 510Ile Pro Asp Glu Lys Glu Glu Ala Thr Ser Asn Ser Pro Ser Lys Glu 515 520 525Ser Lys Lys Glu Ser Ser Leu Lys Lys Ser Arg Ile Leu Leu Gly Lys 530 535 540Thr Gly Val Ile Lys Glu Glu Pro Gln Gln Asn Met Ser Gln Pro Glu545 550 555 560Val Lys Asp Pro Trp Asn Leu Ser Asn Asp Glu Tyr Tyr Tyr Pro Lys 565 570 575Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly Asn Ile Ile Gln His Ser 580 585 590Ile Pro Ala Val Glu Leu Arg Gln Pro Phe Phe Pro Thr His Met Gly 595 600 605Pro Ile Lys Leu Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser 610 615 620Phe Gly Ala Leu Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu625 630 635 640Lys His Ile Lys Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala 645 650 655Ser Gly Gly Gly Glu Met Phe Phe Met Arg Thr Pro Gln Asp Leu Thr 660 665 670Gly Lys Asp Gly Asp Leu Ile Leu Ala Glu Tyr Ser Glu Glu Asn Gly 675 680 685Pro Leu Met Met Gln Val Gly Met Ala Thr Lys Ile Lys Asn Tyr Tyr 690 695 700Lys Arg Lys Pro Gly Lys Asp Pro Gly Ala Pro Asp Cys Lys Tyr Gly705 710 715 720Glu Thr Val Tyr Cys His Thr Ser Pro Phe Leu Gly Ser Leu His Pro 725 730 735Gly Gln Leu Leu Gln Ala Phe Glu Asn Asn Leu Phe Arg Ala Pro Ile 740 745 750Tyr Leu His Lys Met Pro Glu Thr Asp Phe Leu Ile Ile Arg Thr Arg 755 760 765Gln Gly Tyr Tyr Ile Arg Glu Leu Val Asp Ile Phe Val Val Gly Gln 770 775 780Gln Cys Pro Leu Phe Glu Val Pro Gly Pro Asn Ser Lys Arg Ala Asn785 790 795 800Thr His Ile Arg Asp Phe Leu Gln Val Phe Ile Tyr Arg Leu Phe Trp 805 810 815Lys Ser Lys Asp Arg Pro Arg Arg Ile Arg Met Glu Asp Ile Lys Lys 820 825 830Ala Phe Pro Ser His Ser Glu Ser Ser Ile Arg Lys Arg Leu Lys Leu 835 840 845Cys Ala Asp Phe Lys Arg Thr Gly Met Asp Ser Asn Trp Trp Val Leu 850 855 860Lys Ser Asp Phe Arg Leu Pro Thr Glu Glu Glu Ile Arg Ala Met Val865 870 875 880Ser Pro Glu Gln Cys Cys Ala Tyr Tyr Ser Met Ile Ala Ala Glu Gln 885 890 895Arg Leu Lys Asp Ala Gly Tyr Gly Glu Lys Ser Phe Phe Ala Pro Glu 900 905 910Glu Glu Asn Glu Glu Asp Phe Gln Met Lys Ile Asp Asp Glu Val Arg 915 920 925Thr Ala Pro Trp Asn Thr Thr Arg Ala Phe Ile Ala Ala Met Lys Gly 930 935 940Lys Cys Leu Leu Glu Val Thr Gly Val Ala Asp Pro Thr Gly Cys Gly945 950 955 960Glu Gly Phe Ser Tyr Val Lys Ile Pro Asn Lys Pro Thr Gln Gln Lys 965 970 975Asp Asp Lys Glu Pro Gln Pro Val Lys Lys Thr Val Thr Gly Thr Asp 980 985 990Ala Asp Leu Arg Arg Leu Ser Leu Lys Asn Ala Lys Gln Leu Leu Arg 995 1000 1005Lys Phe Gly Val Pro Glu Glu Glu Ile Lys Lys Leu Ser Arg Trp 1010 1015 1020Glu Val Ile Asp Val Val Arg Thr Met Ser Thr Glu Gln Ala Arg 1025 1030 1035Ser Gly Glu Gly Pro Met Ser Lys Phe Ala Arg Gly Ser Arg Phe 1040 1045 1050Ser Val Ala Glu His Gln Glu Arg Tyr Lys Glu Glu Cys Gln Arg 1055 1060 1065Ile Phe Asp Leu Gln Asn Lys Val Leu Ser Ser Thr Glu Val Leu 1070 1075 1080Ser Thr Asp Thr Asp Ser Ser Ser Ala Glu Asp Ser Asp Phe Glu 1085 1090 1095Glu Met Gly Lys Asn Ile Glu Asn Met Leu Gln Asn Lys Lys Thr 1100 1105 1110Ser Ser Gln Leu Ser Arg Glu Arg Glu Glu Gln Glu Arg Lys Glu 1115 1120 1125Leu Gln Arg Met Leu Leu Ala Ala Gly Ser Ala Ala Ser Gly Asn 1130 1135 1140Asn His Arg Asp Asp Asp Thr Ala Ser Val Thr Ser Leu Asn Ser 1145 1150 1155Ser Ala Thr Gly Arg Cys Leu Lys Ile Tyr Arg Thr Phe Arg Asp 1160 1165 1170Glu Glu Gly Lys Glu Tyr Val Arg Cys Glu Thr Val Arg Lys Pro 1175 1180 1185Ala Val Ile Asp Ala Tyr Val Arg Ile Arg Thr Thr Lys Asp Glu 1190 1195 1200Glu Phe Ile Arg Lys Phe Ala Leu Phe Asp Glu Gln His Arg Glu 1205 1210 1215Glu Met Arg Lys Glu Arg Arg Arg Ile Gln Glu Gln Leu Arg Arg 1220 1225 1230Leu Lys Arg Asn Gln Glu Lys Glu Lys Leu Lys Gly Pro Pro Glu 1235 1240 1245Lys Lys Pro Lys Lys Met Lys Glu Arg Pro Asp Leu Lys Leu Lys 1250 1255 1260Cys Gly Ala Cys Gly Ala Ile Gly His Met Arg Thr Asn Lys Phe 1265 1270 1275Cys Pro Leu Tyr Tyr Gln Thr Asn Ala Pro Pro Ser Asn Pro Val 1280 1285 1290Ala Met Thr Glu Glu Gln Glu Glu Glu Leu Glu Lys Thr Val Ile 1295 1300 1305His Asn Asp Asn Glu Glu Leu Ile Lys Val Glu Gly Thr Lys Ile 1310 1315 1320Val Leu Gly Lys Gln Leu Ile Glu Ser Ala Asp Glu Val Arg Arg 1325 1330 1335Lys Ser Leu Val Leu Lys Phe Pro Lys Gln Gln Leu Pro Pro Lys 1340 1345 1350Lys Lys Arg Arg Val Gly Thr Thr Val His Cys Asp Tyr Leu Asn 1355 1360 1365Arg Pro His Lys Ser Ile His Arg Arg Arg Thr Asp Pro Met Val 1370 1375 1380Thr Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg Asp 1385 1390 1395Leu Pro Asn Thr Tyr Pro Phe His Thr Pro Ala Trp Met Thr Asp 1400 1405 1410Gly Asp Pro Val Ser Lys Arg Lys Lys Lys Lys Lys Lys Arg Gly 1415 1420 1425Phe Gln Ser Met Leu Ser Thr Ser Pro Leu Gly Val Ala Leu Cys 1430 1435 1440Pro His Arg Ala Asn Ser Glu Trp Arg Gly Leu Pro Pro Arg Ser 1445 1450 1455Leu Leu 1460971485PRTHomo sapiens 97Met Gly Pro Gly Cys Asp Leu Leu Leu Arg Thr Ala Ala Thr Ile Thr1 5 10 15Ala Ala Ala Ile Met Ser Asp Thr Asp Ser Asp Glu Asp Ser Ala Gly 20 25 30Gly Gly Pro Phe Ser Leu Ala Gly Phe Leu Phe Gly Asn Ile Asn Gly 35 40 45Ala Gly Gln Leu Glu Gly Glu Ser Val Leu Asp Asp Glu Cys Lys Lys 50 55 60His Leu Ala Gly Leu Gly Ala Leu Gly Leu Gly Ser Leu Ile Thr Glu65 70 75 80Leu Thr Ala Asn Glu Glu Leu Thr Gly Thr Asp Gly Ala Leu Val Asn 85 90 95Asp Glu Gly Trp Val Arg Ser Thr Glu Asp Ala Val Asp Tyr Ser Asp 100 105 110Ile Asn Glu Val Ala Glu Asp Glu Ser Arg Arg Tyr Gln Gln Thr Met 115 120 125Gly Ser Leu Gln Pro Leu Cys His Ser Asp Tyr Asp Glu Asp Asp Tyr 130 135 140Asp Ala Asp Cys Glu Asp Ile Asp Cys Lys Leu Met Pro Pro Pro Pro145 150 155 160Pro Pro Pro Gly Pro Met Lys Lys Asp Lys Asp Gln Asp Ser Ile Thr 165 170 175Gly Glu Lys Val Asp Phe Ser Ser Ser Ser Asp Ser Glu Ser Glu Met 180 185 190Gly Pro Gln Glu Ala Thr Gln Ala Glu Ser Glu Asp Gly Lys Leu Thr 195 200 205Leu Pro Leu Ala Gly Ile Met Gln His Asp Ala Thr Lys Leu Leu Pro 210 215 220Ser Val Thr Glu Leu Phe Pro Glu Phe Arg Pro Gly Lys Val Leu Arg225 230 235 240Phe Leu Arg Leu Phe Gly Pro Gly Lys Asn Val Pro Ser Val Trp Arg 245 250 255Ser Ala Arg Arg Lys Arg Lys Lys Lys His Arg Glu Leu Ile Gln Glu 260 265 270Glu Gln Ile Gln Glu Val Glu Cys Ser Val Glu Ser Glu Val Ser Gln 275 280 285Lys Ser Leu Trp Asn Tyr Asp Tyr Ala Pro Pro Pro Pro Pro Glu Gln 290 295 300Cys Leu Ser Asp Asp Glu Ile Thr Met Met Ala Pro Val Glu Ser Lys305 310 315 320Phe Ser Gln Ser Thr Gly Asp Ile Asp Lys Val Thr Asp Thr Lys Pro 325 330 335Arg Val Ala Glu Trp Arg Tyr Gly Pro Ala Arg Leu Trp Tyr Asp Met 340 345 350Leu Gly Val Pro Glu Asp Gly Ser Gly Phe Asp Tyr Gly Phe Lys Leu 355 360 365Arg Lys Thr Glu His Glu Pro Val Ile Lys Ser Arg Met Ile Glu Glu 370 375 380Phe Arg Lys Leu Glu Glu Asn Asn Gly Thr Asp Leu Leu Ala Asp Glu385 390 395 400Asn Phe Leu Met Val Thr Gln Leu His Trp Glu Asp Asp Ile Ile Trp 405 410 415Asp Gly Glu Asp Val Lys His Lys Gly Thr Lys Pro Gln Arg Ala Ser 420 425 430Leu Ala Gly Trp Leu Pro Ser Ser Met Thr Arg Asn Ala Met Ala Tyr 435 440 445Asn Val Gln Gln Gly Phe Ala Ala Thr Leu Asp Asp Asp Lys Pro Trp 450 455 460Tyr Ser Ile Phe Pro Ile Asp Asn Glu Asp Leu Val Tyr Gly Arg Trp465 470 475 480Glu Asp Asn Ile Ile Trp Asp Ala Gln Ala Met Pro Arg Leu Leu Glu 485 490 495Pro Pro Val Leu Thr Leu Asp Pro Asn Asp Glu Asn Leu Ile Leu Glu 500 505 510Ile Pro Asp Glu Lys Glu Glu Ala Thr Ser Asn Ser Pro Ser Lys Glu 515 520 525Ser Lys Lys Glu Ser Ser Leu Lys Lys Ser Arg Ile Leu Leu Gly Lys 530 535 540Thr Gly Val Ile Lys Glu Glu Pro Gln Gln Asn Met Ser Gln Pro Glu545 550 555 560Val Lys Asp Pro Trp Asn Leu Ser Asn Asp Glu Tyr Tyr Tyr Pro Lys 565 570 575Gln Gln Gly Leu Arg Gly Thr Phe Gly Gly Asn Ile Ile Gln His Ser 580 585 590Ile Pro Ala Val Glu Leu Arg Gln Pro Phe Phe Pro Thr His Met Gly 595 600 605Pro Ile Lys Leu Arg Gln Phe His Arg Pro Pro Leu Lys Lys Tyr Ser 610 615 620Phe Gly Ala Leu Ser Gln Pro Gly Pro His Ser Val Gln Pro Leu Leu625 630 635 640Lys His Ile Lys Lys Lys Ala Lys Met Arg Glu Gln Glu Arg Gln Ala 645 650 655Ser Gly Gly Gly Glu Met Phe Phe Met Arg Thr Pro Gln Asp Leu Thr 660 665 670Gly Lys Asp Gly Asp Leu Ile Leu Ala Glu Tyr Ser Glu Glu Asn Gly 675 680 685Pro Leu Met Met Gln Val Gly Met Ala Thr Lys Ile Lys Asn Tyr Tyr 690 695 700Lys Arg Lys Pro Gly Lys Asp Pro Gly Ala Pro Asp Cys Lys Tyr Gly705 710 715 720Glu Thr Val Tyr Cys His Thr Ser Pro Phe Leu Gly Ser Leu His Pro 725 730 735Gly Gln Leu Leu Gln Ala Phe Glu Asn Asn Leu Phe Arg Ala Pro Ile 740 745 750Tyr Leu His Lys Met Pro Glu Thr Asp Phe Leu Ile Ile Arg Thr Arg 755 760 765Gln Gly Tyr Tyr Ile Arg Glu Leu Val Asp Ile Phe Val Val Gly Gln 770 775 780Gln Cys Pro Leu Phe Glu Val Pro Gly Pro Asn Ser Lys Arg Ala Asn785 790 795 800Thr His Ile Arg Asp Phe Leu Gln Val Phe Ile Tyr Arg Leu Phe Trp 805 810 815Lys Ser Lys Asp Arg Pro Arg Arg Ile Arg Met Glu Asp Ile Lys Lys 820 825 830Ala Phe Pro Ser His Ser Glu Ser Ser Ile Arg Lys Arg Leu Lys Leu 835 840 845Cys Ala Asp Phe Lys Arg Thr Gly Met Asp Ser Asn Trp Trp Val Leu 850 855 860Lys Ser Asp Phe Arg Leu Pro Thr Glu Glu Glu Ile Arg Ala Met Val865 870 875 880Ser Pro Glu Gln Cys Cys Ala Tyr Tyr Ser Met Ile Ala Ala Glu Gln 885 890 895Arg Leu Lys Asp Ala Gly Tyr Gly Glu Lys Ser Phe Phe Ala Pro Glu 900 905 910Glu Glu Asn Glu Glu Asp Phe Gln Met Lys Ile Asp Asp Glu Val Arg 915 920 925Thr Ala Pro Trp Asn Thr Thr Arg Ala Phe Ile Ala Ala Met Lys Gly 930 935 940Lys Cys Leu Leu Glu Val Thr Gly Val Ala Asp Pro Thr Gly Cys Gly945 950 955 960Glu Gly Phe Ser Tyr Val Lys Ile Pro Asn Lys Pro Thr Gln Gln Lys 965 970 975Asp Asp Lys Glu Pro Gln Pro Val Lys Lys Thr Val Thr Gly Thr Asp 980 985 990Ala Asp Leu Arg Arg Leu Ser Leu Lys Asn Ala Lys Gln Leu Leu Arg 995 1000 1005Lys Phe Gly Val Pro Glu Glu Glu Ile Lys Lys Leu Ser Arg Trp 1010 1015 1020Glu Val Ile Asp Val Val Arg Thr Met Ser Thr Glu Gln Ala Arg 1025 1030 1035Ser Gly Glu Gly Pro Met Ser Lys Phe Ala Arg Gly Ser Arg Phe 1040 1045 1050Ser Val Ala Glu His Gln Glu Arg Tyr Lys Glu Glu Cys Gln Arg 1055 1060 1065Ile Phe Asp Leu Gln Asn Lys Val Leu Ser Ser Thr Glu Val Leu 1070 1075 1080Ser Thr Asp Thr Asp Ser Ser Ser Ala Glu Asp Ser Asp Phe Glu 1085 1090 1095Glu Met Gly Lys Asn Ile Glu Asn Met Leu Gln Asn Lys Lys Thr 1100 1105 1110Ser Ser Gln Leu Ser Arg Glu Arg Glu Glu Gln Glu Arg Lys Glu 1115 1120 1125Leu Gln Arg Met Leu Leu Ala Ala Gly Ser Ala Ala Ser Gly Asn 1130 1135 1140Asn His Arg Asp Asp Asp Thr Ala Ser Val Thr Ser Leu Asn Ser 1145 1150 1155Ser Ala Thr Gly Arg Cys Leu Lys Ile Tyr Arg Thr Phe Arg Asp 1160 1165 1170Glu Glu Gly Lys Glu Tyr Val Arg Cys Glu Thr Val Arg Lys Pro 1175 1180 1185Ala Val Ile Asp Ala Tyr Val Arg Ile Arg Thr Thr Lys Asp Glu 1190 1195

1200Glu Phe Ile Arg Lys Phe Ala Leu Phe Asp Glu Gln His Arg Glu 1205 1210 1215Glu Met Arg Lys Glu Arg Arg Arg Ile Gln Glu Gln Leu Arg Arg 1220 1225 1230Leu Lys Arg Asn Gln Glu Lys Glu Lys Leu Lys Gly Pro Pro Glu 1235 1240 1245Lys Lys Pro Lys Lys Met Lys Glu Arg Pro Asp Leu Lys Leu Lys 1250 1255 1260Cys Gly Ala Cys Gly Ala Ile Gly His Met Arg Thr Asn Lys Phe 1265 1270 1275Cys Pro Leu Tyr Tyr Gln Thr Asn Ala Pro Pro Ser Asn Pro Val 1280 1285 1290Ala Met Thr Glu Glu Gln Glu Glu Glu Leu Glu Lys Thr Val Ile 1295 1300 1305His Asn Asp Asn Glu Glu Leu Ile Lys Val Glu Gly Thr Lys Ile 1310 1315 1320Val Leu Gly Lys Gln Leu Ile Glu Ser Ala Asp Glu Val Arg Arg 1325 1330 1335Lys Ser Leu Val Leu Lys Phe Pro Lys Gln Gln Leu Pro Pro Lys 1340 1345 1350Lys Lys Arg Arg Val Gly Thr Thr Val His Cys Asp Tyr Leu Asn 1355 1360 1365Arg Pro His Lys Ser Ile His Arg Arg Arg Thr Asp Pro Met Val 1370 1375 1380Thr Leu Ser Ser Ile Leu Glu Ser Ile Ile Asn Asp Met Arg Asp 1385 1390 1395Leu Pro Asn Thr Tyr Pro Phe His Thr Pro Val Asn Ala Lys Val 1400 1405 1410Val Lys Asp Tyr Tyr Lys Ile Ile Thr Arg Pro Met Asp Leu Gln 1415 1420 1425Thr Leu Arg Glu Asn Val Arg Lys Arg Leu Tyr Pro Ser Arg Glu 1430 1435 1440Glu Phe Arg Glu His Leu Glu Leu Ile Val Lys Asn Ser Ala Thr 1445 1450 1455Tyr Asn Gly Lys Asn Gln Met Phe Arg Asp Cys Lys Gly His Cys 1460 1465 1470Ser Asp Pro Tyr Ser Leu Leu Ala Leu Asn Ser Asp 1475 1480 14859822DNAArtificial sequencePrimer 98ccactagaac ctggtcaaat ac 229920DNAArtificial sequencePrimer 99gactgagagt ggagcgcttg 20100271PRTHomo sapiens 100Leu Ser Arg Pro Ser Cys Leu Pro Leu Pro Glu Leu Gly Leu Val Leu1 5 10 15Asn Leu Lys Glu Lys Lys Ala Val Leu Asn Pro Thr Ile Ile Pro Glu 20 25 30Ser Val Ala Gly Asn Gln Glu Ala Ala Asn Asn Pro Ser Ser His Pro 35 40 45Gln Leu Val Gly Phe Gln Asn Pro Glu Asp Asp His Leu Ala Lys Glu 50 55 60Ala Ser Cys Asn Ile Ser Ala His Gln Gln Gly Val Lys Arg Lys Ser65 70 75 80Asp Thr Pro Leu Gly Ser Pro Leu Glu Pro Gly Gln Ile Leu Glu Lys 85 90 95Asn Glu Asp Ser Ser Lys Val Lys Leu Lys Ile Arg Phe Ser Ser Ser 100 105 110Gln Asp Glu Glu Glu Ile Asp Met Asp Thr Val His Asp Ser Gln Ala 115 120 125Phe Ile Ser His His Leu Asn Met Leu Glu Arg Pro Ser Thr Pro Gly 130 135 140Leu Ser Lys Tyr Arg Pro Ala Ser Ser Arg Ser Ala Leu Ile Pro Gln145 150 155 160His Ser Ala Gly Cys Asp Ser Thr Pro Thr Thr Lys Pro Gln Trp Ser 165 170 175Leu Glu Leu Ala Arg Lys Gly Thr Gly Lys Glu Gln Ala Pro Leu Glu 180 185 190Met Ser Met His Pro Ala Ala Ser Ala Pro Leu Ser Val Phe Thr Lys 195 200 205Glu Ser Thr Ala Ser Lys His Ser Asp His His His His His His His 210 215 220Glu His Lys Lys Lys Lys Lys Lys His Lys His Lys His Lys His Lys225 230 235 240His Lys His Asp Ser Lys Glu Lys Asp Lys Glu Pro Phe Thr Phe Ser 245 250 255Ser Pro Ala Ser Gly Arg Ser Ile Arg Ser Pro Ser Leu Ser Asp 260 265 270101239PRTHomo sapiens 101Thr Ser His Asp Trp Arg Leu Arg Cys Gly Ala Val Asp Leu Tyr Phe1 5 10 15Thr Leu Phe Gly Leu Ser Arg Pro Ser Cys Leu Pro Leu Pro Glu Leu 20 25 30Gly Leu Val Leu Asn Leu Lys Glu Lys Lys Ala Val Leu Asn Pro Thr 35 40 45Ile Ile Pro Glu Ser Val Ala Gly Asn Gln Glu Ala Ala Asn Asn Pro 50 55 60Ser Ser His Pro Gln Leu Val Gly Phe Gln Asn Pro Phe Ser Ser Ser65 70 75 80Gln Asp Glu Glu Glu Ile Asp Met Asp Thr Val His Asp Ser Gln Ala 85 90 95Phe Ile Ser His His Leu Asn Met Leu Glu Arg Pro Ser Thr Pro Gly 100 105 110Leu Ser Lys Tyr Arg Pro Ala Ser Ser Arg Ser Ala Leu Ile Pro Gln 115 120 125His Ser Ala Gly Cys Asp Ser Thr Pro Thr Thr Lys Pro Gln Trp Ser 130 135 140Leu Glu Leu Ala Arg Lys Gly Thr Gly Lys Glu Gln Ala Pro Leu Glu145 150 155 160Met Ser Met His Pro Ala Ala Ser Ala Pro Leu Ser Val Phe Thr Lys 165 170 175Glu Ser Thr Ala Ser Lys His Ser Asp His His His His His His His 180 185 190Glu His Lys Lys Lys Lys Lys Lys His Lys His Lys His Lys His Lys 195 200 205His Lys His Asp Ser Lys Glu Lys Asp Lys Glu Pro Phe Thr Phe Ser 210 215 220Ser Pro Ala Ser Gly Arg Ser Ile Arg Ser Pro Ser Leu Ser Asp225 230 23510221DNAArtificial sequencePrimer 102atctgctgga cgaggtcttc t 2110321DNAArtificial sequencePrimer 103tatggtagtt ggggtcacct g 21104653PRTHomo sapiens 104Met Ala Ala Gly Ser Asp Leu Leu Asp Glu Val Phe Phe Asn Ser Glu1 5 10 15Val Asp Glu Lys Val Gly Met Val Leu Val Arg Ser Glu Asn Gly Gln 20 25 30Leu Leu Met Ile Pro Gln Gln Ala Leu Ala Gln Met Gln Ala Gln Ala 35 40 45His Ala Gln Pro Gln Thr Thr Met Ala Pro Arg Pro Ala Thr Pro Thr 50 55 60Ser Ala Pro Pro Val Gln Ile Ser Thr Val Gln Ala Pro Gly Thr Pro65 70 75 80Ile Ile Ala Arg Gln Val Thr Pro Thr Thr Ile Ile Lys Gln Val Ser 85 90 95Gln Ala Gln Thr Thr Val Gln Pro Ser Ala Thr Leu Gln Arg Ser Pro 100 105 110Gly Val Gln Pro Gln Leu Val Leu Gly Gly Ala Ala Gln Thr Ala Ser 115 120 125Leu Gly Thr Ala Thr Ala Val Gln Thr Gly Thr Pro Gln Arg Thr Val 130 135 140Pro Gly Ala Thr Thr Thr Ser Ser Ala Ala Thr Glu Thr Met Glu Asn145 150 155 160Val Lys Lys Cys Lys Asn Phe Leu Ser Thr Leu Ile Lys Leu Ala Ser 165 170 175Ser Gly Lys Gln Ser Thr Glu Thr Ala Ala Asn Val Lys Glu Leu Val 180 185 190Gln Asn Leu Leu Asp Gly Lys Ile Glu Ala Glu Asp Phe Thr Ser Arg 195 200 205Leu Tyr Arg Glu Leu Asn Ser Ser Pro Gln Pro Tyr Leu Val Pro Phe 210 215 220Leu Lys Arg Ser Leu Pro Ala Leu Arg Gln Leu Thr Pro Asp Ser Ala225 230 235 240Ala Phe Ile Gln Gln Ser Gln Gln Gln Pro Pro Pro Pro Thr Ser Gln 245 250 255Ala Thr Thr Ala Leu Thr Ala Val Val Leu Ser Ser Ser Val Gln Arg 260 265 270Thr Ala Gly Lys Thr Ala Ala Thr Val Thr Ser Ala Leu Gln Pro Pro 275 280 285Val Leu Ser Leu Thr Gln Pro Thr Gln Val Gly Val Gly Lys Gln Gly 290 295 300Gln Pro Thr Pro Leu Val Ile Gln Gln Pro Pro Lys Pro Gly Ala Leu305 310 315 320Ile Arg Pro Pro Gln Val Thr Leu Thr Gln Thr Pro Met Val Ala Leu 325 330 335Arg Gln Pro His Asn Arg Ile Met Leu Thr Thr Pro Gln Gln Ile Gln 340 345 350Leu Asn Pro Leu Gln Pro Val Pro Val Val Lys Pro Ala Val Leu Pro 355 360 365Gly Thr Lys Ala Leu Ser Ala Val Ser Ala Gln Ala Ala Ala Ala Gln 370 375 380Lys Asn Lys Leu Lys Glu Pro Gly Gly Gly Ser Phe Arg Asp Asp Asp385 390 395 400Asp Ile Asn Asp Val Ala Ser Met Ala Gly Val Asn Leu Ser Glu Glu 405 410 415Ser Ala Arg Ile Leu Ala Thr Asn Ser Glu Leu Val Gly Thr Leu Thr 420 425 430Arg Ser Cys Lys Asp Glu Thr Phe Leu Leu Gln Ala Pro Leu Gln Arg 435 440 445Arg Ile Leu Glu Ile Gly Lys Lys His Gly Ile Thr Glu Leu His Pro 450 455 460Asp Val Val Ser Tyr Val Ser His Ala Thr Gln Gln Arg Leu Gln Asn465 470 475 480Leu Val Glu Lys Ile Ser Glu Thr Ala Gln Gln Lys Asn Phe Ser Tyr 485 490 495Lys Asp Asp Asp Arg Tyr Glu Gln Ala Ser Asp Val Arg Ala Gln Leu 500 505 510Lys Phe Phe Glu Gln Leu Asp Gln Ile Glu Lys Gln Arg Lys Asp Glu 515 520 525Gln Glu Arg Glu Ile Leu Met Arg Ala Ala Lys Ser Arg Ser Arg Gln 530 535 540Glu Asp Pro Glu Gln Leu Arg Leu Lys Gln Lys Ala Lys Glu Met Gln545 550 555 560Gln Gln Glu Leu Ala Gln Met Arg Gln Arg Asp Ala Asn Leu Thr Ala 565 570 575Leu Ala Ala Ile Gly Pro Arg Lys Lys Arg Lys Val Asp Cys Pro Gly 580 585 590Pro Gly Ser Gly Ala Glu Gly Ser Gly Pro Gly Ser Val Val Pro Gly 595 600 605Ser Ser Gly Val Gly Thr Pro Arg Gln Phe Thr Arg Gln Arg Ile Thr 610 615 620Arg Val Asn Leu Arg Asp Leu Ile Phe Cys Leu Glu Asn Glu Arg Glu625 630 635 640Thr Ser His Ser Leu Leu Leu Tyr Lys Ala Phe Leu Lys 645 6501051085PRTHomo sapiens 105Met Ala Ala Gly Ser Asp Leu Leu Asp Glu Val Phe Phe Asn Ser Glu1 5 10 15Val Asp Glu Lys Val Val Ser Asp Leu Val Gly Ser Leu Glu Ser Gln 20 25 30Leu Ala Ala Ser Ala Ala His His His His Leu Ala Pro Arg Thr Pro 35 40 45Glu Val Arg Ala Ala Ala Ala Gly Ala Leu Gly Asn His Val Val Ser 50 55 60Gly Ser Pro Ala Gly Ala Ala Gly Ala Gly Pro Ala Ala Pro Ala Glu65 70 75 80Gly Ala Pro Gly Ala Ala Pro Glu Pro Pro Pro Ala Gly Arg Ala Arg 85 90 95Pro Gly Gly Gly Gly Pro Gln Arg Pro Gly Pro Pro Ser Pro Arg Arg 100 105 110Pro Leu Val Pro Ala Gly Pro Ala Pro Pro Ala Ala Lys Leu Arg Pro 115 120 125Pro Pro Glu Gly Ser Ala Gly Ser Cys Ala Pro Val Pro Ala Ala Ala 130 135 140Ala Val Ala Ala Gly Pro Glu Pro Ala Pro Ala Gly Pro Ala Lys Pro145 150 155 160Ala Gly Pro Ala Ala Leu Ala Ala Arg Ala Gly Pro Gly Pro Gly Pro 165 170 175Gly Pro Gly Pro Gly Pro Gly Pro Gly Pro Gly Lys Pro Ala Gly Pro 180 185 190Gly Ala Ala Gln Thr Leu Asn Gly Ser Ala Ala Leu Leu Asn Ser His 195 200 205His Ala Ala Ala Pro Ala Val Ser Leu Val Asn Asn Gly Pro Ala Ala 210 215 220Leu Leu Pro Leu Pro Lys Pro Ala Ala Pro Gly Thr Val Ile Gln Thr225 230 235 240Pro Pro Phe Val Gly Ala Ala Ala Pro Pro Ala Pro Ala Ala Pro Ser 245 250 255Pro Pro Ala Ala Pro Ala Pro Ala Ala Pro Ala Ala Ala Pro Pro Pro 260 265 270Pro Pro Pro Ala Pro Ala Thr Leu Ala Arg Pro Pro Gly His Pro Ala 275 280 285Gly Pro Pro Thr Ala Ala Pro Ala Val Pro Pro Pro Ala Ala Ala Gln 290 295 300Asn Gly Gly Ser Ala Gly Ala Ala Pro Ala Pro Ala Pro Ala Ala Gly305 310 315 320Gly Pro Ala Gly Val Ser Gly Gln Pro Gly Pro Gly Ala Ala Ala Ala 325 330 335Ala Pro Ala Pro Gly Val Lys Ala Glu Ser Pro Lys Arg Val Val Gln 340 345 350Ala Ala Pro Pro Ala Ala Gln Thr Leu Ala Ala Ser Gly Pro Ala Ser 355 360 365Thr Ala Ala Ser Met Val Ile Gly Pro Thr Met Gln Gly Ala Leu Pro 370 375 380Ser Pro Ala Ala Val Pro Pro Pro Ala Pro Gly Thr Pro Thr Gly Leu385 390 395 400Pro Lys Gly Ala Ala Gly Ala Val Thr Gln Ser Leu Ser Arg Thr Pro 405 410 415Thr Ala Thr Thr Ser Gly Ile Arg Ala Thr Leu Thr Pro Thr Val Leu 420 425 430Ala Pro Arg Leu Pro Gln Pro Pro Gln Asn Pro Thr Asn Ile Gln Asn 435 440 445Phe Gln Leu Pro Pro Gly Met Val Leu Val Arg Ser Glu Asn Gly Gln 450 455 460Leu Leu Met Ile Pro Gln Gln Ala Leu Ala Gln Met Gln Ala Gln Ala465 470 475 480His Ala Gln Pro Gln Thr Thr Met Ala Pro Arg Pro Ala Thr Pro Thr 485 490 495Ser Ala Pro Pro Val Gln Ile Ser Thr Val Gln Ala Pro Gly Thr Pro 500 505 510Ile Ile Ala Arg Gln Val Thr Pro Thr Thr Ile Ile Lys Gln Val Ser 515 520 525Gln Ala Gln Thr Thr Val Gln Pro Ser Ala Thr Leu Gln Arg Ser Pro 530 535 540Gly Val Gln Pro Gln Leu Val Leu Gly Gly Ala Ala Gln Thr Ala Ser545 550 555 560Leu Gly Thr Ala Thr Ala Val Gln Thr Gly Thr Pro Gln Arg Thr Val 565 570 575Pro Gly Ala Thr Thr Thr Ser Ser Ala Ala Thr Glu Thr Met Glu Asn 580 585 590Val Lys Lys Cys Lys Asn Phe Leu Ser Thr Leu Ile Lys Leu Ala Ser 595 600 605Ser Gly Lys Gln Ser Thr Glu Thr Ala Ala Asn Val Lys Glu Leu Val 610 615 620Gln Asn Leu Leu Asp Gly Lys Ile Glu Ala Glu Asp Phe Thr Ser Arg625 630 635 640Leu Tyr Arg Glu Leu Asn Ser Ser Pro Gln Pro Tyr Leu Val Pro Phe 645 650 655Leu Lys Arg Ser Leu Pro Ala Leu Arg Gln Leu Thr Pro Asp Ser Ala 660 665 670Ala Phe Ile Gln Gln Ser Gln Gln Gln Pro Pro Pro Pro Thr Ser Gln 675 680 685Ala Thr Thr Ala Leu Thr Ala Val Val Leu Ser Ser Ser Val Gln Arg 690 695 700Thr Ala Gly Lys Thr Ala Ala Thr Val Thr Ser Ala Leu Gln Pro Pro705 710 715 720Val Leu Ser Leu Thr Gln Pro Thr Gln Val Gly Val Gly Lys Gln Gly 725 730 735Gln Pro Thr Pro Leu Val Ile Gln Gln Pro Pro Lys Pro Gly Ala Leu 740 745 750Ile Arg Pro Pro Gln Val Thr Leu Thr Gln Thr Pro Met Val Ala Leu 755 760 765Arg Gln Pro His Asn Arg Ile Met Leu Thr Thr Pro Gln Gln Ile Gln 770 775 780Leu Asn Pro Leu Gln Pro Val Pro Val Val Lys Pro Ala Val Leu Pro785 790 795 800Gly Thr Lys Ala Leu Ser Ala Val Ser Ala Gln Ala Ala Ala Ala Gln 805 810 815Lys Asn Lys Leu Lys Glu Pro Gly Gly Gly Ser Phe Arg Asp Asp Asp 820 825 830Asp Ile Asn Asp Val Ala Ser Met Ala Gly Val Asn Leu Ser Glu Glu 835 840 845Ser Ala Arg Ile Leu Ala Thr Asn Ser Glu Leu Val Gly Thr Leu Thr 850 855 860Arg Ser Cys Lys Asp Glu Thr Phe Leu Leu Gln Ala Pro Leu Gln Arg865 870 875 880Arg Ile Leu Glu Ile Gly Lys Lys His Gly Ile Thr Glu Leu His Pro 885 890 895Asp Val Val Ser Tyr Val Ser His Ala Thr Gln Gln Arg Leu Gln Asn 900 905 910Leu Val Glu Lys Ile Ser Glu Thr Ala Gln Gln Lys Asn Phe Ser Tyr 915 920 925Lys Asp Asp Asp Arg Tyr Glu Gln Ala Ser Asp Val Arg Ala Gln Leu 930 935 940Lys Phe Phe Glu Gln Leu Asp Gln Ile Glu Lys

Gln Arg Lys Asp Glu945 950 955 960Gln Glu Arg Glu Ile Leu Met Arg Ala Ala Lys Ser Arg Ser Arg Gln 965 970 975Glu Asp Pro Glu Gln Leu Arg Leu Lys Gln Lys Ala Lys Glu Met Gln 980 985 990Gln Gln Glu Leu Ala Gln Met Arg Gln Arg Asp Ala Asn Leu Thr Ala 995 1000 1005Leu Ala Ala Ile Gly Pro Arg Lys Lys Arg Lys Val Asp Cys Pro 1010 1015 1020Gly Pro Gly Ser Gly Ala Glu Gly Ser Gly Pro Gly Ser Val Val 1025 1030 1035Pro Gly Ser Ser Gly Val Gly Thr Pro Arg Gln Phe Thr Arg Gln 1040 1045 1050Arg Ile Thr Arg Val Asn Leu Arg Asp Leu Ile Phe Cys Leu Glu 1055 1060 1065Asn Glu Arg Glu Thr Ser His Ser Leu Leu Leu Tyr Lys Ala Phe 1070 1075 1080Leu Lys 108510621DNAArtificial sequencePrimer 106cagtcatgaa acgagtgcgt a 2110722DNAArtificial sequencePrimer 107gaatctctca tctacagaca ac 2210885PRTHomo sapiens 108Met Lys Arg Val Arg Thr Glu Gln Ile Gln Met Ala Val Ser Cys Tyr1 5 10 15Leu Lys Arg Arg Gln Tyr Val Asp Ser Asp Gly Pro Leu Lys Gln Gly 20 25 30Leu Arg Leu Ser Gln Thr Ala Glu Glu Met Ala Ala Asn Leu Thr Val 35 40 45Gln Ser Glu Ser Gly Cys Ala Asn Ile Val Ser Ala Ala Pro Cys Gln 50 55 60Ala Glu Pro Gln Gln Tyr Glu Val Gln Phe Gly Arg Leu Arg Asn Phe65 70 75 80Leu Thr Gly Cys Leu 85109120PRTHomo sapiens 109Met Lys Arg Val Arg Thr Glu Gln Ile Gln Met Ala Val Ser Cys Tyr1 5 10 15Leu Lys Arg Arg Gln Tyr Val Asp Ser Asp Gly Pro Leu Lys Gln Gly 20 25 30Leu Arg Leu Ser Gln Thr Ala Glu Glu Met Ala Ala Asn Leu Thr Val 35 40 45Gln Ser Glu Ser Gly Cys Ala Asn Ile Val Ser Ala Ala Pro Cys Gln 50 55 60Ala Glu Pro Gln Gln Tyr Glu Val Gln Phe Gly Arg Leu Arg Asn Phe65 70 75 80Leu Thr Asp Ser Asp Ser Gln His Ser His Glu Val Met Pro Leu Leu 85 90 95Tyr Pro Leu Phe Val Tyr Leu His Leu Asn Leu Val Gln Asn Ser Pro 100 105 110Lys Ser Thr Val Glu Ser Phe Tyr 115 12011021DNAArtificial sequencePrimer 110cctatttcgt aatccgcacc t 2111121DNAArtificial sequencePrimer 111actgactcag agcggcaagt a 21112265PRTHomo sapiens 112Met Cys Leu Gly Pro Tyr Val Arg Cys Leu Val Gly Ser Val Leu Tyr1 5 10 15Cys Val Leu Glu Pro Leu Ala Ala Ser Ile Asn Pro Leu Asn Asp His 20 25 30Trp Thr Leu Arg Asp Gly Ala Ala Leu Leu Leu Ser His Ile Phe Trp 35 40 45Thr His Gly Asp Leu Val Ser Gly Leu Tyr Gln His Ile Leu Leu Ser 50 55 60Leu Gln Lys Ile Leu Ala Asp Pro Val Arg Pro Leu Cys Cys His Tyr65 70 75 80Gly Ala Val Val Gly Leu His Ala Leu Gly Trp Lys Ala Val Glu Arg 85 90 95Val Leu Tyr Pro His Leu Ser Thr Tyr Trp Thr Asn Leu Gln Ala Val 100 105 110Leu Asp Asp Tyr Ser Val Ser Asn Ala Gln Val Lys Ala Asp Gly His 115 120 125Lys Val Tyr Gly Ala Ile Leu Val Ala Val Glu Arg Leu Leu Lys Met 130 135 140Lys Ala Gln Ala Ala Glu Pro Asn Arg Gly Gly Pro Gly Gly Arg Gly145 150 155 160Cys Arg Arg Leu Asp Asp Leu Pro Trp Asp Ser Leu Leu Phe Gln Glu 165 170 175Ser Ser Ser Gly Gly Gly Ala Glu Pro Ser Phe Gly Ser Gly Leu Pro 180 185 190Leu Pro Pro Gly Gly Ala Gly Pro Glu Asp Pro Ser Leu Ser Val Thr 195 200 205Leu Ala Asp Ile Tyr Arg Glu Leu Tyr Ala Phe Phe Gly Asp Ser Leu 210 215 220Ala Thr Arg Phe Gly Thr Gly Leu Ala Leu Arg Ala Glu Thr Ala His225 230 235 240Asp Arg Pro Tyr Gln Pro Pro Arg Pro Pro Val Gly Ala Leu Gly Leu 245 250 255Leu Ala Val Leu Ala Ala Leu Ser Gln 260 265113360PRTHomo sapiens 113Gln Asp Leu Gln Thr Asn Ser Lys Ile Gly Ala Leu Leu Pro Tyr Phe1 5 10 15Val Tyr Val Val Ser Gly Val Lys Ser Val Ser His Asp Leu Glu Gln 20 25 30Leu His Arg Leu Leu Gln Val Ala Arg Ser Leu Phe Arg Asn Pro His 35 40 45Leu Cys Leu Gly Pro Tyr Val Arg Cys Leu Val Gly Ser Val Leu Tyr 50 55 60Cys Val Leu Glu Pro Leu Ala Ala Ser Ile Asn Pro Leu Asn Asp His65 70 75 80Trp Thr Leu Arg Asp Gly Ala Ala Leu Leu Leu Ser His Ile Phe Trp 85 90 95Thr His Gly Asp Leu Val Ser Gly Leu Tyr Gln His Ile Leu Leu Ser 100 105 110Leu Gln Lys Ile Leu Ala Asp Pro Val Arg Pro Leu Cys Cys His Tyr 115 120 125Gly Ala Val Val Gly Leu His Ala Leu Gly Trp Lys Ala Val Glu Arg 130 135 140Val Leu Tyr Pro His Leu Ser Thr Tyr Trp Thr Asn Leu Gln Ala Val145 150 155 160Leu Asp Asp Tyr Ser Val Ser Asn Ala Gln Val Lys Ala Asp Gly His 165 170 175Lys Val Tyr Gly Ala Ile Leu Val Ala Val Glu Arg Leu Leu Lys Met 180 185 190Lys Ala Gln Ala Ala Glu Pro Asn Arg Gly Gly Pro Gly Gly Arg Gly 195 200 205Cys Arg Arg Leu Asp Asp Leu Pro Trp Asp Ser Leu Leu Phe Gln Glu 210 215 220Ser Ser Ser Gly Gly Gly Ala Glu Pro Ser Phe Gly Ser Gly Leu Pro225 230 235 240Leu Pro Pro Gly Gly Ala Gly Pro Glu Asp Pro Ser Leu Ser Val Thr 245 250 255Leu Ala Asp Ile Tyr Arg Glu Leu Tyr Ala Phe Phe Gly Asp Ser Leu 260 265 270Ala Thr Arg Phe Gly Thr Gly Gln Pro Ala Pro Thr Ala Pro Arg Pro 275 280 285Pro Gly Asp Lys Lys Glu Pro Ala Ala Ala Pro Asp Ser Val Arg Lys 290 295 300Met Pro Gln Leu Thr Ala Ser Ala Ile Val Ser Pro His Gly Asp Glu305 310 315 320Ser Pro Arg Gly Ser Gly Gly Gly Gly Pro Ala Ser Ala Ser Gly Pro 325 330 335Ala Ala Ser Glu Ser Arg Pro Leu Pro Arg Val His Arg Ala Arg Gly 340 345 350Ala Pro Arg Gln Gln Gly Pro Gly 355 36011421DNAArtificial sequencePrimer 114agacatgagt gaaagccagg a 2111521DNAArtificial sequencePrimer 115cataaggcaa ctgaagggac a 21116302PRTHomo sapiens 116Met Ser Glu Ser Gln Asp Glu Val Pro Asp Glu Val Glu Asn Gln Phe1 5 10 15Ile Leu Arg Leu Pro Leu Glu His Ala Cys Thr Val Arg Asn Leu Ala 20 25 30Arg Ser Gln Ser Val Lys Met Lys Asp Lys Leu Lys Ile Asp Leu Leu 35 40 45Pro Asp Gly Arg His Ala Val Val Glu Val Glu Asp Val Pro Leu Ala 50 55 60Ala Lys Leu Val Asp Leu Pro Cys Val Ile Glu Ser Leu Arg Thr Leu65 70 75 80Asp Lys Lys Thr Phe Tyr Lys Thr Ala Asp Ile Ser Gln Met Leu Val 85 90 95Cys Thr Ala Asp Gly Asp Ile His Leu Ser Pro Glu Glu Pro Ala Ala 100 105 110Ser Thr Asp Pro Asn Ile Val Arg Lys Lys Glu Arg Gly Arg Glu Glu 115 120 125Lys Cys Val Trp Lys His Gly Ile Thr Pro Pro Leu Lys Asn Val Arg 130 135 140Lys Lys Arg Phe Arg Lys Thr Gln Lys Lys Val Pro Asp Val Lys Glu145 150 155 160Met Glu Lys Ser Ser Phe Thr Glu Tyr Ile Glu Ser Pro Asp Val Glu 165 170 175Asn Glu Val Lys Arg Leu Leu Arg Ser Asp Ala Glu Ala Val Ser Thr 180 185 190Arg Trp Glu Val Ile Ala Glu Asp Gly Thr Lys Glu Ile Glu Ser Gln 195 200 205Gly Ser Ile Pro Gly Phe Leu Ile Ser Ser Gly Met Ser Ser His Lys 210 215 220Gln Gly His Thr Ser Ser Val Met Glu Ile Gln Lys Gln Ile Glu Lys225 230 235 240Lys Glu Lys Lys Leu His Lys Ile Gln Asn Lys Ala Gln Arg Gln Lys 245 250 255Asp Leu Ile Met Lys Val Glu Asn Leu Thr Leu Lys Asn His Phe Gln 260 265 270Ser Val Leu Glu Gln Leu Glu Leu Gln Glu Lys Gln Lys Asn Glu Lys 275 280 285Leu Ile Ser Leu Gln Glu Gln Leu Gln Arg Phe Leu Lys Lys 290 295 300117376PRTHomo sapiens 117Met Ser Glu Ser Gln Asp Glu Val Pro Asp Glu Val Glu Asn Gln Phe1 5 10 15Ile Leu Arg Leu Pro Leu Glu His Ala Cys Thr Val Arg Asn Leu Ala 20 25 30Arg Ser Gln Ser Val Lys Met Lys Asp Lys Leu Lys Ile Asp Leu Leu 35 40 45Pro Asp Gly Arg His Ala Val Val Glu Val Glu Asp Val Pro Leu Ala 50 55 60Ala Lys Leu Val Asp Leu Pro Cys Val Ile Glu Ser Leu Arg Thr Leu65 70 75 80Asp Lys Lys Thr Phe Tyr Lys Thr Ala Asp Ile Ser Gln Met Leu Val 85 90 95Cys Thr Ala Asp Gly Asp Ile His Leu Ser Pro Glu Glu Pro Ala Ala 100 105 110Ser Thr Asp Pro Asn Ile Val Arg Lys Lys Glu Arg Gly Arg Glu Glu 115 120 125Lys Cys Val Trp Lys His Gly Ile Thr Pro Pro Leu Lys Asn Val Arg 130 135 140Lys Lys Arg Phe Arg Lys Thr Gln Lys Lys Val Pro Asp Val Lys Glu145 150 155 160Met Glu Lys Ser Ser Phe Thr Glu Tyr Ile Glu Ser Pro Asp Val Glu 165 170 175Asn Glu Val Lys Arg Leu Leu Arg Ser Asp Ala Glu Ala Val Ser Thr 180 185 190Arg Trp Glu Val Ile Ala Glu Asp Gly Thr Lys Glu Ile Glu Ser Gln 195 200 205Gly Ser Ile Pro Gly Phe Leu Ile Ser Ser Gly Met Ser Ser His Lys 210 215 220Gln Gly His Thr Ser Ser Glu Tyr Asp Met Leu Arg Glu Met Phe Ser225 230 235 240Asp Ser Arg Ser Asn Asn Asp Asp Asp Glu Asp Glu Asp Asp Glu Asp 245 250 255Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Lys Glu Glu Glu 260 265 270Glu Glu Asp Cys Ser Glu Glu Tyr Leu Glu Arg Gln Leu Gln Ala Glu 275 280 285Phe Ile Glu Ser Gly Gln Tyr Arg Ala Asn Glu Gly Thr Ser Ser Ile 290 295 300Val Met Glu Ile Gln Lys Gln Ile Glu Lys Lys Glu Lys Lys Leu His305 310 315 320Lys Ile Gln Asn Lys Ala Gln Arg Gln Lys Asp Leu Ile Met Lys Val 325 330 335Glu Asn Leu Thr Leu Lys Asn His Phe Gln Ser Val Leu Glu Gln Leu 340 345 350Glu Leu Gln Glu Lys Gln Lys Asn Glu Lys Leu Ile Ser Leu Gln Glu 355 360 365Gln Leu Gln Arg Phe Leu Lys Lys 370 37511821DNAArtificial sequencePrimer 118cactacgcca gaacaagatg g 2111921DNAArtificial sequencePrimer 119gtttgcttcc gtgtgtgtct t 21120214PRTHomo sapiens 120Met Ala Asp Ala Ala Ala Thr Ala Gly Ala Gly Gly Ser Gly Thr Arg1 5 10 15Ser Gly Ser Lys Gln Ser Thr Asn Pro Ala Asp Asn Tyr His Leu Ala 20 25 30Arg Arg Arg Thr Leu Gln Val Val Val Ser Ser Leu Leu Thr Glu Ala 35 40 45Gly Phe Glu Ser Ala Glu Lys Ala Ser Val Glu Thr Leu Thr Glu Met 50 55 60Leu Gln Ser Tyr Ile Ser Glu Ile Gly Arg Ser Ala Lys Ser Tyr Cys65 70 75 80Glu His Thr Ala Arg Thr Gln Pro Thr Leu Ser Asp Ile Val Val Thr 85 90 95Leu Val Glu Met Gly Phe Asn Val Asp Thr Leu Pro Ala Tyr Ala Lys 100 105 110Arg Ser Gln Arg Met Val Ile Thr Ala Pro Pro Val Thr Asn Gln Pro 115 120 125Val Thr Pro Lys Ala Leu Thr Ala Gly Gln Asn Arg Pro His Pro Pro 130 135 140His Ile Pro Ser His Phe Pro Glu Phe Pro Asp Pro His Thr Tyr Ile145 150 155 160Lys Thr Pro Glu Asp Ser Gly Ala Glu Lys Glu Asn Thr Ser Val Leu 165 170 175Gln Gln Asn Pro Ser Leu Ser Gly Ser Arg Asn Gly Glu Glu Asn Ile 180 185 190Ile Asp Asn Pro Tyr Leu Arg Pro Val Lys Lys Pro Lys Ile Arg Arg 195 200 205Lys Lys Pro Asp Thr Phe 210121338PRTHomo sapiens 121Met Ala Asp Ala Ala Ala Thr Ala Gly Ala Gly Gly Ser Gly Thr Arg1 5 10 15Ser Gly Ser Lys Gln Ser Thr Asn Pro Ala Asp Asn Tyr His Leu Ala 20 25 30Arg Arg Arg Thr Leu Gln Val Val Val Ser Ser Leu Leu Thr Glu Ala 35 40 45Gly Phe Glu Ser Ala Glu Lys Ala Ser Val Glu Thr Leu Thr Glu Met 50 55 60Leu Gln Ser Tyr Ile Ser Glu Ile Gly Arg Ser Ala Lys Ser Tyr Cys65 70 75 80Glu His Thr Ala Arg Thr Gln Pro Thr Leu Ser Asp Ile Val Val Thr 85 90 95Leu Val Glu Met Gly Phe Asn Val Asp Thr Leu Pro Ala Tyr Ala Lys 100 105 110Arg Ser Gln Arg Met Val Ile Thr Ala Pro Pro Val Thr Asn Gln Pro 115 120 125Val Thr Pro Lys Ala Leu Thr Ala Gly Gln Asn Arg Pro His Pro Pro 130 135 140His Ile Pro Ser His Phe Pro Glu Phe Pro Asp Pro His Thr Tyr Ile145 150 155 160Lys Thr Pro Thr Tyr Arg Glu Pro Val Ser Asp Tyr Gln Val Leu Arg 165 170 175Glu Lys Ala Ala Ser Gln Arg Arg Asp Val Glu Arg Ala Leu Thr Arg 180 185 190Phe Met Ala Lys Thr Gly Glu Thr Gln Ser Leu Phe Lys Asp Asp Val 195 200 205Ser Thr Phe Pro Leu Ile Ala Ala Arg Pro Phe Thr Ile Pro Tyr Leu 210 215 220Thr Ala Leu Leu Pro Ser Glu Leu Glu Met Gln Gln Met Glu Glu Thr225 230 235 240Asp Ser Ser Glu Gln Asp Glu Gln Thr Asp Thr Glu Asn Leu Ala Leu 245 250 255His Ile Ser Met Ile Glu Ser Arg Ser Val Thr Gln Ala Gly Val Gln 260 265 270Trp Gln Asp Leu Gly Ser Leu Gln Pro Pro Pro Pro Gly Phe Lys Arg 275 280 285Phe Ser Ser Leu Ser Leu Leu Ser Ser Trp Asn Tyr Arg Arg Ile Leu 290 295 300Glu Pro Arg Arg Arg Thr Pro Leu Ser Cys Ser Arg Thr Pro Pro Cys305 310 315 320Arg Val Ala Gly Met Gly Arg Arg Thr Ser Ser Ile Thr Leu Ile Cys 325 330 335Gly Arg12221DNAArtificial sequencePrimer 122ttgatgaccc tccttcagct a 2112321DNAArtificial sequencePrimer 123gcaaaactct ggcaatttca c 21124457PRTHomo sapiens 124Met Ser Asp Ser Gly Ser Tyr Gly Gln Ser Gly Gly Glu Gln Gln Ser1 5 10 15Tyr Ser Thr Tyr Gly Asn Pro Gly Ser Gln Gly Tyr Gly Gln Ala Ser 20 25 30Gln Ser Tyr Ser Gly Tyr Gly Gln Thr Thr Asp Ser Ser Tyr Gly Gln 35 40 45Asn Tyr Ser Gly Tyr Ser Ser Tyr Gly Gln Ser Gln Ser Gly Tyr Ser 50 55 60Gln Ser Tyr Gly Gly Tyr Glu Asn Gln Lys Gln Ser Ser Tyr Ser Gln65 70 75 80Gln Pro Tyr Asn Asn Gln Gly Gln Gln Gln Asn Met Glu Ser Ser Gly 85 90 95Ser Gln Gly Gly Arg Ala Pro Ser Tyr Asp

Gln Pro Asp Tyr Gly Gln 100 105 110Gln Asp Ser Tyr Asp Gln Gln Ser Gly Tyr Asp Gln His Gln Gly Ser 115 120 125Tyr Asp Glu Gln Ser Asn Tyr Asp Gln Gln His Asp Ser Tyr Ser Gln 130 135 140Asn Gln Gln Ser Tyr His Ser Gln Arg Glu Asn Tyr Ser His His Thr145 150 155 160Gln Asp Asp Arg Arg Asp Val Ser Arg Tyr Gly Glu Asp Asn Arg Gly 165 170 175Tyr Gly Gly Ser Gln Gly Gly Gly Arg Gly Arg Gly Gly Tyr Asp Lys 180 185 190Asp Gly Arg Gly Pro Met Thr Gly Ser Ser Gly Gly Asp Arg Gly Gly 195 200 205Phe Lys Asn Phe Gly Gly His Arg Asp Tyr Gly Pro Arg Thr Asp Ala 210 215 220Asp Ser Glu Ser Asp Asn Ser Asp Asn Asn Thr Ile Phe Val Gln Gly225 230 235 240Leu Gly Glu Gly Val Ser Thr Asp Gln Val Gly Glu Phe Phe Lys Gln 245 250 255Ile Gly Ile Ile Lys Thr Asn Lys Lys Thr Gly Lys Pro Met Ile Asn 260 265 270Leu Tyr Thr Asp Lys Asp Thr Gly Lys Pro Lys Gly Glu Ala Thr Val 275 280 285Ser Phe Asp Asp Pro Pro Ser Ala Lys Ala Ala Ile Asp Trp Phe Asp 290 295 300Gly Lys Glu Phe His Gly Asn Ile Ile Lys Val Ser Phe Ala Thr Arg305 310 315 320Arg Pro Glu Phe Met Arg Gly Gly Gly Ser Gly Gly Gly Arg Arg Gly 325 330 335Arg Gly Gly Tyr Arg Gly Arg Gly Gly Phe Gln Gly Arg Gly Gly Asp 340 345 350Pro Lys Ser Gly Asp Trp Val Cys Pro Asn Pro Ser Cys Gly Asn Met 355 360 365Asn Phe Ala Arg Arg Asn Ser Cys Asn Gln Cys Asn Glu Pro Arg Pro 370 375 380Glu Asp Ser Arg Pro Ser Gly Gly Glu Thr Thr Thr Glu Met Ile Ser385 390 395 400Ala Thr Asp His Thr Asp Asp Cys Phe Glu Cys Ser Phe Val Ser Asp 405 410 415Met Ile His Ser Glu Ile Ala Arg Val Leu Pro Ala Ala Phe Leu Val 420 425 430Ala Ser Ser Trp Val Val Lys Leu Ser Asp Ile Trp Ile Phe Ile Trp 435 440 445Val Gly Gly Leu Gly Gln Phe Phe Phe 450 455125592PRTHomo sapiens 125Met Ser Asp Ser Gly Ser Tyr Gly Gln Ser Gly Gly Glu Gln Gln Ser1 5 10 15Tyr Ser Thr Tyr Gly Asn Pro Gly Ser Gln Gly Tyr Gly Gln Ala Ser 20 25 30Gln Ser Tyr Ser Gly Tyr Gly Gln Thr Thr Asp Ser Ser Tyr Gly Gln 35 40 45Asn Tyr Ser Gly Tyr Ser Ser Tyr Gly Gln Ser Gln Ser Gly Tyr Ser 50 55 60Gln Ser Tyr Gly Gly Tyr Glu Asn Gln Lys Gln Ser Ser Tyr Ser Gln65 70 75 80Gln Pro Tyr Asn Asn Gln Gly Gln Gln Gln Asn Met Glu Ser Ser Gly 85 90 95Ser Gln Gly Gly Arg Ala Pro Ser Tyr Asp Gln Pro Asp Tyr Gly Gln 100 105 110Gln Asp Ser Tyr Asp Gln Gln Ser Gly Tyr Asp Gln His Gln Gly Ser 115 120 125Tyr Asp Glu Gln Ser Asn Tyr Asp Gln Gln His Asp Ser Tyr Ser Gln 130 135 140Asn Gln Gln Ser Tyr His Ser Gln Arg Glu Asn Tyr Ser His His Thr145 150 155 160Gln Asp Asp Arg Arg Asp Val Ser Arg Tyr Gly Glu Asp Asn Arg Gly 165 170 175Tyr Gly Gly Ser Gln Gly Gly Gly Arg Gly Arg Gly Gly Tyr Asp Lys 180 185 190Asp Gly Arg Gly Pro Met Thr Gly Ser Ser Gly Gly Asp Arg Gly Gly 195 200 205Phe Lys Asn Phe Gly Gly His Arg Asp Tyr Gly Pro Arg Thr Asp Ala 210 215 220Asp Ser Glu Ser Asp Asn Ser Asp Asn Asn Thr Ile Phe Val Gln Gly225 230 235 240Leu Gly Glu Gly Val Ser Thr Asp Gln Val Gly Glu Phe Phe Lys Gln 245 250 255Ile Gly Ile Ile Lys Thr Asn Lys Lys Thr Gly Lys Pro Met Ile Asn 260 265 270Leu Tyr Thr Asp Lys Asp Thr Gly Lys Pro Lys Gly Glu Ala Thr Val 275 280 285Ser Phe Asp Asp Pro Pro Ser Ala Lys Ala Ala Ile Asp Trp Phe Asp 290 295 300Gly Lys Glu Phe His Gly Asn Ile Ile Lys Val Ser Phe Ala Thr Arg305 310 315 320Arg Pro Glu Phe Met Arg Gly Gly Gly Ser Gly Gly Gly Arg Arg Gly 325 330 335Arg Gly Gly Tyr Arg Gly Arg Gly Gly Phe Gln Gly Arg Gly Gly Asp 340 345 350Pro Lys Ser Gly Asp Trp Val Cys Pro Asn Pro Ser Cys Gly Asn Met 355 360 365Asn Phe Ala Arg Arg Asn Ser Cys Asn Gln Cys Asn Glu Pro Arg Pro 370 375 380Glu Asp Ser Arg Pro Ser Gly Gly Asp Phe Arg Gly Arg Gly Tyr Gly385 390 395 400Gly Glu Arg Gly Tyr Arg Gly Arg Gly Gly Arg Gly Gly Asp Arg Gly 405 410 415Gly Tyr Gly Gly Asp Arg Ser Gly Gly Gly Tyr Gly Gly Asp Arg Ser 420 425 430Ser Gly Gly Gly Tyr Ser Gly Asp Arg Ser Gly Gly Gly Tyr Gly Gly 435 440 445Asp Arg Ser Gly Gly Gly Tyr Gly Gly Asp Arg Gly Gly Gly Tyr Gly 450 455 460Gly Asp Arg Gly Gly Gly Tyr Gly Gly Asp Arg Gly Gly Gly Tyr Gly465 470 475 480Gly Asp Arg Gly Gly Tyr Gly Gly Asp Arg Gly Gly Gly Tyr Gly Gly 485 490 495Asp Arg Gly Gly Tyr Gly Gly Asp Arg Gly Gly Tyr Gly Gly Asp Arg 500 505 510Gly Gly Tyr Gly Gly Asp Arg Gly Gly Tyr Gly Gly Asp Arg Ser Arg 515 520 525Gly Gly Tyr Gly Gly Asp Arg Gly Gly Gly Ser Gly Tyr Gly Gly Asp 530 535 540Arg Ser Gly Gly Tyr Gly Gly Asp Arg Ser Gly Gly Gly Tyr Gly Gly545 550 555 560Asp Arg Gly Gly Gly Tyr Gly Gly Asp Arg Gly Gly Tyr Gly Gly Lys 565 570 575Met Gly Gly Arg Asn Asp Tyr Arg Asn Asp Gln Arg Asn Arg Pro Tyr 580 585 59012619DNAArtificial sequencePrimer 126gaaaatggct gcgtcttcg 1912721DNAArtificial sequencePrimer 127ctcatctcta aatcagttgg g 21128136PRTHomo sapiens 128Met Leu Ala Ile Ser Arg Asn Gln Lys Leu Leu Gln Ala Gly Glu Glu1 5 10 15Asn Gln Val Leu Glu Leu Leu Ile His Arg Asp Gly Glu Phe Gln Glu 20 25 30Leu Met Lys Leu Ala Leu Asn Gln Gly Lys Ile His His Glu Met Gln 35 40 45Val Leu Glu Lys Glu Val Glu Lys Arg Asp Ser Asp Ile Gln Gln Leu 50 55 60Gln Lys Gln Leu Lys Glu Ala Glu Gln Ile Leu Ala Thr Ala Val Tyr65 70 75 80Gln Ala Lys Glu Lys Leu Lys Ser Ile Glu Lys Ala Arg Lys Gly Ala 85 90 95Ile Ser Ser Glu Glu Ile Ile Lys Tyr Ala His Arg Ile Ser Ala Ser 100 105 110Asn Ala Val Cys Ala Pro Leu Thr Trp Val Pro Gly Asp Pro Arg Arg 115 120 125Pro Tyr Pro Thr Asp Leu Glu Met 130 135129270PRTHomo sapiens 129Met Ala Ala Ser Ser Ser Gly Glu Lys Glu Lys Glu Arg Leu Gly Gly1 5 10 15Gly Leu Gly Val Ala Gly Gly Asn Ser Thr Arg Glu Arg Leu Leu Ser 20 25 30Ala Leu Glu Asp Leu Glu Val Leu Ser Arg Glu Leu Ile Glu Met Leu 35 40 45Ala Ile Ser Arg Asn Gln Lys Leu Leu Gln Ala Gly Glu Glu Asn Gln 50 55 60Val Leu Glu Leu Leu Ile His Arg Asp Gly Glu Phe Gln Glu Leu Met65 70 75 80Lys Leu Ala Leu Asn Gln Gly Lys Ile His His Glu Met Gln Val Leu 85 90 95Glu Lys Glu Val Glu Lys Arg Asp Ser Asp Ile Gln Gln Leu Gln Lys 100 105 110Gln Leu Lys Glu Ala Glu Gln Ile Leu Ala Thr Ala Val Tyr Gln Ala 115 120 125Lys Glu Lys Leu Lys Ser Ile Glu Lys Ala Arg Lys Gly Ala Ile Ser 130 135 140Ser Glu Glu Ile Ile Lys Tyr Ala His Arg Ile Ser Ala Ser Asn Ala145 150 155 160Val Cys Ala Pro Leu Thr Trp Val Pro Gly Asp Pro Arg Arg Pro Tyr 165 170 175Pro Thr Asp Leu Glu Met Arg Ser Gly Leu Leu Gly Gln Met Asn Asn 180 185 190Pro Ser Thr Asn Gly Val Asn Gly His Leu Pro Gly Asp Ala Leu Ala 195 200 205Ala Gly Arg Leu Pro Asp Val Leu Ala Pro Gln Tyr Pro Trp Gln Ser 210 215 220Asn Asp Met Ser Met Asn Met Leu Pro Pro Asn His Ser Ser Asp Phe225 230 235 240Leu Leu Glu Pro Pro Gly His Asn Lys Glu Asn Glu Asp Asp Val Glu 245 250 255Ile Met Ser Thr Asp Ser Ser Ser Ser Ser Ser Glu Ser Asp 260 265 27013019DNAArtificial sequencePrimer 130caaatggctc aggcaggtc 1913122DNAArtificial sequencePrimer 131tgtagacaat catgaagcca cg 22132164PRTHomo sapiens 132Met Arg Gln Thr Glu Gly Arg Val Pro Val Phe Ser His Glu Val Val1 5 10 15Pro Asp His Leu Arg Thr Lys Pro Asp Pro Glu Val Glu Glu Gln Glu 20 25 30Lys Gln Leu Thr Thr Asp Ala Ala Arg Ile Gly Ala Asp Ala Ala Gln 35 40 45Lys Gln Ile Gln Ser Leu Asn Lys Met Cys Ser Asn Leu Leu Glu Lys 50 55 60Ile Ser Lys Glu Glu Arg Glu Ser Glu Ser Gly Gly Leu Arg Pro Asn65 70 75 80Lys Gln Thr Phe Asn Pro Thr Asp Thr Asn Ala Leu Val Ala Ala Val 85 90 95Ala Phe Gly Lys Gly Leu Ser Asn Trp Arg Pro Ser Gly Ser Ser Gly 100 105 110Pro Gly Gln Ala Gly Gln Pro Gly Ala Gly Thr Ile Leu Ala Gly Thr 115 120 125Ser Gly Leu Gln Gln Val Gln Met Ala Gly Ala Pro Ser Gln Gln Gln 130 135 140Pro Met Leu Ser Gly Val Gln Met Ala Gln Ala Gly Gln Pro Gly Lys145 150 155 160Cys Gln Val Glu133179PRTHomo sapiens 133Met Arg Gln Thr Glu Gly Arg Val Pro Val Phe Ser His Glu Val Val1 5 10 15Pro Asp His Leu Arg Thr Lys Pro Asp Pro Glu Val Glu Glu Gln Glu 20 25 30Lys Gln Leu Thr Thr Asp Ala Ala Arg Ile Gly Ala Asp Ala Ala Gln 35 40 45Lys Gln Ile Gln Ser Leu Asn Lys Met Cys Ser Asn Leu Leu Glu Lys 50 55 60Ile Ser Lys Glu Glu Arg Glu Ser Glu Ser Gly Gly Leu Arg Pro Asn65 70 75 80Lys Gln Thr Phe Asn Pro Thr Asp Thr Asn Ala Leu Val Ala Ala Val 85 90 95Ala Phe Gly Lys Gly Leu Ser Asn Trp Arg Pro Ser Gly Ser Ser Gly 100 105 110Pro Gly Gln Ala Gly Gln Pro Gly Ala Gly Thr Ile Leu Ala Gly Thr 115 120 125Ser Gly Leu Gln Gln Val Gln Met Ala Gly Ala Pro Ser Gln Gln Gln 130 135 140Pro Met Leu Ser Gly Val Gln Met Ala Gln Ala Gly Gln Pro Gly Lys145 150 155 160Met Pro Ser Gly Ile Lys Thr Asn Ile Lys Ser Ala Ser Met His Pro 165 170 175Tyr Gln Arg13421DNAArtificial sequencePrimer 134tcaggatgct cgaagaaggt c 2113521DNAArtificial sequencePrimer 135cagacacttg aggagatcct g 21136112PRTHomo sapiens 136Met Asn Met Phe Val Asp Ser Asn Gln Asp Ala Arg Arg Arg Ser Val1 5 10 15Asn Glu Asp Asp Asn Pro Pro Ser Pro Ile Gly Gly Asp Met Met Asp 20 25 30Ser Leu Ile Ser Gln Leu Gln Pro Pro Pro Gln Gln Gln Pro Phe Pro 35 40 45Lys Gln Pro Gly Thr Ser Gly Ala Tyr Pro Leu Thr Ser Pro Pro Thr 50 55 60Ser Tyr His Ser Thr Val Asn Gln Ser Pro Ser Met Met His Thr Gln65 70 75 80Ser Pro Gly Thr Leu Asp Pro Ser Ser Pro Tyr Thr Met Val Ser Pro 85 90 95Ser Gly Arg Ala Gly Asn Trp Pro Gly Ser Pro Gln Val Ser Gly Pro 100 105 110137462PRTHomo sapiens 137Leu Glu Phe Ala Arg Ser Leu Pro Asp Ile Pro Ala His Leu Asn Ile1 5 10 15Phe Ser Glu Val Arg Val Tyr Asn Tyr Arg Lys Leu Ile Leu Cys Tyr 20 25 30Gly Thr Thr Lys Gly Ser Ser Ile Ser Ile Gln Trp Asn Ser Ile His 35 40 45Gln Lys Phe His Ile Ser Leu Gly Thr Val Gly Pro Asn Ser Gly Cys 50 55 60Ser Asn Cys His Asn Thr Ile Leu His Gln Leu Gln Glu Met Phe Asn65 70 75 80Lys Thr Pro Asn Val Val Gln Leu Leu Gln Val Leu Phe Asp Thr Gln 85 90 95Ala Pro Leu Asn Ala Ile Asn Lys Leu Pro Thr Val Pro Met Leu Gly 100 105 110Leu Thr Gln Arg Thr Asn Thr Ala Tyr Gln Cys Phe Ser Ile Leu Pro 115 120 125Gln Ser Ser Thr His Ile Arg Leu Ala Phe Arg Asn Met Tyr Cys Ile 130 135 140Asp Ile Tyr Cys Arg Ser Arg Gly Val Val Ala Ile Arg Asp Gly Ala145 150 155 160Tyr Ser Leu Phe Asp Asn Ser Lys Leu Val Glu Gly Phe Tyr Pro Ala 165 170 175Pro Gly Leu Lys Thr Phe Leu Asn Met Phe Val Asp Ser Asn Gln Asp 180 185 190Ala Arg Arg Arg Ser Val Asn Glu Asp Asp Asn Pro Pro Ser Pro Ile 195 200 205Gly Gly Asp Met Met Asp Ser Leu Ile Ser Gln Leu Gln Pro Pro Pro 210 215 220Gln Gln Gln Pro Phe Pro Lys Gln Pro Gly Thr Ser Gly Ala Tyr Pro225 230 235 240Leu Thr Ser Pro Pro Thr Ser Tyr His Ser Thr Val Asn Gln Ser Pro 245 250 255Ser Met Met His Thr Gln Ser Pro Gly Asn Leu His Ala Ala Ser Ser 260 265 270Pro Ser Gly Ala Leu Arg Ala Pro Ser Pro Ala Ser Phe Val Pro Thr 275 280 285Pro Pro Pro Ser Ser His Gly Ile Ser Ile Gly Pro Gly Ala Ser Phe 290 295 300Ala Ser Pro His Gly Thr Leu Asp Pro Ser Ser Pro Tyr Thr Met Val305 310 315 320Ser Pro Ser Gly Arg Ala Gly Asn Trp Pro Gly Ser Pro Gln Val Ser 325 330 335Gly Pro Ser Pro Ala Ala Arg Met Pro Gly Met Ser Pro Ala Asn Pro 340 345 350Ser Leu His Ser Pro Val Pro Asp Ala Ser His Ser Pro Arg Ala Gly 355 360 365Thr Ser Ser Gln Thr Met Pro Thr Asn Met Pro Pro Pro Arg Lys Leu 370 375 380Pro Gln Arg Ser Trp Ala Ala Ser Ile Pro Thr Ile Leu Thr His Ser385 390 395 400Ala Leu Asn Ile Leu Leu Leu Pro Ser Pro Thr Pro Gly Leu Val Pro 405 410 415Gly Leu Ala Gly Ser Tyr Leu Cys Ser Pro Leu Glu Arg Phe Leu Gly 420 425 430Ser Val Ile Met Arg Arg His Leu Gln Arg Ile Ile Gln Gln Glu Thr 435 440 445Leu Gln Leu Ile Asn Ser Asn Glu Pro Gly Val Ile Met Phe 450 455 46013819DNAArtificial sequencePrimer 138gctctgccga tcgacttcc 1913920DNAArtificial sequencePrimer 139aggcgatcag cagtgtccac 20140217PRTHomo sapiens 140Met Pro Arg Lys Ser Asp Val Glu Arg Lys Ile Glu Ile Val Gln Phe1 5 10 15Ala Ser Arg Thr Arg Gln Leu Phe Val Arg Leu Leu Ala Leu Val Lys 20 25 30Trp Ala Asn Asn Ala Gly Lys Val Glu Lys Cys Ala Met Ile Ser Ser 35 40 45Phe Leu Asp Gln Gln Ala Ile Leu Phe Val Asp Thr Ala Asp Arg Leu 50 55 60Ala Ser

Leu Ala Arg Asp Ala Leu Val His Ala Arg Leu Pro Ser Phe65 70 75 80Ala Ile Pro Tyr Ala Ile Asp Val Leu Thr Thr Gly Ser Tyr Pro Arg 85 90 95Leu Pro Thr Cys Ile Arg Asp Lys Ile Ile Pro Pro Asp Pro Ile Thr 100 105 110Lys Ile Glu Lys Gln Ala Thr Leu His Gln Leu Asn Gln Ile Leu Arg 115 120 125His Arg Leu Val Thr Thr Asp Leu Pro Pro Gln Leu Ala Asn Leu Thr 130 135 140Val Ala Asn Gly Arg Val Lys Phe Arg Val Glu Gly Glu Phe Glu Ala145 150 155 160Thr Leu Thr Val Met Gly Asp Asp Pro Asp Val Pro Trp Arg Leu Leu 165 170 175Lys Leu Glu Ile Leu Val Glu Asp Lys Glu Thr Gly Asp Gly Arg Ala 180 185 190Leu Val His Ser Met Gln Ile Ser Phe Ile His Gln Leu Val Gln Ser 195 200 205Arg Leu Phe Ala Asp Glu Lys Pro Leu 210 215141420PRTHomo sapiens 141Met Ala Pro Val Gln Leu Glu Asn His Gln Leu Val Pro Pro Gly Gly1 5 10 15Gly Gly Gly Gly Ser Gly Gly Pro Pro Ser Ala Pro Ala Pro Pro Pro 20 25 30Pro Gly Ala Ala Val Ala Ala Ala Ala Ala Ala Ala Ala Ser Pro Gly 35 40 45Tyr Arg Leu Ser Thr Leu Ile Glu Phe Leu Leu His Arg Ala Tyr Ser 50 55 60Glu Leu Met Val Leu Thr Asp Leu Leu Pro Arg Lys Ser Asp Val Glu65 70 75 80Arg Lys Ile Glu Ile Val Gln Phe Ala Ser Arg Thr Arg Gln Leu Phe 85 90 95Val Arg Leu Leu Ala Leu Val Lys Trp Ala Asn Asn Ala Gly Lys Val 100 105 110Glu Lys Cys Ala Met Ile Ser Ser Phe Leu Asp Gln Gln Ala Ile Leu 115 120 125Phe Val Asp Thr Ala Asp Arg Leu Ala Ser Leu Ala Arg Asp Ala Leu 130 135 140Val His Ala Arg Leu Pro Ser Phe Ala Ile Pro Tyr Ala Ile Asp Val145 150 155 160Leu Thr Thr Gly Ser Tyr Pro Arg Leu Pro Thr Cys Ile Arg Asp Lys 165 170 175Ile Ile Pro Pro Asp Pro Ile Thr Lys Ile Glu Lys Gln Ala Thr Leu 180 185 190His Gln Leu Asn Gln Ile Leu Arg His Arg Leu Val Thr Thr Asp Leu 195 200 205Pro Pro Gln Leu Ala Asn Leu Thr Val Ala Asn Gly Arg Val Lys Phe 210 215 220Arg Val Glu Gly Glu Phe Glu Ala Thr Leu Thr Val Met Gly Asp Asp225 230 235 240Pro Asp Val Pro Trp Arg Leu Leu Lys Leu Glu Ile Leu Val Glu Asp 245 250 255Lys Glu Thr Gly Asp Gly Arg Ala Leu Val His Ser Met Gln Ile Ser 260 265 270Phe Ile His Gln Leu Val Gln Ser Arg Leu Phe Ala Asp Glu Lys Pro 275 280 285Leu Gln Asp Met Tyr Asn Cys Leu His Ser Phe Cys Leu Ser Leu Gln 290 295 300Leu Glu Val Leu His Ser Gln Thr Leu Met Leu Ile Arg Glu Arg Trp305 310 315 320Gly Asp Leu Val Gln Val Glu Arg Tyr His Ala Gly Lys Cys Leu Ser 325 330 335Leu Ser Val Trp Asn Gln Gln Val Leu Gly Arg Lys Thr Gly Thr Ala 340 345 350Ser Val His Lys Val Thr Ile Lys Ile Asp Glu Asn Asp Val Ser Lys 355 360 365Pro Leu Gln Ile Phe His Asp Pro Pro Leu Pro Ala Ser Asp Ser Lys 370 375 380Leu Val Glu Arg Ala Met Lys Ile Asp His Leu Ser Ile Glu Lys Leu385 390 395 400Leu Ile Asp Ser Val His Ala Arg Ala His Gln Lys Leu Gln Glu Leu 405 410 415Lys Ala Ile Leu 42014221DNAArtificial sequencePrimer 142tggatgtaag atgagattgg g 2114319DNAArtificial sequencePrimer 143aatgagcctg gccacgaga 1914490PRTHomo sapiens 144Met Arg Lys Ala Gly Val Ala His Ser Lys Ser Ser Lys Asp Met Glu1 5 10 15Ser His Val Phe Leu Lys Ala Lys Thr Arg Asp Glu Tyr Leu Ser Leu 20 25 30Val Ala Arg Leu Ile Ile His Phe Arg Asp Ile His Asn Lys Lys Ser 35 40 45Gln Ala Ser Val Ser Asp Pro Met Asn Ala Leu Gln Ser Leu Thr Gly 50 55 60Gly Pro Ala Ala Gly Ala Ala Gly Ile Gly Met Pro Pro Arg Gly Pro65 70 75 80Gly Gln Ser Leu Gly Gly Met Gly Ser Leu 85 90145180PRTHomo sapiens 145Met Asp Val Ser Gly Gln Glu Thr Asp Trp Arg Ser Thr Ala Phe Arg1 5 10 15Gln Lys Leu Val Ser Gln Ile Glu Asp Ala Met Arg Lys Ala Gly Val 20 25 30Ala His Ser Lys Ser Ser Lys Asp Met Glu Ser His Val Phe Leu Lys 35 40 45Ala Lys Thr Arg Asp Glu Tyr Leu Ser Leu Val Ala Arg Leu Ile Ile 50 55 60His Phe Arg Asp Ile His Asn Lys Lys Ser Gln Ala Ser Val Ser Asp65 70 75 80Pro Met Asn Ala Leu Gln Ser Leu Thr Gly Gly Pro Ala Ala Gly Ala 85 90 95Ala Gly Ile Gly Met Pro Pro Arg Gly Pro Gly Gln Ser Leu Gly Gly 100 105 110Met Gly Ser Leu Gly Ala Met Gly Gln Pro Met Ser Leu Ser Gly Gln 115 120 125Pro Pro Pro Gly Thr Ser Gly Met Ala Pro His Ser Met Ala Val Val 130 135 140Ser Thr Ala Thr Pro Gln Thr Gln Leu Gln Leu Gln Gln Val Ala Leu145 150 155 160Gln Gln Gln Gln Gln Gln Gln Gln Phe Gln Gln Gln Gln Gln Ala Ala 165 170 175Leu Gln Gln Gln 18014622DNAArtificial sequencePrimer 146cacgaatctg atcacacact ac 2214719DNAArtificial sequencePrimer 147ctgggtggtc tggactatg 19148244PRTHomo sapiens 148Met Glu Asn Phe Thr Ala Leu Phe Gly Ala Gln Ala Asp Pro Pro Pro1 5 10 15Pro Pro Thr Ala Leu Gly Phe Gly Pro Gly Lys Pro Pro Pro Pro Pro 20 25 30Pro Pro Pro Ala Gly Gly Gly Pro Gly Thr Ala Pro Pro Pro Thr Ala 35 40 45Ala Thr Ala Pro Pro Gly Ala Asp Lys Ser Gly Ala Gly Cys Gly Pro 50 55 60Phe Tyr Leu Met Arg Glu Leu Pro Gly Ser Thr Glu Leu Thr Gly Ser65 70 75 80Thr Asn Leu Ile Thr His Tyr Asn Leu Glu Gln Ala Tyr Asn Lys Phe 85 90 95Cys Gly Lys Lys Val Lys Glu Lys Leu Ser Asn Phe Leu Pro Asp Leu 100 105 110Pro Gly Met Ile Asp Leu Pro Gly Ser His Asp Asn Ser Ser Leu Arg 115 120 125Ser Leu Ile Glu Lys Pro Pro Ile Leu Ser Ser Ser Phe Asn Pro Ile 130 135 140Thr Gly Thr Met Leu Ala Gly Phe Arg Leu His Thr Gly Pro Leu Pro145 150 155 160Glu Gln Cys Arg Leu Met His Ile Gln Pro Pro Lys Lys Lys Asn Lys 165 170 175His Lys His Lys Gln Ser Arg Thr Gln Asp Pro Val Pro Pro Glu Thr 180 185 190Pro Ser Asp Ser Asp His Lys Lys Lys Lys Lys Lys Lys Glu Glu Asp 195 200 205Pro Glu Arg Lys Arg Lys Lys Lys Glu Lys Lys Lys Lys Lys Asn Arg 210 215 220His Ser Pro Asp His Pro Gly Met Gly Ser Ser Gln Ala Ser Ser Ser225 230 235 240Ser Ser Leu Arg14974PRTHomo sapiens 149Ser His Asp Asn Ser Ser Leu Arg Ser Leu Ile Glu Lys Pro Pro Ile1 5 10 15Leu Ser Ser Ser Phe Asn Pro Ile Thr Gly Thr Met Leu Ala Gly Phe 20 25 30Arg Leu His Thr Gly Pro Leu Pro Glu Gln Cys Arg Leu Met His Ile 35 40 45Gln Pro Pro Lys Lys Lys Asn Lys His Lys His Lys Gln Ser Arg Thr 50 55 60Gln Asp Pro Val Pro Pro Gly Lys Pro Ser65 70150124PRTHomo sapiens 150Ser His Asp Asn Ser Ser Leu Arg Ser Leu Ile Glu Lys Pro Pro Ile1 5 10 15Leu Ser Ser Ser Phe Asn Pro Ile Thr Gly Thr Met Leu Ala Gly Phe 20 25 30Arg Leu His Thr Gly Pro Leu Pro Glu Gln Cys Arg Leu Met His Ile 35 40 45Gln Pro Pro Lys Lys Lys Asn Lys His Lys His Lys Gln Ser Arg Thr 50 55 60Gln Asp Pro Val Pro Pro Glu Thr Pro Ser Asp Ser Asp His Lys Lys65 70 75 80Lys Lys Lys Lys Lys Glu Glu Asp Pro Glu Arg Lys Arg Lys Lys Lys 85 90 95Glu Lys Lys Lys Lys Lys Asn Arg His Ser Pro Asp His Pro Gly Met 100 105 110Gly Ser Ser Gln Ala Ser Ser Ser Ser Ser Leu Arg 115 12015120DNAArtificial sequencePrimer 151cgttactaga gcaggccatg 2015221DNAArtificial sequencePrimer 152taccctcggg agactcaatg a 21153268PRTHomo sapiens 153Met Ile Gly Pro Ser Pro Asn Pro Leu Ile Leu Ser Tyr Leu Lys Tyr1 5 10 15Ala Ile Ser Ser Gln Met Val Ser Tyr Ser Ser Val Leu Thr Ala Ile 20 25 30Ser Lys Phe Asp Asp Phe Ser Arg Asp Leu Cys Val Gln Ala Leu Leu 35 40 45Asp Ile Met Asp Met Phe Cys Asp Arg Leu Ser Cys His Gly Lys Ala 50 55 60Glu Glu Cys Ile Gly Leu Cys Arg Ala Leu Leu Ser Ala Leu His Trp65 70 75 80Leu Leu Arg Cys Thr Ala Ala Ser Ala Glu Arg Leu Arg Glu Gly Leu 85 90 95Glu Ala Gly Thr Pro Ala Ala Gly Glu Lys Gln Leu Ala Met Cys Leu 100 105 110Gln Arg Leu Glu Lys Thr Leu Ser Ser Thr Lys Asn Arg Ala Leu Leu 115 120 125His Ile Ala Lys Leu Glu Glu Ala Ser Leu His Thr Ser Gln Gly Leu 130 135 140Gly Gln Gly Gly Thr Arg Ala Asn Gln Pro Thr Ala Ser Trp Thr Ala145 150 155 160Ile Glu His Ser Leu Leu Lys Leu Gly Glu Ile Leu Ala Asn Leu Ser 165 170 175Asn Pro Gln Leu Arg Ser Gln Ala Glu Gln Cys Gly Thr Leu Ile Arg 180 185 190Ser Ile Pro Thr Met Leu Ser Val His Ala Glu Gln Met His Lys Thr 195 200 205Gly Phe Pro Thr Val His Ala Val Ile Leu Leu Glu Gly Thr Met Asn 210 215 220Leu Thr Gly Glu Thr Gln Ser Leu Val Glu Gln Leu Thr Met Val Lys225 230 235 240Arg Met Gln His Ile Pro Thr Pro Leu Phe Val Leu Glu Ile Trp Lys 245 250 255Ala Cys Phe Val Gly Leu Ile Glu Ser Pro Glu Gly 260 265154341PRTHomo sapiens 154Met Lys Val Val Asn Leu Lys Gln Ala Ile Leu Gln Ala Trp Lys Glu1 5 10 15Arg Trp Ser Asp Tyr Gln Trp Ala Ile Asn Met Lys Lys Phe Phe Pro 20 25 30Lys Gly Ala Thr Trp Asp Ile Leu Asn Leu Ala Asp Ala Leu Leu Glu 35 40 45Gln Ala Met Ile Gly Pro Ser Pro Asn Pro Leu Ile Leu Ser Tyr Leu 50 55 60Lys Tyr Ala Ile Ser Ser Gln Met Val Ser Tyr Ser Ser Val Leu Thr65 70 75 80Ala Ile Ser Lys Phe Asp Asp Phe Ser Arg Asp Leu Cys Val Gln Ala 85 90 95Leu Leu Asp Ile Met Asp Met Phe Cys Asp Arg Leu Ser Cys His Gly 100 105 110Lys Ala Glu Glu Cys Ile Gly Leu Cys Arg Ala Leu Leu Ser Ala Leu 115 120 125His Trp Leu Leu Arg Cys Thr Ala Ala Ser Ala Glu Arg Leu Arg Glu 130 135 140Gly Leu Glu Ala Gly Thr Pro Ala Ala Gly Glu Lys Gln Leu Ala Met145 150 155 160Cys Leu Gln Arg Leu Glu Lys Thr Leu Ser Ser Thr Lys Asn Arg Ala 165 170 175Leu Leu His Ile Ala Lys Leu Glu Glu Ala Ser Ser Trp Thr Ala Ile 180 185 190Glu His Ser Leu Leu Lys Leu Gly Glu Ile Leu Ala Asn Leu Ser Asn 195 200 205Pro Gln Leu Arg Ser Gln Ala Glu Gln Cys Gly Thr Leu Ile Arg Ser 210 215 220Ile Pro Thr Met Leu Ser Val His Ala Glu Gln Met His Lys Thr Gly225 230 235 240Phe Pro Thr Val His Ala Val Ile Leu Leu Glu Gly Thr Met Asn Leu 245 250 255Thr Gly Glu Thr Gln Ser Leu Val Glu Gln Leu Thr Met Val Lys Arg 260 265 270Met Gln His Ile Pro Thr Pro Leu Phe Val Leu Glu Ile Trp Lys Ala 275 280 285Cys Phe Val Gly Leu Ile Glu Ser Pro Glu Gly Thr Glu Glu Leu Lys 290 295 300Trp Thr Ala Phe Thr Phe Leu Lys Ile Pro Gln Val Leu Val Lys Leu305 310 315 320Lys Lys Tyr Ser His Gly Asp Lys Asp Phe Thr Glu Asp Val Asn Cys 325 330 335Ala Phe Glu Phe Leu 34015521DNAArtificial sequencePrimer 155agatgactcg cttgctggat a 2115621DNAArtificial sequencePrimer 156aggttaattc cgagacctcc a 21157950PRTHomo sapiens 157Met Asp Pro Glu Tyr Glu Glu Lys Met Lys Ala Asp Arg Ala Lys Arg1 5 10 15Phe Glu Phe Leu Leu Lys Gln Thr Glu Leu Phe Ala His Phe Ile Gln 20 25 30Pro Ser Ala Gln Lys Ser Pro Thr Ser Pro Leu Asn Met Lys Leu Gly 35 40 45Arg Pro Arg Ile Lys Lys Asp Glu Lys Gln Ser Leu Ile Ser Ala Gly 50 55 60Asp Tyr Arg His Arg Arg Thr Glu Gln Glu Glu Asp Glu Glu Leu Leu65 70 75 80Ser Glu Ser Arg Lys Thr Ser Asn Val Cys Ile Arg Phe Glu Val Ser 85 90 95Pro Ser Tyr Val Lys Gly Gly Pro Leu Arg Asp Tyr Gln Ile Arg Gly 100 105 110Leu Asn Trp Leu Ile Ser Leu Tyr Glu Asn Gly Val Asn Gly Ile Leu 115 120 125Ala Asp Glu Met Gly Leu Gly Lys Thr Leu Gln Thr Ile Ala Leu Leu 130 135 140Gly Tyr Leu Lys His Tyr Arg Asn Ile Pro Gly Pro His Met Val Leu145 150 155 160Val Pro Lys Ser Thr Leu His Asn Trp Met Asn Glu Phe Lys Arg Trp 165 170 175Val Pro Ser Leu Arg Val Ile Cys Phe Val Gly Asp Lys Asp Ala Arg 180 185 190Ala Ala Phe Ile Arg Asp Glu Met Met Pro Gly Glu Trp Asp Val Cys 195 200 205Val Thr Ser Tyr Glu Met Val Ile Lys Glu Lys Ser Val Phe Lys Lys 210 215 220Phe His Trp Arg Tyr Leu Val Ile Asp Glu Ala His Arg Ile Lys Asn225 230 235 240Glu Lys Ser Lys Leu Ser Glu Ile Val Arg Glu Phe Lys Ser Thr Asn 245 250 255Arg Leu Leu Leu Thr Gly Thr Pro Leu Gln Asn Asn Leu His Glu Leu 260 265 270Trp Ala Leu Leu Asn Phe Leu Leu Pro Asp Val Phe Asn Ser Ala Asp 275 280 285Asp Phe Asp Ser Trp Phe Asp Thr Lys Asn Cys Leu Gly Asp Gln Lys 290 295 300Leu Val Glu Arg Leu His Ala Val Leu Lys Pro Phe Leu Leu Arg Arg305 310 315 320Ile Lys Thr Asp Val Glu Lys Ser Leu Pro Pro Lys Lys Glu Ile Lys 325 330 335Ile Tyr Leu Gly Leu Ser Lys Met Gln Arg Glu Trp Tyr Thr Lys Ile 340 345 350Leu Met Lys Asp Ile Asp Val Leu Asn Ser Ser Gly Lys Met Asp Lys 355 360 365Met Arg Leu Leu Asn Ile Leu Met Gln Leu Arg Lys Cys Cys Asn His 370 375 380Pro Tyr Leu Phe Asp Gly Ala Glu Pro Gly Pro Pro Tyr Thr Thr Asp385 390 395 400Glu His Ile Val Ser Asn Ser Gly Lys Met Val Val Leu Asp Lys Leu 405 410 415Leu Ala Lys Leu Lys Glu Gln Gly Ser Arg Val Leu Ile Phe Ser Gln 420 425 430Met Thr Arg Leu Leu Asp Ile Leu Glu Asp

Tyr Cys Met Trp Arg Gly 435 440 445Tyr Glu Tyr Cys Arg Leu Asp Gly Gln Thr Pro His Glu Glu Arg Glu 450 455 460Glu Ala Ile Glu Ala Phe Asn Ala Pro Asn Ser Ser Lys Phe Ile Phe465 470 475 480Met Leu Ser Thr Arg Ala Gly Gly Leu Gly Ile Asn Leu Ala Ser Ala 485 490 495Asp Val Val Ile Leu Tyr Asp Ser Asp Trp Asn Pro Gln Val Asp Leu 500 505 510Gln Ala Met Asp Arg Ala His Arg Ile Gly Gln Lys Lys Pro Val Arg 515 520 525Val Phe Arg Leu Ile Thr Asp Asn Thr Val Glu Glu Arg Ile Val Glu 530 535 540Arg Ala Glu Ile Lys Leu Arg Leu Asp Ser Ile Val Ile Gln Gln Gly545 550 555 560Arg Leu Ile Asp Gln Gln Ser Asn Lys Leu Ala Lys Glu Glu Met Leu 565 570 575Gln Met Ile Arg His Gly Ala Thr His Val Phe Ala Ser Lys Glu Ser 580 585 590Glu Leu Thr Asp Glu Asp Ile Thr Thr Ile Leu Glu Arg Gly Glu Lys 595 600 605Lys Thr Ala Glu Met Asn Glu Arg Leu Gln Lys Met Gly Glu Ser Ser 610 615 620Leu Arg Asn Phe Arg Met Asp Ile Glu Gln Ser Leu Tyr Lys Phe Glu625 630 635 640Gly Glu Asp Tyr Arg Glu Lys Gln Lys Leu Gly Met Val Glu Trp Ile 645 650 655Glu Pro Pro Lys Arg Glu Arg Lys Ala Asn Tyr Ala Val Asp Ala Tyr 660 665 670Phe Arg Glu Ala Leu Arg Val Ser Glu Pro Lys Ile Pro Lys Ala Pro 675 680 685Arg Pro Pro Lys Gln Pro Asn Val Gln Asp Phe Gln Phe Phe Pro Pro 690 695 700Arg Leu Phe Glu Leu Leu Glu Lys Glu Ile Leu Tyr Tyr Arg Lys Thr705 710 715 720Ile Gly Tyr Lys Val Pro Arg Asn Pro Asp Ile Pro Asn Pro Ala Leu 725 730 735Ala Gln Arg Glu Glu Gln Lys Lys Ile Asp Gly Ala Glu Pro Leu Thr 740 745 750Pro Glu Glu Thr Glu Glu Lys Glu Lys Leu Leu Thr Gln Gly Phe Thr 755 760 765Asn Trp Thr Lys Arg Asp Phe Asn Gln Phe Ile Lys Ala Asn Glu Lys 770 775 780Tyr Gly Arg Asp Asp Ile Asp Asn Ile Ala Arg Glu Val Glu Gly Lys785 790 795 800Ser Pro Glu Glu Val Met Glu Tyr Ser Ala Val Phe Trp Glu Arg Cys 805 810 815Asn Glu Leu Gln Asp Ile Glu Lys Ile Met Ala Gln Ile Glu Arg Gly 820 825 830Glu Ala Arg Ile Gln Arg Arg Ile Ser Ile Lys Lys Ala Leu Asp Ala 835 840 845Lys Ile Ala Arg Tyr Lys Ala Pro Phe His Gln Leu Arg Ile Gln Tyr 850 855 860Gly Thr Ser Lys Gly Lys Asn Tyr Thr Glu Glu Glu Asp Arg Phe Leu865 870 875 880Ile Cys Met Leu His Lys Met Gly Phe Asp Arg Glu Asn Val Tyr Glu 885 890 895Glu Leu Arg Gln Cys Val Arg Asn Ala Pro Gln Phe Arg Phe Asp Trp 900 905 910Phe Ile Lys Ser Arg Thr Ala Met Glu Phe Gln Arg Arg Cys Asn Thr 915 920 925Leu Ile Ser Leu Ile Glu Lys Glu Asn Met Glu Ile Glu Glu Arg Glu 930 935 940Arg Ala Lys Lys Lys Lys945 950158180PRTHomo sapiens 158Asn Ser Ser Gly Lys Met Asp Lys Met Arg Leu Leu Asn Ile Leu Met1 5 10 15Gln Leu Arg Lys Cys Cys Asn His Pro Tyr Leu Phe Asp Gly Ala Glu 20 25 30Pro Gly Pro Pro Tyr Thr Thr Asp Glu His Ile Val Ser Asn Ser Gly 35 40 45Lys Met Val Val Leu Asp Lys Leu Leu Ala Lys Leu Lys Glu Gln Gly 50 55 60Ser Arg Val Leu Ile Phe Ser Gln Met Thr Arg Leu Leu Asp Ile Leu65 70 75 80Glu Asp Tyr Cys Met Trp Arg Gly Tyr Glu Tyr Cys Arg Leu Asp Gly 85 90 95Gln Thr Pro His Glu Glu Arg Glu Asp Lys Phe Leu Glu Val Glu Phe 100 105 110Leu Gly Gln Arg Glu Ala Ile Glu Ala Phe Asn Ala Pro Asn Ser Ser 115 120 125Lys Phe Ile Phe Met Leu Ser Thr Arg Ala Gly Gly Leu Gly Ile Asn 130 135 140Leu Ala Ser Ala Asp Val Val Ile Leu Tyr Asp Ser Asp Trp Asn Pro145 150 155 160Gln Val Asp Leu Gln Ala Met Asp Arg Ala His Arg Ile Gly Gln Lys 165 170 175Lys Pro Val Arg 180159168PRTHomo sapiens 159Asn Ser Ser Gly Lys Met Asp Lys Met Arg Leu Leu Asn Ile Leu Met1 5 10 15Gln Leu Arg Lys Cys Cys Asn His Pro Tyr Leu Phe Asp Gly Ala Glu 20 25 30Pro Gly Pro Pro Tyr Thr Thr Asp Glu His Ile Val Ser Asn Ser Gly 35 40 45Lys Met Val Val Leu Asp Lys Leu Leu Ala Lys Leu Lys Glu Gln Gly 50 55 60Ser Arg Val Leu Ile Phe Ser Gln Met Thr Arg Leu Leu Asp Ile Leu65 70 75 80Glu Asp Tyr Cys Met Trp Arg Gly Tyr Glu Tyr Cys Arg Leu Asp Gly 85 90 95Gln Thr Pro His Glu Glu Arg Glu Glu Ala Ile Glu Ala Phe Asn Ala 100 105 110Pro Asn Ser Ser Lys Phe Ile Phe Met Leu Ser Thr Arg Ala Gly Gly 115 120 125Leu Gly Ile Asn Leu Ala Ser Ala Asp Val Val Ile Leu Tyr Asp Ser 130 135 140Asp Trp Asn Pro Gln Val Asp Leu Gln Ala Met Asp Arg Ala His Arg145 150 155 160Ile Gly Gln Lys Lys Pro Val Arg 16516021DNAArtificial sequencePrimer 160atcatggcct acaagatgct g 2116121DNAArtificial sequencePrimer 161atccgctcgt tctctttctt c 21162128PRTHomo sapiens 162Met Ala Tyr Lys Met Leu Ala Arg Gly Gln Pro Leu Pro Asp His Leu1 5 10 15Leu Asn Phe Gln Arg Gln Leu Arg Gln Glu Val Val Val Cys Met Arg 20 25 30Arg Asp Thr Ala Leu Glu Thr Ala Leu Asn Ala Lys Ala Tyr Lys Arg 35 40 45Ser Lys Arg Gln Ser Leu Arg Glu Ala Arg Ile Thr Glu Lys Leu Glu 50 55 60Lys Gln Gln Lys Ile Glu Gln Glu Arg Lys Arg Arg Gln Lys His Gln65 70 75 80Glu Tyr Leu Asn Ser Ile Leu Gln His Ala Lys Asp Phe Lys Glu Tyr 85 90 95His Arg Ser Val Thr Gly Lys Ile Gln Lys Leu Thr Lys Ala Val Ala 100 105 110Thr Tyr His Ala Asn Thr Glu Arg Glu Gln Lys Lys Glu Asn Glu Arg 115 120 125163420PRTHomo sapiens 163Pro Leu Gly Gly Ser Glu His Ala Ser Ser Pro Val Pro Ala Ser Gly1 5 10 15Pro Ser Ser Gly Pro Gln Met Ser Ser Gly Pro Gly Gly Ala Pro Leu 20 25 30Asp Gly Ala Asp Pro Gln Ala Leu Gly Gln Gln Asn Arg Gly Pro Thr 35 40 45Pro Phe Asn Gln Asn Gln Leu His Gln Leu Arg Ala Gln Ile Met Ala 50 55 60Tyr Lys Met Leu Ala Arg Gly Gln Pro Leu Pro Asp His Leu Gln Met65 70 75 80Ala Val Gln Gly Lys Arg Pro Met Pro Gly Met Gln Gln Gln Met Pro 85 90 95Thr Leu Pro Pro Pro Ser Val Ser Ala Thr Gly Pro Gly Pro Gly Pro 100 105 110Gly Pro Gly Pro Gly Pro Gly Pro Gly Pro Ala Pro Pro Asn Tyr Ser 115 120 125Arg Pro His Gly Met Gly Gly Pro Asn Met Pro Pro Pro Gly Pro Ser 130 135 140Gly Val Pro Pro Gly Met Pro Gly Gln Pro Pro Gly Gly Pro Pro Lys145 150 155 160Pro Trp Pro Glu Gly Pro Met Ala Asn Ala Ala Ala Pro Thr Ser Thr 165 170 175Pro Gln Lys Leu Ile Pro Pro Gln Pro Thr Gly Arg Pro Ser Pro Ala 180 185 190Pro Pro Ala Val Pro Pro Ala Ala Ser Pro Val Met Pro Pro Gln Thr 195 200 205Gln Ser Pro Gly Gln Pro Ala Gln Pro Ala Pro Met Val Pro Leu His 210 215 220Gln Lys Gln Ser Arg Ile Thr Pro Ile Gln Lys Pro Arg Gly Leu Asp225 230 235 240Pro Val Glu Ile Leu Gln Glu Arg Glu Tyr Arg Leu Gln Ala Arg Ile 245 250 255Ala His Arg Ile Gln Glu Leu Glu Asn Leu Pro Gly Ser Leu Ala Gly 260 265 270Asp Leu Arg Thr Lys Ala Thr Ile Glu Leu Lys Ala Leu Arg Leu Leu 275 280 285Asn Phe Gln Arg Gln Leu Arg Gln Glu Val Val Val Cys Met Arg Arg 290 295 300Asp Thr Ala Leu Glu Thr Ala Leu Asn Ala Lys Ala Tyr Lys Arg Ser305 310 315 320Lys Arg Gln Ser Leu Arg Glu Ala Arg Ile Thr Glu Lys Leu Glu Lys 325 330 335Gln Gln Lys Ile Glu Gln Glu Arg Lys Arg Arg Gln Lys His Gln Glu 340 345 350Tyr Leu Asn Ser Ile Leu Gln His Ala Lys Asp Phe Lys Glu Tyr His 355 360 365Arg Ser Val Thr Gly Lys Ile Gln Lys Leu Thr Lys Ala Val Ala Thr 370 375 380Tyr His Ala Asn Thr Glu Arg Glu Gln Lys Lys Glu Asn Glu Arg Ile385 390 395 400Glu Lys Glu Arg Met Arg Arg Leu Met Ala Glu Asp Glu Glu Gly Tyr 405 410 415Arg Lys Leu Ile 42016478PRTHomo sapiens 164Met Ala Tyr Lys Met Leu Ala Arg Gly Gln Pro Leu Pro Asp His Leu1 5 10 15Gln Met Ala Val Gln Glu Arg Lys Arg Arg Gln Lys His Gln Glu Tyr 20 25 30Leu Asn Ser Ile Leu Gln His Ala Lys Asp Phe Lys Glu Tyr His Arg 35 40 45Ser Val Thr Gly Lys Ile Gln Lys Leu Thr Lys Ala Val Ala Thr Tyr 50 55 60His Ala Asn Thr Glu Arg Glu Gln Lys Lys Glu Asn Glu Arg65 70 75165360PRTHomo sapiens 165Gln Ile Met Ala Tyr Lys Met Leu Ala Arg Gly Gln Pro Leu Pro Asp1 5 10 15His Leu Gln Met Ala Val Gln Gly Lys Arg Pro Met Pro Gly Met Gln 20 25 30Gln Gln Met Pro Thr Leu Pro Pro Pro Ser Val Ser Ala Thr Gly Pro 35 40 45Gly Pro Gly Pro Gly Pro Gly Pro Gly Pro Gly Pro Gly Pro Ala Pro 50 55 60Pro Asn Tyr Ser Arg Pro His Gly Met Gly Gly Pro Asn Met Pro Pro65 70 75 80Pro Gly Pro Ser Gly Val Pro Pro Gly Met Pro Gly Gln Pro Pro Gly 85 90 95Gly Pro Pro Lys Pro Trp Pro Glu Gly Pro Met Ala Asn Ala Ala Ala 100 105 110Pro Thr Ser Thr Pro Gln Lys Leu Ile Pro Pro Gln Pro Thr Gly Arg 115 120 125Pro Ser Pro Ala Pro Pro Ala Val Pro Pro Ala Ala Ser Pro Val Met 130 135 140Pro Pro Gln Thr Gln Ser Pro Gly Gln Pro Ala Gln Pro Ala Pro Met145 150 155 160Val Pro Leu His Gln Lys Gln Ser Arg Ile Thr Pro Ile Gln Lys Pro 165 170 175Arg Gly Leu Asp Pro Val Glu Ile Leu Gln Glu Arg Glu Tyr Arg Leu 180 185 190Gln Ala Arg Ile Ala His Arg Ile Gln Glu Leu Glu Asn Leu Pro Gly 195 200 205Ser Leu Ala Gly Asp Leu Arg Thr Lys Ala Thr Ile Glu Leu Lys Ala 210 215 220Leu Arg Leu Leu Asn Phe Gln Arg Gln Leu Arg Gln Glu Val Val Val225 230 235 240Cys Met Arg Arg Asp Thr Ala Leu Glu Thr Ala Leu Asn Ala Lys Ala 245 250 255Tyr Lys Arg Ser Lys Arg Gln Ser Leu Arg Glu Ala Arg Ile Thr Glu 260 265 270Lys Leu Glu Lys Gln Gln Lys Ile Glu Gln Glu Arg Lys Arg Arg Gln 275 280 285Lys His Gln Glu Tyr Leu Asn Ser Ile Leu Gln His Ala Lys Asp Phe 290 295 300Lys Glu Tyr His Arg Ser Val Thr Gly Lys Ile Gln Lys Leu Thr Lys305 310 315 320Ala Val Ala Thr Tyr His Ala Asn Thr Glu Arg Glu Gln Lys Lys Glu 325 330 335Asn Glu Arg Ile Glu Lys Glu Arg Met Arg Arg Leu Met Ala Glu Asp 340 345 350Glu Glu Gly Tyr Arg Lys Leu Ile 355 36016621DNAArtificial sequencePrimer 166gctcggcaag aactacaaga a 2116721DNAArtificial sequencePrimer 167cggacacttt gttccagtca t 21168130PRTHomo sapiens 168Met Leu Gly Lys Asn Tyr Lys Lys Tyr Ile Gln Ala Glu Pro Pro Thr1 5 10 15Asn Lys Ser Leu Ser Ser Leu Val Val Gln Leu Leu Gln Phe Gln Glu 20 25 30Glu Val Phe Gly Lys His Val Leu Ala Asp Thr Pro Ser Gly Leu Val 35 40 45Pro Leu Gln Pro Lys Thr Pro Gln Gln Thr Ser Ala Ser Gln Gln Met 50 55 60Leu Asn Phe Pro Asp Lys Gly Lys Glu Lys Pro Thr Asp Met Gln Asn65 70 75 80Phe Gly Leu Arg Thr Asp Met Tyr Thr Lys Lys Asn Val Pro Ser Lys 85 90 95Ser Lys Ala Ala Ala Ser Ala Thr Arg Glu Trp Thr Glu Gln Glu Thr 100 105 110Leu Leu Leu Leu Glu Ala Leu Glu Met Tyr Lys Asp Asp Trp Asn Lys 115 120 125Val Ser 130169660PRTHomo sapiens 169Met Ala Val Arg Lys Lys Asp Gly Gly Pro Asn Val Lys Tyr Tyr Glu1 5 10 15Ala Ala Asp Thr Val Thr Gln Phe Asp Asn Val Arg Leu Trp Leu Gly 20 25 30Lys Asn Tyr Lys Lys Tyr Ile Gln Ala Glu Pro Pro Thr Asn Lys Ser 35 40 45Leu Ser Ser Leu Val Val Gln Leu Leu Gln Phe Gln Glu Glu Val Phe 50 55 60Gly Lys His Val Ser Asn Ala Pro Leu Thr Lys Leu Pro Ile Lys Cys65 70 75 80Phe Leu Asp Phe Lys Ala Gly Gly Ser Leu Cys His Ile Leu Ala Ala 85 90 95Ala Tyr Lys Phe Lys Ser Asp Gln Gly Trp Arg Arg Tyr Asp Phe Gln 100 105 110Asn Pro Ser Arg Met Asp Arg Asn Val Glu Met Phe Met Thr Ile Glu 115 120 125Lys Ser Leu Val Gln Asn Asn Cys Leu Ser Arg Pro Asn Ile Phe Leu 130 135 140Cys Pro Glu Ile Glu Pro Lys Leu Leu Gly Lys Leu Lys Asp Ile Ile145 150 155 160Lys Arg His Gln Gly Thr Val Thr Glu Asp Lys Asn Asn Ala Ser His 165 170 175Val Val Tyr Pro Val Pro Gly Asn Leu Glu Glu Glu Glu Trp Val Arg 180 185 190Pro Val Met Lys Arg Asp Lys Gln Val Leu Leu His Trp Gly Tyr Tyr 195 200 205Pro Asp Ser Tyr Asp Thr Trp Ile Pro Ala Ser Glu Ile Glu Ala Ser 210 215 220Val Glu Asp Ala Pro Thr Pro Glu Lys Pro Arg Lys Val His Ala Lys225 230 235 240Trp Ile Leu Asp Thr Asp Thr Phe Asn Glu Trp Met Asn Glu Glu Asp 245 250 255Tyr Glu Val Asn Asp Asp Lys Asn Pro Val Ser Arg Arg Lys Lys Ile 260 265 270Ser Ala Lys Thr Leu Thr Asp Glu Val Asn Ser Pro Asp Ser Asp Arg 275 280 285Arg Asp Lys Lys Gly Gly Asn Tyr Lys Lys Arg Lys Arg Ser Pro Ser 290 295 300Pro Ser Pro Thr Pro Glu Ala Lys Lys Lys Asn Ala Lys Lys Gly Pro305 310 315 320Ser Thr Pro Tyr Thr Lys Ser Lys Arg Gly His Arg Glu Glu Glu Gln 325 330 335Glu Asp Leu Thr Lys Asp Met Asp Glu Pro Ser Pro Val Pro Asn Val 340 345 350Glu Glu Val Thr Leu Pro Lys Thr Val Asn Thr Lys Lys Asp Ser Glu 355 360 365Ser Ala Pro Val Lys Gly Gly Thr Met Thr Asp Leu Asp Glu Gln Glu 370 375 380Asp Glu Ser Met Glu Thr Thr Gly Lys Asp Glu Asp Glu Asn Ser Thr385 390 395 400Gly Asn Lys Gly Glu Gln Thr Lys Asn Pro Asp Leu His Glu Asp Asn 405 410 415Val Thr Glu

Gln Thr His His Ile Ile Ile Pro Ser Tyr Ala Ala Trp 420 425 430Phe Asp Tyr Asn Ser Val His Ala Ile Glu Arg Arg Ala Leu Pro Glu 435 440 445Phe Phe Asn Gly Lys Asn Lys Ser Lys Thr Pro Glu Ile Tyr Leu Ala 450 455 460Tyr Arg Asn Phe Met Ile Asp Thr Tyr Arg Leu Asn Pro Gln Glu Tyr465 470 475 480Leu Thr Ser Thr Ala Cys Arg Arg Asn Leu Ala Gly Asp Val Cys Ala 485 490 495Ile Met Arg Val His Ala Phe Leu Glu Gln Trp Gly Leu Ile Asn Tyr 500 505 510Gln Val Asp Ala Glu Ser Arg Pro Thr Pro Met Gly Pro Pro Pro Thr 515 520 525Ser His Phe His Val Leu Ala Asp Thr Pro Ser Gly Leu Val Pro Leu 530 535 540Gln Pro Lys Thr Pro Gln Gln Thr Ser Ala Ser Gln Gln Met Leu Asn545 550 555 560Phe Pro Asp Lys Gly Lys Glu Lys Pro Thr Asp Met Gln Asn Phe Gly 565 570 575Leu Arg Thr Asp Met Tyr Thr Lys Lys Asn Val Pro Ser Lys Ser Lys 580 585 590Ala Ala Ala Ser Ala Thr Arg Glu Trp Thr Glu Gln Glu Thr Leu Leu 595 600 605Leu Leu Glu Ala Leu Glu Met Tyr Lys Asp Asp Trp Asn Lys Val Ser 610 615 620Glu His Val Gly Ser Arg Thr Gln Asp Glu Cys Ile Leu His Phe Leu625 630 635 640Arg Leu Pro Ile Glu Asp Pro Tyr Leu Glu Asp Ser Glu Ala Ser Leu 645 650 655Gly Pro Leu Ala 660170208PRTHomo sapiens 170Ser Ser Leu Val Val Gln Leu Leu Gln Phe Gln Glu Glu Val Phe Gly1 5 10 15Lys His Val Ser Asn Ala Pro Leu Thr Lys Leu Pro Ile Lys Cys Phe 20 25 30Leu Asp Phe Lys Ala Gly Gly Ser Leu Cys His Ile Leu Ala Ala Ala 35 40 45Tyr Arg Asn Phe Met Ile Asp Thr Tyr Arg Leu Asn Pro Gln Glu Tyr 50 55 60Leu Thr Ser Thr Ala Cys Arg Arg Asn Leu Ala Gly Asp Val Cys Ala65 70 75 80Ile Met Arg Val His Ala Phe Leu Glu Gln Trp Gly Leu Ile Asn Tyr 85 90 95Gln Val Asp Ala Glu Ser Arg Pro Thr Pro Met Gly Pro Pro Pro Thr 100 105 110Ser His Phe His Val Leu Ala Asp Thr Pro Ser Gly Leu Val Pro Leu 115 120 125Gln Pro Lys Thr Pro Gln Gln Thr Ser Ala Ser Gln Gln Met Leu Asn 130 135 140Phe Pro Asp Lys Gly Lys Glu Lys Pro Thr Asp Met Gln Asn Phe Gly145 150 155 160Leu Arg Thr Asp Met Tyr Thr Lys Lys Asn Val Pro Ser Lys Ser Lys 165 170 175Ala Ala Ala Ser Ala Thr Arg Glu Trp Thr Glu Gln Glu Thr Leu Leu 180 185 190Leu Leu Glu Ala Leu Glu Met Tyr Lys Asp Asp Trp Asn Lys Val Ser 195 200 20517196PRTHomo sapiens 171Met Ser Ser Leu Val Val Gln Leu Leu Gln Phe Gln Glu Glu Val Phe1 5 10 15Gly Lys His Val Ser Asn Ala Pro Leu Thr Lys Leu Pro Ile Lys Cys 20 25 30Phe Leu Asp Lys Gly Lys Glu Lys Pro Thr Asp Met Gln Asn Phe Gly 35 40 45Leu Arg Thr Asp Met Tyr Thr Lys Lys Asn Val Pro Ser Lys Ser Lys 50 55 60Ala Ala Ala Ser Ala Thr Arg Glu Trp Thr Glu Gln Glu Thr Leu Leu65 70 75 80Leu Leu Glu Ala Leu Glu Met Tyr Lys Asp Asp Trp Asn Lys Val Ser 85 90 9517220DNAArtificial sequencePrimer 172gcggtgtctc agattcattc 2017322DNAArtificial sequencePrimer 173ttgccggatg ctgtaatagt tg 2217477PRTHomo sapiens 174Met Ser Lys Arg Pro Ser Tyr Ala Pro Pro Pro Thr Pro Ala Pro Ala1 5 10 15Thr Gln Met Pro Ser Thr Pro Gly Phe Val Gly Tyr Asn Pro Tyr Ser 20 25 30His Leu Ala Tyr Asn Asn Tyr Arg Leu Gly Gly Asn Pro Gly Thr Asn 35 40 45Ser Arg Val Thr Val Gly Glu Ser Thr Ile Thr Ala Ser Gly Lys Gln 50 55 60Leu Glu Leu Thr Arg Asn Ala Phe Arg Ile Arg Ser Phe65 70 75175180PRTHomo sapiens 175Met Ser Lys Arg Pro Ser Tyr Ala Pro Pro Pro Thr Pro Ala Pro Ala1 5 10 15Thr Gln Met Pro Ser Thr Pro Gly Phe Val Gly Tyr Asn Pro Tyr Ser 20 25 30His Leu Ala Tyr Asn Asn Tyr Arg Leu Gly Gly Asn Pro Gly Thr Asn 35 40 45Ser Arg Val Thr Ala Ser Ser Gly Ile Thr Ile Pro Lys Pro Pro Lys 50 55 60Pro Pro Asp Lys Pro Leu Met Pro Tyr Met Arg Tyr Ser Arg Lys Val65 70 75 80Trp Asp Gln Val Lys Ala Ser Asn Pro Asp Leu Lys Leu Trp Glu Ile 85 90 95Gly Lys Ile Ile Gly Gly Met Trp Arg Asp Leu Thr Asp Glu Glu Lys 100 105 110Gln Glu Tyr Leu Asn Glu Tyr Glu Ala Glu Lys Ile Glu Tyr Asn Glu 115 120 125Ser Met Lys Ala Tyr His Asn Ser Pro Ala Tyr Leu Ala Tyr Ile Asn 130 135 140Ala Lys Ser Arg Ala Glu Ala Ala Leu Glu Glu Glu Ser Arg Gln Arg145 150 155 160Gln Ser Arg Met Glu Lys Gly Glu Pro Tyr Met Ser Ile Gln Pro Ala 165 170 175Glu Asp Pro Asp 180

Claims

1. An isolated peptide of fewer than 100 amino acids that specifically binds to: (a) SEQ ID NO: 11 and not SEQ ID NO: 10, or (b) SEQ ID NO: 13 and not SEQ ID NO: 12.

2. The peptide of claim 1 that is labeled with a detectable marker.

3. The peptide of claim 1 that comprises the amino acid sequence of SEQ ID NO: 1 or a conservatively modified variant thereof having the amino acid sequence of SEQ ID NO: 7.

4. The peptide of claim 1 that comprises the amino acid sequence of SEQ ID NO: 2 or a conservatively modified variant thereof having the amino acid sequence of SEQ ID NO: 8.

5. The peptide of claim 1, further comprising a cell penetrating peptide (CPP).

6. The peptide of claim 5, wherein the CPP has the amino acid sequence RRRRRRR (SEQ ID NO: 3).

7. The peptide of claim 1, further comprising a nuclear localizing signal (NLS).

8. The peptide of claim 7, wherein the NLS has the amino acid sequence PKKRKV (SEQ ID NO: 4).

9. The peptide of claim 1, wherein the peptide has the amino acid sequence PKKRKVRRRRRRRPQMQQNVFQYPGAGMVPQGEANF (TRAP100 P05; SEQ ID NO: 5) or PKKRKVRRRRRRRNDRLSDGDSKYSQTSHKLVQLL (BAF57 P12; SEQ ID NO: 6).

10. The peptide of claim 1, wherein the peptide is a recombinant or synthetic peptide having the amino acid sequence PKKRKVRRRRRRRPQMQQNVFQYPGAGMVPQGEANF (TRAP100 P05; SEQ ID NO: 5), and wherein the peptide is labeled with a detectable marker.

11. The peptide of claim 1, wherein the peptide is a recombinant or synthetic peptide having the amino acid sequence PKKRKVRRRRRRRNDRLSDGDSKYSQTSHKLVQLL (BAF57 P12; SEQ ID NO: 6), and wherein the peptide is labeled with a detectable marker.

12. A method for detecting cancer in a tissue specimen, comprising: (a) contacting a tissue specimen with the peptide of claim 1, wherein the peptide has been labeled with a detectable marker to form a detectable molecule, and (b) detecting presence of the detectable molecule, wherein presence of the detectable molecule is indicative of cancer.

13. The method of claim 12, wherein the cancer is melanoma, glioblastoma, breast or colorectal cancer.

14. The method of claim 12, wherein the tissue specimen is a tumor sample or cerebrospinal fluid.

15. The method of claim 12, wherein the detectable marker comprises a fluorescent label.

16. A kit comprising the peptide of claim 2 and a container that is compartmentalized to receive the peptide.

17. The kit of claim 16, further comprising an antibody that specifically recognizes and binds the peptide.

18. The kit of claim 17, wherein the antibody is labeled with a detectable marker.

19. The kit of claim 16, further comprising a label provided on the container, wherein the label indicates that the kit is for use in the detection of cancer.

20. The kit of claim 16, wherein the peptide has the amino acid sequence PKKRKVRRRRRRRPQMQQNVFQYPGAGMVPQGEANF (TRAP100 P05; SEQ ID NO: 5) or PKKRKVRRRRRRRNDRLSDGDSKYSQTSHKLVQLL (BAF57 P12; SEQ ID NO: 6).