Patent application title: GIPs, a Family of Polypeptides with Transcription Factor Activity that Interact with Goodpasture Antigen Binding Protein
Inventors:
Juan Saus (Valencia, ES)
Francisco Revert-Ros (Valencia, ES)
IPC8 Class: AA61K39395FI
USPC Class:
4241391
Class name: Drug, bio-affecting and body treating compositions immunoglobulin, antiserum, antibody, or antibody fragment, except conjugate or complex of the same with nonimmunoglobulin material binds antigen or epitope whose amino acid sequence is disclosed in whole or in part (e.g., binds specifically-identified amino acid sequence, etc.)
Publication date: 2010-06-03
Patent application number: 20100136014
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Patent application title: GIPs, a Family of Polypeptides with Transcription Factor Activity that Interact with Goodpasture Antigen Binding Protein
Inventors:
Juan Saus
Francisco Revert-Ros
Agents:
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
Assignees:
Origin: CHICAGO, IL US
IPC8 Class: AA61K39395FI
USPC Class:
4241391
Publication date: 06/03/2010
Patent application number: 20100136014
Abstract:
The present invention provides isolated GPBP-interacting 90 and 130 kDa
polypeptides, and portions thereof (GIP90/130 polypeptides), antibodies
to the GIP90/130 polypeptides, and pharmaceutical compositions thereof.
The present invention also provides isolated GIP90/130 nucleic acid
sequences, expression vectors comprising the nucleic acid sequences, and
host cells transfected with the expression vectors. The invention further
provides methods for detecting the GIP90/130 polypeptides or nucleic acid
sequences, methods for inhibiting interactions between GPBP and GIP90/130
polypeptides, between pol k76 and GIP90/130 polypeptides or aggregation
of GIP90/130 polypeptides, and methods for treating patients with
autoimmune disorders or cancer.Claims:
1. An isolated polypeptide comprising at least 6 amino acids of the amino
acid of SEQ ID NO:2.
2. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:2.
3. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:4.
4. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:6.
5. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:8.
6. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:10.
7. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:12.
8. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:14.
9. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:16.
10. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:32.
11. The isolated polypeptide of claim 1 comprising the amino acid sequence of SEQ ID NO:36.
12-22. (canceled)
23. An isolated polypeptide selected from the group consisting of SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:34, and SEQ ID NO:38.
24. An antibody directed against a polypeptide comprising an amino acid sequence of one or more of the amino acid sequences selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, and SEQ ID NO:38.
25. An isolated nucleic acid sequence comprising a sequence that hybridizes under high stringency conditions to a nucleic acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:17, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:31, and SEQ ID NO:35.
26. A recombinant expression vector comprising the isolated nucleic acid sequence of claims 25.
27. A recombinant host cell transfected with the recombinant expression vector of claim 26.
28. A method for modifying interactions between GPBP and GIP 90/130 polypeptides and/or pol k76 and GIP 90/130 polypeptides, comprising contacting cells with an amount effective of one or more GIP90/130 polypeptide or an antibody directed against one or more GIP90/130 polypeptide to modify the interaction between GPBP and GIP 90/130 polypeptides and/or pol k76 and GIP 90/130 polypeptides.
29. A method for modifying aggregation of GIP 90/130 polypeptides comprising contacting cells with an amount effective of one or more GIP90/130 polypeptide or an antibody directed against one or more GIP90/130 polypeptide to modify the aggregation of GIP 90/130 polypeptides.
30. A pharmaceutical composition comprising:a) an isolated polypeptide according to claim 1; andb) a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising:a) an antibody according to claim 24; andb) a pharmaceutically acceptable carrier.
32. A method for treating a patient with an autoimmune disorder, comprising modifying the expression or activity of one or more GIP90/130 polypeptides in the patient with the autoimmune disorder.
33. A method for treating a patient with a tumor, comprising modifying the expression or activity of one or more GIP90/130 polypeptides in the patient with the tumor.
Description:
CROSS REFERENCE
[0001]This application is a continuation of U.S. Utility patent application Ser. No. 10/309,851, filed Dec. 4, 2002, which claims priority to U.S. Provisional Patent Application Nos. 60/338,287 filed Dec. 7, 2001 and 60/382,004 filed May 20, 2002.
FIELD OF THE INVENTION
[0002]The present invention is in the general fields of molecular biology, cell biology, protein-protein interactions, autoimmunity, cancer, and drug discovery.
BACKGROUND
[0003]Goodpasture antigen binding protein (GPBP) is a ubiquitous protein kinase with a Mr of 80-89 kDa that is preferentially expressed in tissues and cells that are common targets of autoimmune responses, such as the Langerhans islets (type I diabetes); the white matter of the central nervous system (multiple sclerosis); the biliary ducts (primary biliary cirrhosis); the cortical cells of the adrenal gland (Addison disease); striated muscle cells (myasthenia gravis); spermatogonium (male infertility); Purkinje cells of the cerebellum (paraneoplasic cerebellar degeneration syndrome); and intestinal epithelial cells (pernicious anemia, autoimmune gastritis and enteritis).
[0004]GPBP is expressed as two isoforms (GPBP and GPBPΔ26) which result from exon alternative splicing of the corresponding pre-mRNA. GPBP is the more active variant, and its expression is still more restricted to histological structures targeted by common autoimmune responses including human alveolar and glomerular basement membranes (Goodpasture disease). GPBP binds to and phosphorylates the human α3 NC1 domain of type IV collagen (α3(IV)NC1) also called the Goodpasture antigen (WO 00/50607), as this domain is the target of the pathogenic autoantibodies mediating the Goodpasture autoimmune response. Phosphorylation activates the α3(IV)NC1 domain for aggregation, a process that is catalyzed at least in part by GPBP and which comprises conformational isomerization reactions and disulfide-bond exchange (WO 02/061430).
[0005]An augmented expression of GPBP with respect to GPBPΔ26 has been associated with the production of non-tolerized, aberrant conformational versions of the human α3(IV)NC1 domain ("aberrant conformers") and the subsequent autoantibody production that causes Goodpasture disease (WO 02/061430). The evidence suggests that a similar pathogenic mechanism is involved in other autoimmune conditions, including cutaneous lupus erythematosus, pemphigus, pemphigoid and lichen planus, and that aberrant GPBP expression and autoimmune pathogenesis are related processes. Furthermore, GPBP is down-regulated in cancer cell lines (WO 00/50607), suggesting that the cell machinery harboring GPBP/GPBPΔ26 is also involved in signaling pathways that decrease cell division or induce cell death. These pathways could be up regulated during autoimmune pathogenesis to cause altered antigen presentation in individuals carrying specific MHC haplotypes, and down regulated during cell transformation to prevent autoimmune attack of the transformed cells during tumor growth.
[0006]Based on all of the above, there exists a need in the art to identify methods and reagents for modifying GPBP activity for use in treating autoimmune disorders and cancer.
SUMMARY OF THE INVENTION
[0007]In one aspect, the present invention provides isolated GPBP-interacting 90 and 130 kDa polypeptides, and portions thereof (GIP90/130 polypeptides), antibodies to the GIP 90/130 polypeptides, and pharmaceutical compositions thereof. In a further aspect, the present invention provides isolated GIP90/130 nucleic acid sequences, expression vectors comprising the nucleic acid sequences, and host cells transfected with the expression vectors. The invention further provides methods for detecting the GIP90/130 polypeptides or nucleic acid sequences, methods for modifying interactions between GPBP and GIP90/130 polypeptides, aggregation of GIP90/130 polypeptides, and GIP90/130 polypeptide-mediated gene transcription, and methods for treating patients with autoimmune disorders or cancer.
BRIEF DESCRIPTION OF THE FIGURES
[0008]FIG. 1 is a diagram of the exon-intron structure of the GIP90 genomic DNA as determined by BLAST search against Human Genome NCBI in May 20, 2002.
[0009]FIG. 2 is a representation of differences between various GIP90/130 mRNA and polypeptide species.
[0010]FIG. 3 is a sequence alignment of the full length GIP90/130 polypeptides and DOC1 and DOC1-related protein.
[0011]FIG. 4 is the amino acid sequence of I-20. Residues in bold font are those identified as essential for interactions between GIP90/130 and GPBP; in small letters are other residues identified as participating in interaction between GIP90/130 and GPBP, but not essential; and underlined are the residues implicated in GIP90/130 aggregation.
DETAILED DESCRIPTION OF THE INVENTION
[0012]Within this application, unless otherwise stated, the techniques utilized may be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, Calif.), "Guide to Protein Purification" in Methods in Enzymology (M. P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, Calif.), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R. I. Freshney. 1987. Liss, Inc. New York, N.Y.), Gene Transfer and Expression Protocols, pp. 109-128, ed. E. J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, Tex.).
[0013]As used herein, the term "GIP90/130" and "GIP90/130 polypeptide(s)" refers to the family of GPBP-interacting proteins that includes GIP90, GIP130a, GIP130b, and GIP130c, amino acid sequences derived therefrom, and includes both monomers and oligomers thereof.
[0014]As used herein, the term "GIP90" refers to the 90 kDa form of GIP, which consists of the amino acid sequence of SEQ ID NO:10, and includes both monomers and oligomers thereof.
[0015]As used herein, the term "GIP130a" refers to one of the 130 kDa forms of GIP, which consists of the amino acid sequence of SEQ ID NO:12, and includes both monomers and oligomers thereof.
[0016]As used herein, the term "GIP130b" refers to one of the 130 kDa forms of GIP, which consists of the amino acid sequence of SEQ ID NO:14, and includes both monomers and oligomers thereof.
[0017]As used herein, the term "GIP130c" refers to one of the 130 kDa forms of GIP, which consists of the amino acid sequence of SEQ ID NO:16, and includes both monomers and oligomers thereof.
[0018]The numbering of nucleotides and residues used below for GIP proteins refer to the GenBank accession number AF329092.
[0019]As used herein, the term "DOC proteins" or "DOC1 proteins" refers to down regulated in ovarian cancer-1 (DOC1) (Genbank accession number NM 014890) and DOC1-related protein (Genbank accession number BC027860). DOC1 and DOC1-related protein are derived from the same gene since they are identical in the homology region at nucleotide and amino acid levels
[0020]As used herein, the term "GPBP" refers to Goodpasture antigen binding protein, and includes both monomers and oligomers thereof, as disclosed in WO 00/50607.
[0021]As used herein, the term "GPBPΔ26" refers to the Goodpasture antigen binding protein alternatively spliced product deleted for 26 amino acid residues as disclosed in WO 00/50607, and includes both monomers and oligomers thereof.
[0022]As used herein pol κ means the primary protein product of the POLK as disclosed in WO 02/46378.
[0023]As used herein, pol κ76 means the 76 kDa alternatively spliced isoform product of the POLK as disclosed in WO 02/46378.
[0024]As used herein, "aggregation" refers to both self-aggregation of an individual GIP90/130 polypeptide, and aggregation of two or more different GIP90/130 polypeptides.
[0025]In one aspect, the present invention provides isolated GIP90/130 polypeptides. In one embodiment, the isolated GIP90/130 polypeptide comprises at least 6 amino acids of the amino acid sequence of SEQ ID NO:2, which is a unique 10 amino acid polypeptide (SYRRILGQLL) that is herein demonstrated to be essential for the interaction between GIP90/130 and GPBP (discussed in detail below), and is not present in DOC proteins. In further embodiments, the isolated GIP90/130 polypeptide comprises at least 7, 8, 9, or 10 amino acids of the amino acid sequence of SEQ ID NO:2. In still further embodiments, the isolated GIP90/130 polypeptide consists of at least 6, 7, 8, 9, or 10 amino acids of the amino acid sequence of SEQ ID NO:2. These polypeptides can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides or to raise antibodies that interfere with GPBP-GIP90/130 interaction.
[0026]In further embodiments, the isolated GIP90/130 polypeptide comprises and/or consists of the amino acid sequence of SEQ ID NO:4, which is the N-terminal region of GIP90/130a/c that is not present in DOC proteins (described in detail below), and which is encoded by exon II-IV and part of exon V (FIG. 3). These polypeptides are thus useful, for example, to develop reagents, such as antibodies, that can distinguish between GIP90/130 and DOC proteins. This polypeptide includes sequences implicated in the interaction between GPBP and GIP90/130 (including SEQ ID NO:2), and thus can be used (or antibodies to the polypeptides can be used), for example, to modify interactions between GPBP and GIP90/130 polypeptides. This polypeptide also includes sequences implicated in GIP90/130 aggregation, and thus can further be used (or antibodies to the polypeptides can be used) to modify GIP90/130 aggregation. This polypeptide also includes sequences implicated in the transcriptional activity of GIP90/130 and thus the polypeptides, or antibodies derived therefrom, can be further used for modulating specific gene expression.
[0027]The polypeptides of the invention also include polypeptides comprising and/or consisting of the amino acid sequence of SEQ ID NO:6, which is referred to as I-20, a 265 amino acid polypeptide that is described in detail below. This polypeptide interacts more strongly with GPBP and pol κ76 than the full length GIP90/130 polypeptides, and aggregates more efficiently than the full length GIP90/130 polypeptides. Furthermore, I-20 does not induce gene transcription, in contrast to the full length GIP90/130 polypeptides. Therefore this polypeptide can be used (or antibodies to the polypeptides can be used), for example, to modify (a) interactions between GPBP and GIP90/130 polypeptides; (b) interactions between pol κ76 and GIP90/130 polypeptides; (c) GIP90/130 polypeptide aggregation; and (d) other functions of the GIP90/130 polypeptides, such as induction of gene transcription.
[0028]The polypeptides of the invention also include polypeptides comprising and/or consisting of the amino acid sequence of SEQ ID NO:8, which consists of the N-terminus of GIP90 to the end of I-20, and is encoded by exons II-IV and part of exon V up to the end of the I-20 coding sequence. This polypeptide includes sequences implicated in (a) the interaction between GPBP and GIP90/130 polypeptides, (b) GIP90/130 polypeptide aggregation, and (c) the transcriptional activity of GIP90/130 polypeptides, and thus the polypeptides, or antibodies derived therefrom, can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides, to modify GIP90/130 aggregation, and to modulate gene expression.
[0029]The polypeptides of the invention also include polypeptides comprising and/or consisting of the amino acid sequence of SEQ ID NO:10 (GIP90), SEQ ID NO:12 (GIP130a), SEQ ID NO:14 (GIP130b), or SEQ ID NO:16 (GIP130c). These full length polypeptides, described in more detail below, interact with GPBP and are capable of aggregation. These polypeptides can be used, for example, to modify GPBP-GIP90/130 interactions, to modify GIP90/130 aggregation, to modulate gene expression, as well as for other purposes described herein.
[0030]In a further embodiment, the isolated GIP 90/130 polypeptide comprises at least 8 amino acids of the amino acid sequence of SEQ ID NO:18, which is a unique 15 amino acid peptide that is present at the C-terminus of GIP90 and is not present in DOC proteins, GIP130a, GIP130b, or GIP130c, and thus can be used, for example, to generate reagents, such as antibodies, to distinguish GIP90 from other members of the GIP90/130 polypeptide family. Furthermore, the polypeptides, or antibodies thereto, can be used to specifically modify GIP90 self-aggregation. In further embodiments, the isolated GIP90/130 polypeptide comprises or consists of at least 9, 10, 11, 12, 13, 14, or 15 amino acids of the amino acid sequence of SEQ ID NO:18.
[0031]In a further embodiment, the isolated GIP90/130 polypeptide consists of at least 8 amino acids of the amino acid sequence of SEQ ID NO:20, which is a 30 amino acid polypeptide present within I-20 that has been implicated in the interaction of GIP90/130 with GPBP and also in GIP90/130 aggregation. In further embodiments, the isolated GIP90/130 polypeptide consists of at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids the amino acid sequence of SEQ ID NO:20. Thus, these polypeptides, or antibodies to the polypeptides, can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides. Furthermore, since this polypeptide is present in each of GIP90, GIP130a, GIP130b, GIP130c, and DOC1 proteins, these polypeptides, or antibodies thereto, can be used to generally modify aggregation of the GIP90/130 polypeptides and DOC1 proteins. Despite the fact that DOC1 proteins contain SEQ ID NO:20, they do not interact in a two hybrid assay with GPBP (see below), and thus SEQ ID NO:20, while implicated in the interaction of GIP90/130 polypeptides and GPBP, is not sufficient for GPBP interaction.
[0032]In a still further embodiment, the isolated GIP90/130 polypeptide comprises or consists of the amino acid sequence of SEQ ID NO:22, which is a unique 386 amino acid polypeptide that is present at the C-terminus of GIP130a but is not present in GIP90, is not wholly present in DOC1, and includes variations from GIP130b, GIP130c, and DOC1-related protein, and thus can be used, for example, to modify GIP130a aggregation, and to generate reagents, such as antibodies, to distinguish GIP130a from other members of the GIP90/130 polypeptide family, and the DOC proteins. This region contains sequences that down-regulate GIP 90/130 interaction with GPBP which can be used to modify GIP90/130-GPBP interaction, or to generate reagents, such as antibodies for the same purposes.
[0033]In a still further embodiment, the isolated GIP90/130 polypeptide comprises or consists of the amino acid sequence of SEQ ID NO:24, which is GIP130a deleted from the N-terminus to the end of I-20. This polypeptide lacks critical regions of the GIP90/130 polypeptides implicated in GPBP interaction and induction of gene expression, and like the C terminus of GIP130b/c contains amino acid sequences that down-regulate interaction with GPPB. Thus, the polypeptides, or antibodies thereto, can be used, for example, to modify GPBP-GIP90/130 polypeptide interactions or to modify GIP90/130 polypeptide aggregation.
[0034]In a still further embodiment, the isolated GIP 90/130 polypeptide comprises or consists of the amino acid sequence of SEQ ID NO:26, which is a unique 7 amino acid polypeptide present at the C-terminus of GIP130a, and is not present in any of GIP90, GIP130b, GIP130c, and DOC proteins. Thus, these polypeptides can be used to produce reagents, such as antibodies, that are specific for GIP130a, and which can be used, for example, to specifically modify GIP130a aggregation.
[0035]In another embodiment, the isolated GIP90/130 polypeptide comprises at least 6 amino acids of the amino acid sequence of SEQ ID NO:28, which is a unique 10 amino acid polypeptide (LDKVVEKHKE) within I-20 that participates in interactions between GIP90/130 polypeptides and GPBP, is essential for GIP90/130 polypeptide aggregation, and is not present in DOC proteins. In further embodiments, the isolated GIP90/130 polypeptide comprises or consists of at least 7, 8, 9, or 10 amino acids of the amino acid sequence of SEQ ID NO:28. These polypeptides or antibodies raised against them can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides or to modify GIP90/130 polypeptide aggregation.
[0036]In another embodiment, the isolated GIP90/130 polypeptide consists of at least 6 amino acids of the amino acid sequence of SEQ ID NO:30, which is an 10 amino acid polypeptide (EEEQKATRLE) within I-20 that participates in interactions between GIP90/130 polypeptides and GPBP, is essential for GIP90/130 polypeptide aggregation, and is present in DOC proteins. In further embodiments, the isolated GIP90/130 polypeptide consists of at least 7, 8, 9, or 10 amino acids of the amino acid sequence of SEQ ID NO:30. These polypeptides or antibodies raised against them can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides or to modify GIP90/130 polypeptide aggregation. Furthermore, since this polypeptide is present in each of GIP90, GIP130a, GIP130b, GIP130c, and DOC1 proteins, these polypeptides, or antibodies thereto, can be used to generally modify aggregation of the GIP90/130 polypeptides and DOC1/DOC1-related proteins. Despite the fact that DOC1 proteins contain SEQ ID NO:20, they do not interact in a two hybrid assay with GPBP (see below), and thus SEQ ID NO:20, while implicated in the interaction of GIP90/130 polypeptides and GPBP, is not sufficient for GPBP interaction.
[0037]In another embodiment, the isolated GIP90/130 polypeptide comprises at least 8 amino acids of the amino acid sequence of SEQ ID NO:32, which is a unique 20 amino acid polypeptide (LDKVVEKHKESYRRILGQLL) within I-20 that contains essential residues for the interaction between GIP90/130 polypeptides and GPBP and for GIP90/130 polypeptide aggregation, and is not present in DOC proteins. In further embodiments, the isolated GIP90/130 polypeptide comprises or consists of at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids of the amino acid sequence of SEQ ID NO:32. These polypeptides can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides and to modify GIP90/130 polypeptide aggregation, or to raise antibodies that modify interactions between GPBP and GIP90/130 polypeptides and to modify GIP90/130 polypeptide aggregation.
[0038]In another embodiment, the isolated GIP90/130 polypeptide consists of at least 8 amino acids of the amino acid sequence of SEQ ID NO:34, which is a 50 amino acid polypeptide that is contained within I-20, contains regions essential for the interaction between GIP90/130 polypeptides and GPBP and for GIP90/130 polypeptide aggregation, and is present in DOC proteins. In further embodiments, the isolated GIP90/130 polypeptide consists of at least 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acids of the amino acid sequence of SEQ ID NO:34. These polypeptides can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides and to modify GIP90/130 polypeptide aggregation, or to raise antibodies that modify interactions between GPBP and GIP90/130 polypeptides and to modify GIP90/130 polypeptide aggregation. Furthermore, since this polypeptide is present in each of GIP90, GIP130a, GIP130b, GIP130c, and DOC1 proteins, these polypeptides, or antibodies thereto, can be used to generally modify aggregation of the GIP90/130 polypeptides and DOC1/DOC1-related proteins. Despite the fact that DOC1 proteins contain SEQ ID NO:20, they do not interact in a two hybrid assay with GPBP (see below), and thus SEQ ID NO:20, while implicated in the interaction of GIP90/130 polypeptides and GPBP, is not sufficient for GPBP interaction.
[0039]The polypeptides of the invention also include polypeptides comprising and/or consisting of the amino acid sequence of SEQ ID NO:36, which consists of the first 240 amino acids of the N-terminus of GIP130b, which is not present in DOC1 proteins, and which differs from the corresponding sequence in GIP90, GIP130a, and GIP130c by a single amino acid residue at position 168. This polypeptide includes sequences implicated in (a) the interaction between GPBP and GIP90/130 polypeptides, (b) GIP90/130 polypeptide aggregation, and (c) the transcriptional activity of GIP90/130 polypeptides, and thus the polypeptides, or antibodies derived therefrom, can be used, for example, to modify interactions between GPBP and GIP90/130 polypeptides, to modify GIP90/130 aggregation, and to modulate gene expression.
[0040]In a still further embodiment, the isolated GIP 90/130 polypeptide consists of the amino acid sequence of SEQ ID NO:38 which is a unique 384 amino acid polypeptide that is present at the C terminus of GIP130b/c and DOC1-related protein but is not present in GIP90, is not wholly present in DOC1, and includes variations from GIP130a, and thus can be used, for example, to modify GIP130b/c aggregation, and to generate reagents, such as antibodies, to distinguish GIP130b/c and the DOC1-related protein from other members of the GIP90/130 polypeptide family.
[0041]As used herein, an "isolated polypeptide" refers to a polypeptide that is substantially free of other proteins, cellular material and culture medium when isolated from cells or produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Thus, the protein can either be purified from natural sources, chemically synthesized, or recombinant protein can be purified from the recombinant host cells disclosed below.
[0042]Synthetic polypeptides, prepared using the well known techniques of solid phase, liquid phase, or peptide condensation techniques, or any combination thereof, can include natural and unnatural amino acids. Amino acids used for peptide synthesis may be standard Boc (Nα-amino protected Nα-t-butyloxycarbonyl) amino acid resin with the standard deprotecting, neutralization, coupling and wash protocols of the original solid phase procedure of Merrifield (1963, J. Am. Chem. Soc. 85:2149-2154), or the base-labile Nα-amino protected 9-fluorenylmethoxycarbonyl (Fmoc) amino acids first described by Carpino and Han (1972, J. Org. Chem. 37:3403-3409). Both Fmoc and Boc Nα-amino protected amino acids can be obtained from Sigma, Cambridge Research Biochemical, or other chemical companies familiar to those skilled in the art. In addition, the polypeptides can be synthesized with other Nα-protecting groups that are familiar to those skilled in this art.
[0043]Solid phase peptide synthesis may be accomplished by techniques familiar to those in the art and provided, for example, in Stewart and Young, 1984, Solid Phase Synthesis, Second Edition, Pierce Chemical Co., Rockford, Ill.; Fields and Noble, 1990, Int. J. Pept. Protein Res. 35:161-214, or using automated synthesizers. The polypeptides of the invention may comprise D-amino acids (which are resistant to L-amino acid-specific proteases in vivo), a combination of D- and L-amino acids, and various "designer" amino acids (e.g., β-methyl amino acids, Cα-methyl amino acids, and Nα-methyl amino acids, etc.) to convey special properties. Synthetic amino acids include ornithine for lysine, fluorophenylalanine for phenylalanine, and norleucine for leucine or isoleucine.
[0044]In addition, the polypeptides can have peptidomimetic bonds, such as ester bonds, to prepare peptides with novel properties. For example, a peptide may be generated that incorporates a reduced peptide bond, i.e., R1--CH2--NH--R2, where R1 and R2 are amino acid residues or sequences. A reduced peptide bond may be introduced as a dipeptide subunit. Such a polypeptide would be resistant to protease activity, and would possess an extended half-live in vivo.
[0045]Alternatively, the proteins are produced by the recombinant host cells disclosed below, and purified using standard techniques. (See for example, Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press.)) The protein can thus be purified from prokaryotic or eukaryotic sources. In various further preferred embodiments, the protein is purified from bacterial, yeast, or mammalian cells.
[0046]The protein may comprise additional sequences useful for promoting purification of the protein, such as epitope tags and transport signals. Examples of such epitope tags include, but are not limited to FLAG (Sigma Chemical, St. Louis, Mo.), myc (9E10) (Invitrogen, Carlsbad, Calif.), 6-His (Invitrogen; Novagen, Madison, Wis.), and HA (Boehringer Manheim Biochemicals). Examples of such transport signals include, but are not limited to, export signals, secretory signals, nuclear localization signals, and plasma membrane localization signals.
[0047]In another aspect, the present invention provides antibodies against the GIP90/130 polypeptides disclosed herein. Such antibodies can be used in a manner similar to the polypeptides they recognize in modifying GPBP-GIP90/130 interactions, modifying GIP90/130 aggregation, and/or modifying GIP90/130-mediated transcriptional activity. Furthermore, such antibodies can be used to distinguish between members of the GIP90/130 family, as discussed above.
[0048]In one embodiment, the antibodies are directed against an epitope present in a polypeptide of one or more of the amino acid sequences selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:18, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:32, and SEQ ID NO:36. In a further embodiment, the antibodies are directed against an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO: 28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, and SEQ ID NO:38.
[0049]Antibodies can be made by well-known methods, such as described in Harlow and Lane, Antibodies; A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., (1988). In one example, pre-immune serum is collected prior to the first immunization. A peptide portion of the amino acid sequence of a GIP90/130 polypeptide, together with an appropriate adjuvant, is injected into an animal in an amount and at intervals sufficient to elicit an immune response. Animals are bled at regular intervals, preferably weekly, to determine antibody titer. The animals may or may not receive booster injections following the initial immunization. At about 7 days after each booster immunization, or about weekly after a single immunization, the animals are bled, the serum collected, and aliquots are stored at about -20° C. Polyclonal antibodies against GIP90/130 polypeptides can then be purified directly by passing serum collected from the animal through a column to which non-antigen-related proteins prepared from the same expression system without GIP90/130 polypeptides bound.
[0050]Monoclonal antibodies can be produced by obtaining spleen cells from the animal. (See Kohler and Milstein, Nature 256, 495-497 (1975)). In one example, monoclonal antibodies (mAb) of interest are prepared by immunizing inbred mice with a GIP90/130 polypeptide, or portion thereof. The mice are immunized by the IP or SC route in an amount and at intervals sufficient to elicit an immune response. The mice receive an initial immunization on day 0 and are rested for about 3 to about 30 weeks. Immunized mice are given one or more booster immunizations of by the intravenous (IV) route. Lymphocytes from antibody positive mice are obtained by removing spleens from immunized mice by standard procedures known in the art. Hybridoma cells are produced by mixing the splenic lymphocytes with an appropriate fusion partner under conditions which will allow the formation of stable hybridomas. The antibody producing cells and fusion partner cells are fused in polyethylene glycol at concentrations from about 30% to about 50%. Fused hybridoma cells are selected by growth in hypoxanthine, thymidine and aminopterin supplemented Dulbecco's Modified Eagles Medium (DMEM) by procedures known in the art. Supernatant fluids are collected from growth positive wells and are screened for antibody production by an immunoassay such as solid phase immunoradioassay. Hybridoma cells from antibody positive wells are cloned by a technique such as the soft agar technique of MacPherson, Soft Agar Techniques, in Tissue Culture Methods and Applications, Kruse and Paterson, Eds., Academic Press, 1973.
[0051]To generate such an antibody response, a GIP90/130 polypeptide or portion thereof is typically formulated with a pharmaceutically acceptable carrier for parenteral administration. Such acceptable adjuvants include, but are not limited to, Freund's complete, Freund's incomplete, alum-precipitate, water in oil emulsion containing Corynebacterium parvum and tRNA. The formulation of such compositions, including the concentration of the polypeptide and the selection of the vehicle and other components, is within the skill of the art.
[0052]The term antibody as used herein is intended to include antibody fragments thereof which are selectively reactive with GIP90/130 polypeptides. Antibodies can be fragmented using conventional techniques, and the fragments screened for utility in the same manner as described above for whole antibodies. For example, F(ab')2 fragments can be generated by treating antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments.
[0053]In another aspect, the present invention provides isolated nucleic acids that encode GIP90/130 polypeptides. In one embodiment, the isolated nucleic acid sequences comprise sequences encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO: 28, SEQ ID NO:32, and SEQ ID NO:36. In a further embodiment, the isolated nucleic acid sequences consist of sequences encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO: 28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO; 34, SEQ ID NO:36, and SEQ ID NO:38.
[0054]In another embodiment, the isolated nucleic acids comprise sequences that hybridize under high stringency conditions to a nucleic acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:17, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:31, and SEQ ID NO:35, their complement, or their transcription product. Stringency of hybridization is used herein to refer to conditions under which nucleic acid hybrids are stable. As known to those of skill in the art, the stability of hybrids is reflected in the melting temperature (TM) of the hybrids. TM decreases approximately 1-1.5° C. with every 1% decrease in sequence homology. In general, the stability of a hybrid is a function of sodium ion concentration and temperature. Typically, the hybridization reaction is performed under conditions of lower stringency, followed by washes of varying, but higher, stringency. Reference to hybridization stringency relates to such washing conditions. Thus, as used herein, high stringency refers to conditions that permit hybridization of those nucleic acid sequences that form stable hybrids in 0.1% SSPE at 65° C. It is understood that these conditions may be duplicated using a variety of buffers and temperatures and that they are not necessarily precise. Denhardt's solution and SSPE (see, e.g., Sambrook, Fritsch, and Maniatis, in: Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1989) are well known to those of skill in the art, as are other suitable hybridization buffers.
[0055]In another embodiment, the isolated nucleic acids comprise one or more sequences selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:17, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:31, and SEQ ID NO:35, their complement, or their transcription product. In a further embodiment, the isolated nucleic acid sequences comprise one or more sequences selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:31, and SEQ ID NO:35, their complement, or their transcription product. In a further embodiment, the isolated nucleic acid sequences consist of one or more sequences selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, and SEQ ID NO:37, their complement, or their transcription product.
[0056]As used herein, an "isolated nucleic acid sequence" refers to a nucleic acid sequence that is free of gene sequences which naturally flank the nucleic acid in the genomic DNA of the organism from which the nucleic acid is derived (i.e., genetic sequences that are located adjacent to the gene for the isolated nucleic molecule in the genomic DNA of the organism from which the nucleic acid is derived). An "isolated" GIP90/130 nucleic acid sequence according to the present invention may, however, be linked to other nucleotide sequences that do not normally flank the recited sequence, such as a heterologous promoter sequence, or other vector sequences. It is not necessary for the isolated nucleic acid sequence to be free of other cellular material to be considered "isolated", as a nucleic acid sequence according to the invention may be part of an expression vector that is used to transfect host cells (see below).
[0057]In all of these embodiments, the isolated nucleic acid sequence may comprise RNA or DNA, and may be single stranded or double stranded. Such single stranded sequences can comprise the disclosed sequence, its complement, or the transcription product thereof. The isolated sequence may further comprise additional sequences useful for promoting expression and/or purification of the encoded protein, including but not limited to polyA sequences, modified Kozak sequences, and sequences encoding epitope tags, export signals, and secretory signals, nuclear localization signals, and plasma membrane localization signals.
[0058]In another embodiment, the present invention provides an expression vector comprising an isolated nucleic acid as described above, operatively linked to a promoter. In a preferred embodiment, the promoter is heterologous (i.e.: is not the naturally occurring GIP90/130 promoter). A promoter and a GIP90/130 nucleic acid sequence are "operatively linked" when the promoter is capable of driving expression of the GIP90/130 DNA into RNA.
[0059]As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA into which additional DNA segments may be cloned. Another type of vector is a viral vector, wherein additional DNA segments may be cloned into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors), are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of nucleic acid sequences to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors". In the present invention, the expression of any nucleic acid sequence is directed by operatively linking the promoter sequences of the invention to the nucleic acid sequence to be expressed. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
[0060]The vector may also contain additional sequences, such as a polylinker for subcloning of additional nucleic acid sequences and a polyadenylation signal to effect proper polyadenylation of the transcript. The nature of the polyadenylation signal is not believed to be crucial to the successful practice of the invention, and any such sequence may be employed, including but not limited to the SV40 and bovine growth hormone poly-A sites. The vector may further include a termination sequence, which can serve to enhance message levels and to minimize read through from the construct into other sequences. Finally, expression vectors typically have selectable markers, often in the form of antibiotic resistance genes, that permit selection of cells that carry these vectors.
[0061]In a further embodiment, the present invention provides recombinant host cells in which the expression vectors disclosed herein have been introduced. As used herein, the term "host cell" is intended to refer to a cell into which a nucleic acid of the invention, such as a recombinant expression vector of the invention, has been introduced. Such cells may be prokaryotic or eukaryotic.
[0062]The terms "host cell" and "recombinant host cell" are used interchangeably herein. It should be understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.
[0063]The host cells can be transiently or stably transfected with one or more of the expression vectors of the invention. Such transfection of expression vectors into prokaryotic and eukaryotic cells can be accomplished via any technique known in the art, including but not limited to standard bacterial transformations, calcium phosphate co-precipitation, electroporation, or liposome mediated-, DEAE dextran mediated-, polycationic mediated-, or viral mediated transfection. Alternatively, the host cells can be infected with a recombinant viral vector comprising the GIP90/130 nucleic acid. (See, for example, Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press; Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R. I. Freshney. 1987. Liss, Inc. New York, N.Y.).
[0064]In a further aspect, the invention provides methods for detecting the presence of the GIP90/130 polypeptides in a protein sample, comprising providing a protein sample to be screened, contacting the protein sample to be screened with an antibody against one or more GIP90/130 polypeptides, and detecting the formation of antibody-GIP90/130 polypeptide complexes. The antibody can be either polyclonal or monoclonal, although monoclonal antibodies are preferred. As used herein, the term "protein sample" refers to any sample that may contain GIP90/130 polypeptides, including but not limited to tissues and portions thereof, tissue sections, intact cells, cell extracts, purified or partially purified protein samples, bodily fluids, and nucleic acid expression libraries. Accordingly, this aspect of the present invention may be used to test for the presence of GIP90/130 polypeptides in these various protein samples by standard techniques including, but not limited to, immunolocalization, immunofluorescence analysis, Western blot analysis, ELISAs, and nucleic acid expression library screening, (See for example, Sambrook et al, 1989.) In one embodiment, the techniques may determine only the presence or absence of GIP90/130 polypeptides. Alternatively, the techniques may be quantitative, and provide information about the relative amount of GIP90/130 polypeptides in the sample. For quantitative purposes, ELISAs are preferred.
[0065]Detection of immunocomplex formation between GIP90/130 polypeptides and antibodies or fragments thereof directed against GIP90/130 polypeptides can be accomplished by standard detection techniques. For example, detection of immunocomplexes can be accomplished by using labeled antibodies or secondary antibodies. Such methods, including the choice of label are known to those ordinarily skilled in the art. (Harlow and Lane, Supra). Alternatively, the polyclonal or monoclonal antibodies can be coupled to a detectable substance. The term "coupled" is used to mean that the detectable substance is physically linked to the antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase. Examples of suitable prosthetic-group complexes include streptavidin/biotin and avidin/biotin. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin. An example of a luminescent material includes luminol. Examples of suitable radioactive material include 125I, 131I, 35S or 3H.
[0066]Such methods of detection are useful for a variety of purposes, including but not limited to detecting an autoimmune condition, identifying cell division arrest or cell death, detecting GIP90/130 interactions with GPBP or other proteins, immunolocalization of GIP90/130 polypeptides in a tissue sample, Western blot analysis, and screening of expression libraries to find related proteins.
[0067]In yet another aspect, the invention provides methods for detecting the presence of nucleic acid sequences encoding GIP90/130 polypeptides in a sample comprising providing a nucleic acid sample to be screened, contacting the sample with a nucleic acid probe derived from the isolated nucleic acid sequences of the invention, or fragments thereof, and detecting complex formation.
[0068]As used herein, the term "sample" refers to any sample that may contain a GIP90/130 polypeptide-encoding nucleic acid, including but not limited to tissues and portions thereof, tissue sections, intact cells, cell extracts, purified or partially purified nucleic acid samples, DNA libraries, and bodily fluids. Accordingly, this aspect of the present invention may be used to test for the presence of GIP90/130 polypeptide-encoding mRNA or DNA in these various samples by standard techniques including, but not limited to, in situ hybridization, Northern blotting, Southern blotting, DNA library screening, polymerase chain reaction (PCR) or reverse transcription-PCR (RT-PCR). (See for example, Sambrook et al, 1989.) In one embodiment, the techniques may determine only the presence or absence of the nucleic acid of interest. Alternatively, the techniques may be quantitative, and provide information about the relative amount of the nucleic acid of interest in the sample. For quantitative purposes, quantitative PCR and RT-PCR are preferred. Thus, in one example, RNA is isolated from a sample, and contacted with an oligonucleotide derived from the GIP90/130 polypeptide-encoding nucleic acid sequence, together with reverse transcriptase, under suitable buffer and temperature conditions to produce cDNAs from the GIP90/130 RNA. The cDNA is then subjected to PCR using primer pairs derived from the appropriate nucleic acid sequence disclosed herein. In a preferred embodiment, the primers are designed to detect the presence of the RNA expression product of GIP90/130, and the amount of GIP90/130 gene expression in the sample is compared to the level in a control sample.
[0069]For detecting GIP90/130 nucleic acid sequences, standard labeling techniques can be used to label the probe, the nucleic acid of interest, or the complex between the probe and the nucleic acid of interest, including, but not limited to radio-, enzyme-, chemiluminescent-, or avidin or biotin-labeling techniques, all of which are well known in the art. (See, for example, Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, Calif.); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, Calif.)).
[0070]Such methods of nucleic acid detection are useful for a variety of purposes, including but not limited to detecting an autoimmune condition, identifying cell division arrest or cell death, identifying cells that express GIP90/130 nucleic acid sequences, in situ hybridization for GIP90/130 gene expression, Northern and Southern blot analysis, and DNA library screening.
[0071]As discussed above, GIP90/130 polypeptides are likely to be involved in cell signaling pathways that impair cell division or cause cell death, which are thought to be up-regulated during autoimmune pathogenesis and down-regulated in cancer cells to prevent autoimmune attack during tumor growth. Thus, the detection methods disclosed herein can be used to detect cells that are undergoing such cell death-related processes.
[0072]Furthermore, the present invention provides method for treating an autoimmune disorder or cancer comprising modifying the expression or activity of GIP90/130 RNA or GIP90/130 polypeptides, such as by increasing or decreasing their expression or activity. Modifying the expression or activity of GIP90/130 RNA or GIP90/130 polypeptides can be accomplished by using specific inducers or inhibitors of GIP90/130 polypeptide expression or activity, such as GIP90/130 antibodies, polypeptides representing interactive motifs of GIP90/130 such as those disclosed herein, antisense or RNA interference therapy based on the design of antisense oligonucleotides or double stranded RNAs to the GIP90/130 nucleic acid sequences disclosed herein, cell therapy using host cells expressing one or more GIP90/130 polypeptides, or other techniques known in the art. As used herein, "modification of expression or activity" refers to modifying expression or activity of either the RNA or protein product.
[0073]For example, knowing that the GIP90/130 gene is a tumor suppressor gene, that aberrantly increased cell death processes are the basis of specific autoimmune pathogenesis (WO 00/50607), and that aggregates of GIP90/130 polypeptides are expressed in a number of human tissues that are common target of autoimmune responses, the administration of GIP90/130 polypeptides or nucleic acids of the invention, particularly those representing essential interactive motifs for GIP90/130 polypeptide aggregation and/or interaction with other cellular components, such as GPBP, would impact pathogenesis and therefore serve as therapeutic agents for autoimmunity. Alternatively, tumor cells express little or no GPBP or GIP90/130, and thus the administration of the GIP90/130 polypeptide or nucleic acid sequences of the invention, particularly the full length GIP90, GIP130a, GIP130b, and/or GIP130c, alone or in combination with GPBP, is expected to provide a therapeutic benefit in patients with cancer.
[0074]While not being limited to any specific mechanism of action, it is believed that a therapeutic benefit in cancer patients would be derived by promoting GIP90/130 interactions with other cellular constituents, such as GPBP and/or GIP90/130 aggregation, whereas a therapeutic benefit to autoimmunity patients would be derived by inhibiting these interactions and/or aggregation.
[0075]In another aspect, the invention provides methods for modifying GIP90/130 activity comprising contacting cells with an amount effective of one or more of the polypeptides, antibodies, nucleic acids, or pharmaceutical compositions thereof, of the invention to modify GIP90/130 activity. Such cell contacting can be in vitro or in vivo, and "modifying" includes both increasing or decreasing GIP90/130 activity, including transcription-promoting activity.
[0076]In another aspect, the invention provides methods for modifying GPBP activity, comprising contacting cells with an amount effective of one or more of the polypeptides, antibodies, nucleic acids, or pharmaceutical compositions thereof, of the invention to modify GPBP activity. Such cell contacting can be in vitro or in vivo, and "modifying" includes both increasing or decreasing GPBP activity. For example, augmented GPBP activity is associated with autoimmunity, and thus the administration of the GIP90/130 polypeptides or antibodies of the invention (or gene therapy by administration of the GIP90/130 nucleic acid sequences or vectors thereof of the invention) would be expected to impact GPBP-GIP90/130 interactions, and to provide a therapeutic benefit in patients with an autoimmune disorder. Alternatively, tumor cells express little or no GPBP, and thus the co-administration of the GIP90/130 polypeptides of the invention, particularly the full length GIP90, GIP130a, GIP130b, and/or GIP130c, in combination with GPBP, would be expected to provide a therapeutic benefit in patients with cancer.
[0077]In another aspect, the present invention provides methods for modifying pol κ76 polypeptide activity, comprising contacting cells with an amount effective of one or more of the polypeptides, antibodies, nucleic acids, or pharmaceutical compositions thereof, of the invention to modify pol κ76 activity. Such cell contacting can be in vitro or in vivo, and "modifying" includes both increasing or decreasing pol κ76 activity. For example, augmented pol κ76 activity is associated with autoimmunity (WO 02/46378), and thus the administration of the GIP90/130 polypeptides or antibodies of the invention (or gene therapy by administration of the GIP90/130 nucleic acid sequences or vectors thereof of the invention) would be expected to impact pol κ76-GIP90/130 interactions, and to provide a therapeutic benefit in patients with an autoimmune disorder.
[0078]In practicing the therapeutic methods of the invention, the amount or dosage range of the GIP90/130 polypeptides or antibodies thereto generally ranges between about 0.01 μg/kg body weight and about 10 mg/kg body weight, preferably ranging between about 0.10 μg/kg and about 5 mg/kg body weight, and more preferably between about 1 μg/kg and about 5 mg/kg body weight.
[0079]In a further aspect, the present invention provides pharmaceutical compositions, comprising an amount effective of the GIP90/130 polypeptides, antibodies thereto, and nucleic acids disclosed herein to carry out one or more of the therapeutic methods of the invention, and a pharmaceutically acceptable carrier. The GIP90/130 polypeptides, or antibodies thereto, may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
[0080]For administration, the polypeptides are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
[0081]The polypeptides or pharmaceutical compositions thereof may be administered by any suitable route, including orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intra-arterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally. In preferred embodiments, the polypeptides are administered intravenously or subcutaneously.
[0082]The polypeptides may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The polypeptides of the invention may be applied in a variety of solutions. Suitable solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the polypeptides, and are not harmful for the proposed application.
[0083]The present invention may be better understood with reference to the accompanying examples that are intended for purposes of illustration only and should not be construed to limit the scope of the invention, as defined by the claims appended hereto.
Examples
Identification and Characterization of GIP90/130 Polypeptides
[0084]We performed a yeast two-hybrid screening on several human cDNA libraries searching for GPBP-interactive proteins. The screenings were performed using full length GPBP as bait, cloned in vector pGBT9 to generate the GAL4 binding domain-fusion protein. With the resulting construct we transformed yeast HF7c cells to obtain a stably transfected cell line which was subsequently transformed with the different cDNA libraries we have used: Human Skeletal Muscle (pGAD10 vector), Human Kidney (pGAD10), Human Pancreas (pGAD10), Human Brain (pACT2) and Hela (pGADGH) cDNA libraries (all from Clontech). The transformations were carried out according to the supplier's instructions and plated on medium deficient in Trp, Leu and His containing 20 mM 3-amino-1,2,4-triazol. Interactions were assessed following the manufacture's recommendations. Specifically β-galactosidase activity was assayed with X-GAL (0.75 mg/ml) for the lift colony assays and with ortho-nitrophenyl β-D galactopyranoside (0.66 mg/ml) for the in-solution determinations.
[0085]We isolated an 800 by cDNA ("I-20 cDNA") encompassing an open reading frame (ORF) which encodes a 265 residue polypeptide, I-20 (SEQ ID NO:6); from a human skeletal muscle library. Part of the ORF coincided with the ORF encoding DOC1 (down-regulated in ovarian cancer 1) (GenBank accession NP--055705) (Mok et al., Gynecol. Oncol. 52(2):247-252 (1994)), a polypeptide whose encoding mRNA is not found in ovarian cancer cell lines, but is abundantly expressed in normal ovarian cell lines. For this reason, the DOC-1 gene is considered to be a tumor suppressor gene.
[0086]Using the I-20 cDNA, we probed a multi-tissue Northern blot (Clontech) to determine the level of expression of the I-20 encoding mRNA in normal human tissues and in a number of human cancer cell lines. The membranes were hybridized with 32P-α-dCTP labelled I-20 cDNA (SEQ ID NO:5), and specific mRNAs species were identified by autoradiography, We identified four mRNA species of 9, 4.4, 4 and 3 Kb. The species of 9, 4.4 and 3 Kb were more abundant in skeletal muscle, while the 4 Kb species displayed similar expression in skeletal muscle, pancreas and lung, and higher expression in heart tissue. With the exception of heart, which contained traces of the 9, 4.4 and 3 Kb species, the rest of the tissues tested mainly expressed the 4 Kb mRNA species. As expected from previous studies for DOC1, I-20 cDNA did not hybridize significantly to any mRNA species from the individual human cancer cell lines tested (MTN human cancer cell line blot from Clontech), thus confirming I-20 as being encoded by a tumor suppressor gene.
[0087]Since the I-20 ORF contained no stop codon and extended 5' past the ORF proposed for DOC1, we explored the possibility that in skeletal muscle I-20 represents a partial sequence of a larger protein. By probing the corresponding cDNA library with the I-20 cDNA, we isolated and characterized by nucleotide sequencing four overlapping cDNA clones which in total comprise an ORF encoding a predicted 764-amino acid polypeptide of 90 kDa that was named GIP90 (SEQ ID NO:10), for GPBP interacting protein 90 kDa. The existence of GIP90 mRNA was confirmed by isolating and nucleotide sequencing a continuous PCR fragment derived from the same library containing the proposed overlapping ORF. The more remarkable structural features of GIP90 are the presence of two nuclear localization signals (NLS), one in the N terminal region and another at the C terminal region, and a highly predictable coiled-coil formation through most of its sequence including two leucine zippers.
[0088]Using the cDNA nucleotide sequence of GIP90 ("GIP90 cDNA") (SEQ ID NO: 9) we carried out a BLAST search against the human genome and found that GIP90 cDNA matched at chromosome 3 (3q12) (genomic DNA accession numbers NT--030634 for exon I and NT--033050 for the rest of the exons). We determined the exon/intron structure for the GIP90 genomic sequence, which encompass a total of six exons (FIG. 1). Exons I-IV of the GIP90 gene contain 5' untranslatable sequence and encode the first 201 residues of an N-terminal segment of 240 residues that is absent in DOC1 and DOC1-related protein (GenBank accession number AAH27860). Exon V encodes the remaining 39 residues not present in DOC proteins as well as the additional 524-residues of GIP90, and exon VI contains 3' untranslatable sequence.
[0089]Comparison of the GIP90 cDNA and the GIP90 genomic sequence revealed the existence of an adenine (A) at position 2720 (A2720) in the GIP90 cDNA that was not present in the GIP90 genomic DNA, suggesting that GIP90 cDNA represents either a cDNA artifact, or a native mRNA species that derives from a DNA polymorphism or mRNA editing. Mutational artifacts are generally unique events unlikely to be found in more than one cDNA molecular species. We have identified A2720 in at least two different GIP90 cDNA fragments, representing two different reverse transcription events, and PCR on total cDNA from the human muscle library (Clontech) using a forward primer from exon I and a reverse primer from exon VI, and subsequent direct sequencing, revealed that the resulting cDNA exclusively contained A2720. A homologous nucleotide was also found in a DOC1 encoding sequence, but not in DOC1-related protein encoding sequences. These results indicate that the A2720 in the GIP90 cDNA does not represent an artifact.
[0090]In order to further analyze the origin of GIP90 cDNA, we studied the expression of GIP90 in two independent human skeletal muscle tissue samples by RT-PCR. We were unable to amplify GIP90 mRNA from these samples. In contrast, we isolated and characterized a continuous cDNA fragment (SEQ ID NO:11) representing a related mRNA species that encodes a 130 kDa polypeptide (1135-residues) that we named GIP130a (SEQ ID NO:12). GIP130a results from faithful transcription and translation of the GIP90 genomic sequence (ie: no A2720), suggesting that a specific mechanism for mRNA diversification is responsible for the production of GIP90 encoding mRNA from the GIP90 genomic sequence.
[0091]To further explore the mRNA diversification mechanism of the DOC1/GIP90/130 family, we compared the nucleotide sequences encoding DOC1/DOC1-related protein, GIP90, and GIP130a. Several nucleotide differences were identified, namely: (1) DOC-1 and DOC1-related mRNA are devoid of exon I-IV; (2) DOC1 mRNA showed nucleotide deletions of 42- and 18-bp in exon V, and both DOC1 and DOC1-related mRNA contain an additional 276-bp at the 3' end of this exon, which corresponds to an intron sequence in GIP90/130a; (3) DOC-1 and DOC1-related mRNAs are both devoid of exon VI.
[0092]Therefore, it appeared that the expression of exon VI is associated with expression of GIP90/130a mRNAs, and that DOC-1 and DOC1-related mRNAs are exclusively encoded by an intron-extended exon V. The existence of DOC-1 mRNAs containing exons I-IV was then assessed by PCR of mRNA from human skeletal muscle and from human 293 cells. We obtained two different cDNAs (SEQ ID NOS: 13 and 15) both containing exon I-V sequences and DOC-1 exclusive exon V, and diverging with respect to each other in one single nucleotide (A/G) at position 975, which leads to an amino acid change at position 168 (H168/R168). This results in two different 1133-residue long polypeptides (130-kDa) which we named GIP130b (SEQ ID NO: 14) and GIP130c (SEQ ID NO: 16), respectively. A comparison of the amino acid sequences of GP90/130 polypeptides and the DOC1 polypeptide family is shown in FIG. 3.
[0093]The amino acid sequence of rat filamin A-interacting protein (FILIP) (Genbank accession number BAC00851) and hypothetical human KIAA1275 protein (Genbank accession number BAA86589) are highly homologous (approximately 50%) to the GIP90/130 and DOC proteins. This suggests that these genes are related and that FILIP, KIAA1275 and GIP90/130 are likely to share biological functions. Therefore, knowing that FILIP impairs cell migration of cortical neurons (Nature Cell Biology 2002 July; 4(7):495-501), it is plausible to hypothesize that GIP90/130 polypeptides exert their tumor suppressor activity, at least in part, by impairing cell migration.
[0094]The above data demonstrate that the DOC-1/GIP90/130 mRNA family results from a complex diversification mechanism operating on the expression of the corresponding gene (GIP90 genomic sequence). Thus, we have found that the presence of R168 or H168 is the result of a GIP90 genomic sequence polymorphism. The presence of exon V, which is characteristic of GIP90/GIP130a (exon Va), is linked to the expression of exon VI and represents a complex alternative exon splicing in which the alternative use of two 5' splice sites of an intron is coordinated with the splicing of an alternative 3' terminal exon. Thus, when the more upstream 5' splice site is used to yield a shorter exon V (exon Va), the 3' terminal exon (exon VI) is spliced, whereas when using the more downstream 5' splice site resulting in a larger exon V (exon Vb), the 3' terminal exon (exon VI) is not spliced. Regarding A2720, we still are in the process of determining the specific diversification mechanism responsible for its presence. The exon/intron structure of the gene for the DOC-1/GIP90/130 family is shown in FIG. 1 and a scheme for the more relevant features regarding mRNA and protein structure for the GIP family is presented in FIG. 2. Finally, similar genetic diversification mechanisms perhaps are responsible for the deletion of C2708 in DOC1 and an aberrant alternative splicing within long exons (previously described for other genes) appears to account for the 42- and 18-by deletions found in DOC1 mRNA.
[0095]The presence of R168 in GIP90 generates a putative bipartite NLS signal and a consensus for PKA phosphorylation, whereas the presence of A2720 causes a frame-shift in the ORF encoding GIP90, which results in the appearance of a second nuclear localization signal and a premature stop codon. The latter removes a total of 386 residues of the C terminal region that is present in GIP130 proteins. These residues appear to conform to a domain with no predictable coiled-coils containing a number of putative O-glycosylation sites (FIG. 2).
Characterization of GIP90/130 Interactions
[0096]Using a yeast two-hybrid system, we found that the four members of the GIP90/130 interact with GPBP, although to a more limited extent than I-20 (SEQ ID NO:6). GIP90 displayed the strongest interaction with GPBP, whereas individual GIP130 proteins interacted similarly with GPBP, although to a lesser extent than GIP90. These data implicate the C-terminal residues of the GIP130 proteins, which are not present in GIP90, and also the C-terminal residues of GIP90 not present in I-20 in a negative modulation of the interaction of GIP90/130 polypeptides with GPBP. Deletion of the N terminal 240-residues of GIP90, GIP130b, and GIP130c resulted in molecular species that do not interact with GPBP, indicating that the N-terminal region contains residues involved in the interaction of GIP90/130 polypeptides with GPBP. All of these findings account for the observation that I-20 (SEQ ID NO: 6), which contains the bulk of this N terminal region (residues 86-240), and does not harbor the inhibitory C terminal regions, displayed the strongest interaction in a two hybrid system with GPBP. The production of additional I-20 deletion mutants and their use in specific two hybrid studies permitted the identification of two specific regions of I-20 that are essential for GPBP interaction as well as the identification of other residues directly involved but not essential for the interaction (FIG. 4).
[0097]GIP90/130 polypeptides self-aggregate and aggregate with each other in a yeast two-hybrid assays, indicating that, similarly to GPBP (WO 00/50607), GIP90/130 polypeptides aggregate to form homo and hetero oligomers. No significant differences were found among GIP90/130 full length polypeptides in their ability to self-aggregate. Deletion of the N-terminal 240-residues from GIP130b/c results in DOC1-related protein, which aggregates more efficiently and does not interact with GPBP. Since the deleted residues contain motifs for I-20 self-aggregation, it is conceivable that the deleted region contains residues that are critical for GIP90/130 aggregation, but not for DOC/DOC1-related protein aggregation, and that GIP90/130 polypeptides and DOC1 polypeptides aggregate in a different manner. Since the N terminal 240 residues also contain essential residues for GIP90/130 polypeptide interactions with GPBP, this further suggests that GPBP interaction negatively modulates GIP90/130 polypeptide aggregation but not DOC aggregation. Consistently, two hybrid assays using I-20 deletion mutants show that essential sequences for GIP90/130 interactions with GPBP and for I-20 aggregation overlap extensively (FIG. 4), strongly suggesting that GPBP binding to GIP90/130 polypeptides prevents GIP90/130 polypeptide aggregation but not DOC aggregation. Accordingly, we have observed with a yeast three-hybrid system that GPBP expression efficiently impairs both I-20 and GIP90 aggregation, and that I-20 and GIP90 efficiently impair GPBP aggregation.
[0098]Deletion mutants were obtained using specific primers and PCR, followed by cloning of the resulting cDNAs in the pGBT9 and pGAD424 vectors. The assays were performed in SFY526 or HF7c Saccharomyces cerevisiae strains, with pGBT9 as GAL4 binding domain vector and pGAD424 as GAL4 activation domain vector, by the lift colony assay procedure. Briefly, the yeast cells were co-transformed with constructs of both binding domain and activation domain vectors, and the co-transformants were selected in medium deficient in both tryptophan and leucine. After five days of incubation at 30° C. the colonies were tested for the expression of β-galactosidase with X-Gal substrate (0.75 mg/ml). The intensity of the blue color displayed in the assay informed us about the relative strength of the interactions. When the assays were performed with the HF7c strain, the interactions were assessed by the lift colony assay procedure and by growth in medium deficient in histidine, tryptophan and leucine. For yeast three-hybrid system, we used the pBRIDGE vector, which allows the conditional expression of a third protein apart from the usual GAL4 binding and activation domain-fusion proteins of the two-hybrid system. In this case, the expression of GPBP or I-20 or GIP90 was driven by Met25 promoter, active in absence of methionine. In these experiments, the transformed SFY526 cells were plated in medium deficient in tryptophan, leucine and methionine, and subjected to the colony lift assay after five days at 30° C. In the case of the strain HF7c the colonies grown in the cited plates were streaked on medium with the additional deficiency of histidine.
[0099]In an attempt to establish the viability of these molecular interactions in human cells, the interaction between GIP90 and GPBP was assessed in a mammalian two-hybrid system using 293 cells. We used the CLONTECH mammalian two hybrid kit, with vectors pM and pRK5-GAL4BD as GAL4 binding domain vectors and pVP16 as activation domain vector. We transfected 293 cells by the calcium phosphate procedure with the appropriate constructs and reporter vectors and the interactions determined by the CAT ELISA kit (Roche), following the manufacturer's instructions.
[0100]Finally, using a yeast two hybrid system, we investigated the interactions between pol κ/pol κ76 and GPBP/GPBPΔ26 and we got no positive results. However, when we challenged interaction between pol κ or pol κ76 and I-20, we obtained positive results with pol κ76 but not with pol κ. The positive interaction of I-20 with pol κ76 suggests that GIP90 is a biological bridge between GPBP and pol κ76 and that the three proteins are partners in specific strategies which become deregulated during autoimmune pathogenesis.
[0101]From all these data, we conclude that: (1) GIP90/130 polypeptides aggregate in a different manner than DOC/DOC1-related polypeptides; (2) GPBP interacts with GIP90/130 polypeptides and this interaction counteracts GIP90/130 polypeptide aggregation; (3) GPBP does not interact with DOC/DOC1-related proteins, and therefore GPBP is not expected to influence DOC/DOC1-related protein aggregation; (4) I-20 contains essential amino acid sequences involved in GPBP interaction with GIP90/130 polypeptides and in GIP90/130 polypeptide aggregation; (5) the C terminal domain of GIP130 species exerts a negative effect on their interactions with GPBP, and (6) GIP90/130 polypeptides contain sequences not present in I-20 that negatively modulate both GIP90/130 polypeptide interaction with GPBP and GIP90/130 polypeptide aggregation.
Further Characterization of GIP90/130
[0102]Given that GPBP is a protein kinase, we assessed the capacity of GPBP to phosphorylate GIP90 in vitro by using purified yeast recombinant counterparts. GIP90 was cloned in pHIL-D2 vector in frame with the FLAG tag at N-terminal position and with a 6 histidine tail at C-terminal position. It was expressed in the Pichia pastoris expression system (Invitrogen) and purified with an affinity resin (Clontech) making profit of the polyhistidine tail, using an 8 M urea-containing breaking buffer, which was eliminated by dialysis against Tris-buffered saline. The purified protein was incubated with yeast recombinant GPBP in a suitable reaction buffer and labelled for 12 hours at 30° C. The phosphorylation mixtures were analysed by Western blot using FLAG-specific antibodies (Sigma) and autoradiography. Incubation of purified GIP90 and GPBP in the presence of [y32P] ATP resulted in 32P incorporation into GIP90, thus confirming that GPBP interacts with GIP90 and phosphorylates it.
[0103]Remarkable structural features of GIP90/130 proteins are (1) the existence of two nuclear localization sequences (NLS) whose presence appears to be regulated by single nucleotide replacement or addition (see above); and (2) the existence of a large number of predictable coiled-coil motifs including two leucine zippers. Consequently we have assayed the ability of GIP90/130 and DOC1-related protein to induce transcription from a heterologous promoter of a reporter gene. This was accomplished by fusing either GIP90, GIP130a, GIP130b or DOC1-related protein to the binding domain of GAL4 transcription factor in a high level expression pAS2-1 vector (Clontech) and transforming SFY526 yeast cells carrying a LacZ reporter gene under the control of a promoter with a GAL4 binding site. Transformants were selected in tryptophan-deficient medium at 30° C. for five days and colony lift assays performed. The GIP90, GIP130a, and GIP130b fusion polypeptides, but not DOC1-related protein fusion polypeptides, efficiently induced expression of LacZ, as estimated by the appearance of β-galactosidase activity.
[0104]We have also expressed GIP90 in bacteria, and have used the corresponding recombinant protein to immunize both rabbits and mice to obtain respectively polyclonal and monoclonal antibodies specific for GIP proteins. GIP90 was cloned in pGEX vector, in frame with glutathione-S-transpherase cDNA. The resulting construct was used to transform DH5α cells and expression of the GST-GIP90 fusion protein was induced with IPTG and further purified on glutathione affinity column. GST-GIP90 purified protein was used to immunize both rabbits and mice in order to obtain respectively polyclonal and monoclonal antibodies. These antibodies were used to identify a native protein in 293 cells displaying the same mobility as recombinant GIP130 which likely represents endogenous GIP130b or GIP130c, since exon VI appears to not be expressed in these cells, as determined by specific RT-PCR approaches. One of the monoclonal antibodies (Mab3) maps in the N terminal 240 residues of GIP90, whereas Mab 8 maps within the next 509 residues (i.e.: between residues 241-750).
[0105]By indirect immunofluorescence on COS-7 cells transiently expressing recombinant GIP90 we have identified cells that expressed GIP90 in the nucleus, cells expressing GIP90 in the cytosol, and cells that expressed GIP90 in both the nucleus and the cytosol. When these cells co-expressed recombinant GIP90 and GPBP, double indirect immunofluorescence revealed expression of the two proteins at the cytosol and in some cells GIP90 was also detected in the nucleus. We have not seen GIP90 and GPBP being co-expressed in the nucleus. Finally, using confocal microscopy and NIH3T3 or 293 cells, we have confirmed nuclear localization of GIP90 and cytosolic co-localization GIP90/GPBP. These cells do not express detectable levels of GIP90/130 polypeptides, as no significant fluorescence was detected when non-transfected cells were incubated with anti-GIP antibodies and an appropriate secondary antibody. For immunofluorescence and confocal microscopy studies, GIP90 cDNA was cloned in pRK5 mammalian expression vector, and this construct was used alone or co-transfected with GPBP cloned in pCDNA3 vector (Invitrogen), using the DEAE-dextran or calcium phosphate procedures. After 24 hours of incubation at 37° C., the cells were washed with phosphate-buffered saline (PBS), fixed with methanol or methanol:acetone, blocked with 3% BSA in PBS and incubated with a pool of mouse anti-GIP90 monoclonal antibodies and rabbit anti-GPBP polyclonal antibodies. FITC-conjugated anti-mouse IgG and TRITC-conjugated anti-rabbit IgG antibodies were respectively used as secondary antibody.
[0106]Finally, we have performed immunohistochemistry studies on paraffin embedded human tissues and have found GIP proteins to localize in a number of cells and structures also expressing GPBP. Immunohistochemistry studies were done on human multi-tissue control slides (Biomeda, Dako), using the ABC peroxidase method. GIP proteins are widely expressed in human tissues, but are more abundantly expressed in some locations. A strong staining is found in smooth muscle cells, particularly in those of vessel walls, with a diffuse cytoplasmic pattern. There is intense expression in alveolar septa, with a linear pattern suggestive of being associated to basement membrane locations, along with cytoplasmic staining of the pneumocytes. The kidneys show expression in the epithelial cells of the tubules, mainly in distant ones, and also in mesangial cells and podocytes of the glomerulus. In the pancreas there is staining in the cells of endocrine Langerhans islets. In the adrenal gland, the cortical cells show higher expression than the medullar cells. In the liver, hepatocytes show expression of the GIP90/130, which is higher at the epithelial cells of the biliary ducts. The white matter of the central nervous system shows diffuse staining with a fibrillar pattern, with presence also found in some neuronal bodies. Expression of the GIP90/130 is also evident at the epithelial cells of the prostate, breast, bronchi and intestine, in striated muscle cells of the myocardium, in secretory cells of the pituitary, and in spermatogonium and Leydig cells in the testicle.
[0107]The expression of the GIP90/130 is quite similar to that previously described for GPBP (WO 00/50607), with staining in tissues targeted by autoimmune responses, such as the Langerhans islets (type I diabetes), the white matter of the central nervous system (multiple sclerosis), the biliary ducts (primary biliary cirrhosis), the cortex of the adrenal gland (Addison disease), alveolar septa (Goodpasture syndrome), and spermatogonium (male infertility).
[0108]The evidence suggests that GIP90/130 is a family of proteins encoded by a tumor suppressor gene, which display transcription factor activity, and which interact and are phosphorylated by GPBP. Given the role of GPBP in autoimmune pathogenesis and in cancer, GIP90/130 represent a potential therapeutic or therapeutic target in these disorders.
Sequence CWU
1
38130DNAHomo sapiensCDS(1)..(30) 1tct tac aga cga atc ctg gga cag ctt tta
30Ser Tyr Arg Arg Ile Leu Gly Gln Leu Leu1
5 10210PRTHomo sapiens 2Ser Tyr Arg Arg Ile
Leu Gly Gln Leu Leu1 5 103720DNAHomo
sapiensCDS(1)..(720) 3atg cgt tcc aga ggc agt gat acc gag ggc tca gcc caa
aag aaa ttt 48Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln
Lys Lys Phe1 5 10 15cca
aga cat act aaa ggc cac agt ttc caa ggg cct aaa aac atg aag 96Pro
Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys 20
25 30cat aga cag caa gac aaa gac tcc
ccc agt gag tcg gat gta ata ctt 144His Arg Gln Gln Asp Lys Asp Ser
Pro Ser Glu Ser Asp Val Ile Leu 35 40
45ccg tgt ccc aag gca gag aag cca cac agt ggt aat ggc cac caa gca
192Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln Ala
50 55 60gaa gac ctc tca aga gat gac ctg
tta ttt ctc ctc agc att ctg gag 240Glu Asp Leu Ser Arg Asp Asp Leu
Leu Phe Leu Leu Ser Ile Leu Glu65 70 75
80gga gaa ctg cag gct cga gat gag gtc ata ggc att tta
aag gct gaa 288Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu
Lys Ala Glu 85 90 95aaa
atg gac ctg gct ttg ctg gaa gct cag tat ggg ttt gtc act cca 336Lys
Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro
100 105 110aaa aag gtg tta gag gct ctc
cag aga gat gct ttt caa gcg aaa tct 384Lys Lys Val Leu Glu Ala Leu
Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120
125acc cct tgg cag gag gac atc tat gag aaa cca atg aat gag ttg
gac 432Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu Leu
Asp 130 135 140aaa gtt gtg gaa aaa cat
aaa gaa tct tac aga cga atc ctg gga cag 480Lys Val Val Glu Lys His
Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150
155 160ctt tta gtg gca gaa aaa tcc cgt agg caa acc
ata ttg gag ttg gag 528Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr
Ile Leu Glu Leu Glu 165 170
175gaa gaa aag aga aaa cat aaa gaa tac atg gag aag agt gat gaa ttc
576Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
180 185 190ata tgc cta cta gaa cag
gaa tgt gaa aga tta aag aag cta att gat 624Ile Cys Leu Leu Glu Gln
Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195 200
205caa gaa atc aag tct cag gag gag aag gag caa gaa aag gag
aaa agg 672Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu
Lys Arg 210 215 220gtc acc acc ctg aaa
gag gag ctg acc aag ctg aag tct ttt gct ttg 720Val Thr Thr Leu Lys
Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225 230
235 2404240PRTHomo sapiens 4Met Arg Ser Arg Gly
Ser Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1 5
10 15Pro Arg His Thr Lys Gly His Ser Phe Gln Gly
Pro Lys Asn Met Lys 20 25
30His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp Val Ile Leu
35 40 45Pro Cys Pro Lys Ala Glu Lys Pro
His Ser Gly Asn Gly His Gln Ala 50 55
60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65
70 75 80Gly Glu Leu Gln Ala
Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu 85
90 95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr
Gly Phe Val Thr Pro 100 105
110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser
115 120 125Thr Pro Trp Gln Glu Asp Ile
Tyr Glu Lys Pro Met Asn Glu Leu Asp 130 135
140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu Gly
Gln145 150 155 160Leu Leu
Val Ala Glu Lys Ser Arg Arg Gln Thr Ile Leu Glu Leu Glu
165 170 175Glu Glu Lys Arg Lys His Lys
Glu Tyr Met Glu Lys Ser Asp Glu Phe 180 185
190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys Lys Leu
Ile Asp 195 200 205Gln Glu Ile Lys
Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210
215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys Leu Lys
Ser Phe Ala Leu225 230 235
2405795DNAHomo sapiensCDS(1)..(795) 5cga gat gag gtc ata ggc att tta aag
gct gaa aaa atg gac ctg gct 48Arg Asp Glu Val Ile Gly Ile Leu Lys
Ala Glu Lys Met Asp Leu Ala1 5 10
15ttg ctg gaa gct cag tat ggg ttt gtc act cca aaa aag gtg tta
gag 96Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro Lys Lys Val Leu
Glu 20 25 30gct ctc cag aga
gat gct ttt caa gcg aaa tct acc cct tgg cag gag 144Ala Leu Gln Arg
Asp Ala Phe Gln Ala Lys Ser Thr Pro Trp Gln Glu 35
40 45gac atc tat gag aaa cca atg aat gag ttg gac aaa
gtt gtg gaa aaa 192Asp Ile Tyr Glu Lys Pro Met Asn Glu Leu Asp Lys
Val Val Glu Lys 50 55 60cat aaa gaa
tct tac aga cga atc ctg gga cag ctt tta gtg gca gaa 240His Lys Glu
Ser Tyr Arg Arg Ile Leu Gly Gln Leu Leu Val Ala Glu65 70
75 80aaa tcc cgt agg caa acc ata ttg
gag ttg gag gaa gaa aag aga aaa 288Lys Ser Arg Arg Gln Thr Ile Leu
Glu Leu Glu Glu Glu Lys Arg Lys 85 90
95cat aaa gaa tac atg gag aag agt gat gaa ttc ata tgc cta
cta gaa 336His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe Ile Cys Leu
Leu Glu 100 105 110cag gaa tgt
gaa aga tta aag aag cta att gat caa gaa atc aag tct 384Gln Glu Cys
Glu Arg Leu Lys Lys Leu Ile Asp Gln Glu Ile Lys Ser 115
120 125cag gag gag aag gag caa gaa aag gag aaa agg
gtc acc acc ctg aaa 432Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg
Val Thr Thr Leu Lys 130 135 140gag gag
ctg acc aag ctg aag tct ttt gct ttg atg gtg gtg gat gaa 480Glu Glu
Leu Thr Lys Leu Lys Ser Phe Ala Leu Met Val Val Asp Glu145
150 155 160cag caa agg ctg acg gca cag
ctc acc ctt caa aga cag aaa atc caa 528Gln Gln Arg Leu Thr Ala Gln
Leu Thr Leu Gln Arg Gln Lys Ile Gln 165
170 175gag ctg acc aca aat gca aag gaa aca cat acc aaa
cta gcc ctt gct 576Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr Lys
Leu Ala Leu Ala 180 185 190gaa
gcc aga gtt cag gag gaa gag cag aag gca acc aga cta gag aag 624Glu
Ala Arg Val Gln Glu Glu Glu Gln Lys Ala Thr Arg Leu Glu Lys 195
200 205gaa ctg caa acg cag acc aca aag ttt
cac caa gac caa gac aca att 672Glu Leu Gln Thr Gln Thr Thr Lys Phe
His Gln Asp Gln Asp Thr Ile 210 215
220atg gcg aag ctc acc aat gag gac agt caa aat cgc cag ctt caa caa
720Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn Arg Gln Leu Gln Gln225
230 235 240aag ctg gca gca
ctc agc cgg cag att gat gag tta gaa gag aca aac 768Lys Leu Ala Ala
Leu Ser Arg Gln Ile Asp Glu Leu Glu Glu Thr Asn 245
250 255agg tct tta cga aaa gca gaa gag gag
795Arg Ser Leu Arg Lys Ala Glu Glu Glu
260 2656265PRTHomo sapiens 6Arg Asp Glu Val Ile Gly
Ile Leu Lys Ala Glu Lys Met Asp Leu Ala1 5
10 15Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro Lys
Lys Val Leu Glu 20 25 30Ala
Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser Thr Pro Trp Gln Glu 35
40 45Asp Ile Tyr Glu Lys Pro Met Asn Glu
Leu Asp Lys Val Val Glu Lys 50 55
60His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln Leu Leu Val Ala Glu65
70 75 80Lys Ser Arg Arg Gln
Thr Ile Leu Glu Leu Glu Glu Glu Lys Arg Lys 85
90 95His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
Ile Cys Leu Leu Glu 100 105
110Gln Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp Gln Glu Ile Lys Ser
115 120 125Gln Glu Glu Lys Glu Gln Glu
Lys Glu Lys Arg Val Thr Thr Leu Lys 130 135
140Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu Met Val Val Asp
Glu145 150 155 160Gln Gln
Arg Leu Thr Ala Gln Leu Thr Leu Gln Arg Gln Lys Ile Gln
165 170 175Glu Leu Thr Thr Asn Ala Lys
Glu Thr His Thr Lys Leu Ala Leu Ala 180 185
190Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala Thr Arg Leu
Glu Lys 195 200 205Glu Leu Gln Thr
Gln Thr Thr Lys Phe His Gln Asp Gln Asp Thr Ile 210
215 220Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn Arg
Gln Leu Gln Gln225 230 235
240Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu Leu Glu Glu Thr Asn
245 250 255Arg Ser Leu Arg Lys
Ala Glu Glu Glu 260 26571050DNAHomo
sapiensCDS(1)..(1050) 7atg cgt tcc aga ggc agt gat acc gag ggc tca gcc
caa aag aaa ttt 48Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala
Gln Lys Lys Phe1 5 10
15cca aga cat act aaa ggc cac agt ttc caa ggg cct aaa aac atg aag
96Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys
20 25 30cat aga cag caa gac aaa gac
tcc ccc agt gag tcg gat gta ata ctt 144His Arg Gln Gln Asp Lys Asp
Ser Pro Ser Glu Ser Asp Val Ile Leu 35 40
45ccg tgt ccc aag gca gag aag cca cac agt ggt aat ggc cac caa
gca 192Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln
Ala 50 55 60gaa gac ctc tca aga gat
gac ctg tta ttt ctc ctc agc att ctg gag 240Glu Asp Leu Ser Arg Asp
Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65 70
75 80gga gaa ctg cag gct cga gat gag gtc ata ggc
att tta aag gct gaa 288Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly
Ile Leu Lys Ala Glu 85 90
95aaa atg gac ctg gct ttg ctg gaa gct cag tat ggg ttt gtc act cca
336Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro
100 105 110aaa aag gtg tta gag gct
ctc cag aga gat gct ttt caa gcg aaa tct 384Lys Lys Val Leu Glu Ala
Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120
125acc cct tgg cag gag gac atc tat gag aaa cca atg aat gag
ttg gac 432Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu
Leu Asp 130 135 140aaa gtt gtg gaa aaa
cat aaa gaa tct tac aga cga atc ctg gga cag 480Lys Val Val Glu Lys
His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150
155 160ctt tta gtg gca gaa aaa tcc cgt agg caa
acc ata ttg gag ttg gag 528Leu Leu Val Ala Glu Lys Ser Arg Arg Gln
Thr Ile Leu Glu Leu Glu 165 170
175gaa gaa aag aga aaa cat aaa gaa tac atg gag aag agt gat gaa ttc
576Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
180 185 190ata tgc cta cta gaa cag
gaa tgt gaa aga tta aag aag cta att gat 624Ile Cys Leu Leu Glu Gln
Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195 200
205caa gaa atc aag tct cag gag gag aag gag caa gaa aag gag
aaa agg 672Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu
Lys Arg 210 215 220gtc acc acc ctg aaa
gag gag ctg acc aag ctg aag tct ttt gct ttg 720Val Thr Thr Leu Lys
Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225 230
235 240atg gtg gtg gat gaa cag caa agg ctg acg
gca cag ctc acc ctt caa 768Met Val Val Asp Glu Gln Gln Arg Leu Thr
Ala Gln Leu Thr Leu Gln 245 250
255aga cag aaa atc caa gag ctg acc aca aat gca aag gaa aca cat acc
816Arg Gln Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr
260 265 270aaa cta gcc ctt gct gaa
gcc aga gtt cag gag gaa gag cag aag gca 864Lys Leu Ala Leu Ala Glu
Ala Arg Val Gln Glu Glu Glu Gln Lys Ala 275 280
285acc aga cta gag aag gaa ctg caa acg cag acc aca aag ttt
cac caa 912Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe
His Gln 290 295 300gac caa gac aca att
atg gcg aag ctc acc aat gag gac agt caa aat 960Asp Gln Asp Thr Ile
Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn305 310
315 320cgc cag ctt caa caa aag ctg gca gca ctc
agc cgg cag att gat gag 1008Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu
Ser Arg Gln Ile Asp Glu 325 330
335tta gaa gag aca aac agg tct tta cga aaa gca gaa gag gag
1050Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu
340 345 3508350PRTHomo sapiens 8Met Arg
Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1 5
10 15Pro Arg His Thr Lys Gly His Ser
Phe Gln Gly Pro Lys Asn Met Lys 20 25
30His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp Val Ile
Leu 35 40 45Pro Cys Pro Lys Ala
Glu Lys Pro His Ser Gly Asn Gly His Gln Ala 50 55
60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile
Leu Glu65 70 75 80Gly
Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu
85 90 95Lys Met Asp Leu Ala Leu Leu
Glu Ala Gln Tyr Gly Phe Val Thr Pro 100 105
110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln Ala
Lys Ser 115 120 125Thr Pro Trp Gln
Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu Leu Asp 130
135 140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg
Ile Leu Gly Gln145 150 155
160Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr Ile Leu Glu Leu Glu
165 170 175Glu Glu Lys Arg Lys
His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe 180
185 190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys
Lys Leu Ile Asp 195 200 205Gln Glu
Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210
215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys Leu
Lys Ser Phe Ala Leu225 230 235
240Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr Leu Gln
245 250 255Arg Gln Lys Ile
Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 260
265 270Lys Leu Ala Leu Ala Glu Ala Arg Val Gln Glu
Glu Glu Gln Lys Ala 275 280 285Thr
Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe His Gln 290
295 300Asp Gln Asp Thr Ile Met Ala Lys Leu Thr
Asn Glu Asp Ser Gln Asn305 310 315
320Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp
Glu 325 330 335Leu Glu Glu
Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu 340
345 35093998DNAHomo sapiensCDS(473)..(2767) 9cacacacaca
cacacacaca gacgtgctca cggagcctgt gcctgcctct acttgtctgc 60tctgcgcaga
tggttcctgg cttttgggtc acctcatcct gcagcccagt ccagttagaa 120cctttcttcc
acagagactg gcaagctgtg gggtaagagt tttggtaagg ctgcctgtct 180tcagagcatg
aaggacactg cccggagagg gaagagggca atatttagtg tttgggccta 240cttgttgttg
ggctccccac tgcctctcct ttgcagagct atcactggcc cctggttgca 300aactctcggt
ggctttcaag cctacaaaac aaaaactgag agggtgtcca aaaagagaag 360aagaaaacgt
tgttgttggt cctggattcc actgttggat tttggtgggg atgagaagaa 420ggaattacca
ggtgtgatca acacctgcac ggtacctgca cggctttaaa ga atg cgt 478
Met Arg
1tcc aga ggc agt gat acc
gag ggc tca gcc caa aag aaa ttt cca aga 526Ser Arg Gly Ser Asp Thr
Glu Gly Ser Ala Gln Lys Lys Phe Pro Arg 5 10
15cat act aaa ggc cac agt ttc caa ggg cct aaa aac atg aag
cat aga 574His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys
His Arg 20 25 30cag caa gac aaa gac
tcc ccc agt gag tcg gat gta ata ctt ccg tgt 622Gln Gln Asp Lys Asp
Ser Pro Ser Glu Ser Asp Val Ile Leu Pro Cys35 40
45 50ccc aag gca gag aag cca cac agt ggt aat
ggc cac caa gca gaa gac 670Pro Lys Ala Glu Lys Pro His Ser Gly Asn
Gly His Gln Ala Glu Asp 55 60
65ctc tca aga gat gac ctg tta ttt ctc ctc agc att ctg gag gga gaa
718Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu Gly Glu
70 75 80ctg cag gct cga gat gag
gtc ata ggc att tta aag gct gaa aaa atg 766Leu Gln Ala Arg Asp Glu
Val Ile Gly Ile Leu Lys Ala Glu Lys Met 85 90
95gac ctg gct ttg ctg gaa gct cag tat ggg ttt gtc act cca
aaa aag 814Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro
Lys Lys 100 105 110gtg tta gag gct ctc
cag aga gat gct ttt caa gcg aaa tct acc cct 862Val Leu Glu Ala Leu
Gln Arg Asp Ala Phe Gln Ala Lys Ser Thr Pro115 120
125 130tgg cag gag gac atc tat gag aaa cca atg
aat gag ttg gac aaa gtt 910Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met
Asn Glu Leu Asp Lys Val 135 140
145gtg gaa aaa cat aaa gaa tct tac aga cga atc ctg gga cag ctt tta
958Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln Leu Leu
150 155 160gtg gca gaa aaa tcc cgt
agg caa acc ata ttg gag ttg gag gaa gaa 1006Val Ala Glu Lys Ser Arg
Arg Gln Thr Ile Leu Glu Leu Glu Glu Glu 165 170
175aag aga aaa cat aaa gaa tac atg gag aag agt gat gaa ttc
ata tgc 1054Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
Ile Cys 180 185 190cta cta gaa cag gaa
tgt gaa aga tta aag aag cta att gat caa gaa 1102Leu Leu Glu Gln Glu
Cys Glu Arg Leu Lys Lys Leu Ile Asp Gln Glu195 200
205 210atc aag tct cag gag gag aag gag caa gaa
aag gag aaa agg gtc acc 1150Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu
Lys Glu Lys Arg Val Thr 215 220
225acc ctg aaa gag gag ctg acc aag ctg aag tct ttt gct ttg atg gtg
1198Thr Leu Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu Met Val
230 235 240gtg gat gaa cag caa agg
ctg acg gca cag ctc acc ctt caa aga cag 1246Val Asp Glu Gln Gln Arg
Leu Thr Ala Gln Leu Thr Leu Gln Arg Gln 245 250
255aaa atc caa gag ctg acc aca aat gca aag gaa aca cat acc
aaa cta 1294Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr
Lys Leu 260 265 270gcc ctt gct gaa gcc
aga gtt cag gag gaa gag cag aag gca acc aga 1342Ala Leu Ala Glu Ala
Arg Val Gln Glu Glu Glu Gln Lys Ala Thr Arg275 280
285 290cta gag aag gaa ctg caa acg cag acc aca
aag ttt cac caa gac caa 1390Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr
Lys Phe His Gln Asp Gln 295 300
305gac aca att atg gcg aag ctc acc aat gag gac agt caa aat cgc cag
1438Asp Thr Ile Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn Arg Gln
310 315 320ctt caa caa aag ctg gca
gca ctc agc cgg cag att gat gag tta gaa 1486Leu Gln Gln Lys Leu Ala
Ala Leu Ser Arg Gln Ile Asp Glu Leu Glu 325 330
335gag aca aac agg tct tta cga aaa gca gaa gag gag ctg caa
gat ata 1534Glu Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu Leu Gln
Asp Ile 340 345 350aaa gaa aaa atc agt
aag gga gaa tat gga aac gct ggt atc atg gct 1582Lys Glu Lys Ile Ser
Lys Gly Glu Tyr Gly Asn Ala Gly Ile Met Ala355 360
365 370gaa gtg gaa gag ctc agg aaa cgt gtg cta
gat atg gaa ggg aaa gat 1630Glu Val Glu Glu Leu Arg Lys Arg Val Leu
Asp Met Glu Gly Lys Asp 375 380
385gaa gag ctc ata aaa atg gag gag cag tgc aga gat ctc aat aag agg
1678Glu Glu Leu Ile Lys Met Glu Glu Gln Cys Arg Asp Leu Asn Lys Arg
390 395 400ctt gaa agg gag acg tta
cag agt aaa gac ttt aaa cta gag gtt gaa 1726Leu Glu Arg Glu Thr Leu
Gln Ser Lys Asp Phe Lys Leu Glu Val Glu 405 410
415aaa ctc agt aaa aga att atg gct ctg gaa aag tta gaa gac
gct ttc 1774Lys Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu Glu Asp
Ala Phe 420 425 430aac aaa agc aaa caa
gaa tgc tac tct ctg aaa tgc aat tta gaa aaa 1822Asn Lys Ser Lys Gln
Glu Cys Tyr Ser Leu Lys Cys Asn Leu Glu Lys435 440
445 450gaa agg atg acc aca aag cag ttg tct caa
gaa ctg gag agt tta aaa 1870Glu Arg Met Thr Thr Lys Gln Leu Ser Gln
Glu Leu Glu Ser Leu Lys 455 460
465gta agg atc aaa gag cta gaa gcc att gaa agt cgg cta gaa aag aca
1918Val Arg Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg Leu Glu Lys Thr
470 475 480gaa ttc act cta aaa gag
gat tta act aaa ctg aaa aca tta act gtg 1966Glu Phe Thr Leu Lys Glu
Asp Leu Thr Lys Leu Lys Thr Leu Thr Val 485 490
495atg ttt gta gat gaa cgg aaa aca atg agt gaa aaa tta aag
aaa act 2014Met Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys
Lys Thr 500 505 510gaa gat aaa tta caa
gct gct tct tct cag ctt caa gtg gag caa aat 2062Glu Asp Lys Leu Gln
Ala Ala Ser Ser Gln Leu Gln Val Glu Gln Asn515 520
525 530aaa gta aca aca gtt act gag aag tta att
gag gaa act aaa agg gcg 2110Lys Val Thr Thr Val Thr Glu Lys Leu Ile
Glu Glu Thr Lys Arg Ala 535 540
545ctc aag tcc aaa acc gat gta gaa gaa aag atg tac agc gta acc aag
2158Leu Lys Ser Lys Thr Asp Val Glu Glu Lys Met Tyr Ser Val Thr Lys
550 555 560gag aga gat gat tta aaa
aac aaa ttg aaa gcg gaa gaa gag aaa gga 2206Glu Arg Asp Asp Leu Lys
Asn Lys Leu Lys Ala Glu Glu Glu Lys Gly 565 570
575aat gat ctc ctg tca aga gtt aat atg ttg aaa aat agg ctt
caa tca 2254Asn Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu
Gln Ser 580 585 590ttg gaa gca att gag
aaa gat ttc cta aaa aac aaa tta aat caa gac 2302Leu Glu Ala Ile Glu
Lys Asp Phe Leu Lys Asn Lys Leu Asn Gln Asp595 600
605 610tct ggg aaa tcc aca aca gca tta cac caa
gaa aac aat aag att aag 2350Ser Gly Lys Ser Thr Thr Ala Leu His Gln
Glu Asn Asn Lys Ile Lys 615 620
625gag ctc tct caa gaa gtg gaa aga ctg aaa ctg aag cta aag gac atg
2398Glu Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys Leu Lys Asp Met
630 635 640aaa gcc att gag gat gac
ctc atg aaa aca gaa gat gaa tat gag act 2446Lys Ala Ile Glu Asp Asp
Leu Met Lys Thr Glu Asp Glu Tyr Glu Thr 645 650
655cta gaa cga agg tat gct aat gaa cga gac aaa gct caa ttt
tta tct 2494Leu Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala Gln Phe
Leu Ser 660 665 670aaa gag cta gaa cat
gtt aaa atg gaa ctt gct aag tac aag tta gca 2542Lys Glu Leu Glu His
Val Lys Met Glu Leu Ala Lys Tyr Lys Leu Ala675 680
685 690gaa aag aca gag acc agc cat gaa caa tgg
ctt ttc aaa agg ctt caa 2590Glu Lys Thr Glu Thr Ser His Glu Gln Trp
Leu Phe Lys Arg Leu Gln 695 700
705gaa gaa gaa gct aag tca ggg cac ctc tca aga gaa gtg gat gca tta
2638Glu Glu Glu Ala Lys Ser Gly His Leu Ser Arg Glu Val Asp Ala Leu
710 715 720aaa gag aaa att cat gaa
tac atg gca act gaa gac cta ata tgt cac 2686Lys Glu Lys Ile His Glu
Tyr Met Ala Thr Glu Asp Leu Ile Cys His 725 730
735ctc cag gga gat cac tca gtc ctg caa aaa aaa act aaa tca
aca aga 2734Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Thr Lys Ser
Thr Arg 740 745 750aaa cag gaa cag aga
ttt agg aag aga gat tga aaacctcact aaggagttag 2787Lys Gln Glu Gln Arg
Phe Arg Lys Arg Asp755 760agaggtaccg gcatttcagt
aagagcctca ggcctagtct caatggaaga agaatttccg 2847atcctcaagt attttctaaa
gaagttcaga cagaagcagt agacaatgaa ccacctgatt 2907acaagagcct cattcctctg
gaacgtgcag tcatcaatgg tcagttatat gaggagagtg 2967agaatcaaga cgaggaccct
aatgatgagg gatctgtgct gtccttcaaa tgcagccagt 3027ctactccatg tcctgttaac
agaaagctat ggattccctg gatgaaatcc aaggagggcc 3087atcttcagaa tggaaaaatg
caaactaaac ccaatgccaa ctttgtgcaa cctggagatc 3147tagtcctaag ccacacacct
gggcagccac ttcatataaa ggttactcca gaccatgtac 3207aaaacacagc cactcttgaa
atcacaagtc caaccacaga gagtcctcac tcttacacga 3267gtactgcagt gataccgaac
tgtggcacgc caaagcaaag gataaccatc ctccaaaacg 3327cctccataac accagtaaag
tccaaaacct ctaccgaaga cctcatgaat ttagaacaag 3387gcatgtcccc aattaccatg
gcaacctttg ccagagcaca gaccccagag tcttgtggtt 3447ctctaactcc agaaaggaca
atgtccccta ttcaggtttt ggctgtgact ggttcagcta 3507gctctcctga gcagggacgc
tccccagaac caacagaaat cagtgccaag catgcgatat 3567tcagagtctc cccagaccgg
cagtcatcat ggcagtttca gcgttcaaac agcaatagct 3627caagtgtgat aactactgag
gataataaaa tccacattca cttaggaagt ccttacatgc 3687aagctgtagc cagccctgtg
agacctgcca gcccttcagc accactgcag gataaccgaa 3747ctcaaggctt aattaacggg
gcactaaaca aaacaaccaa taaagtcacc agcagtatta 3807ctatcacacc aacagccaca
cctcttcctc gacaatcaca aattacagtg gaaccacttc 3867ttctgcctca ttgaactcaa
catccttcag acttttaagg cattccaaat cccagtcttc 3927atgttgaact gggttaagca
tttattaaaa aatcgttttc ttctacaaaa aaaaaaaaaa 3987aaaaaaaaaa a
399810764PRTHomo sapiens
10Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1
5 10 15Pro Arg His Thr Lys Gly
His Ser Phe Gln Gly Pro Lys Asn Met Lys 20 25
30His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp
Val Ile Leu 35 40 45Pro Cys Pro
Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln Ala 50
55 60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu
Ser Ile Leu Glu65 70 75
80Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu
85 90 95Lys Met Asp Leu Ala Leu
Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro 100
105 110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe
Gln Ala Lys Ser 115 120 125Thr Pro
Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu Leu Asp 130
135 140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg
Arg Ile Leu Gly Gln145 150 155
160Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr Ile Leu Glu Leu Glu
165 170 175Glu Glu Lys Arg
Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe 180
185 190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu
Lys Lys Leu Ile Asp 195 200 205Gln
Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210
215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys
Leu Lys Ser Phe Ala Leu225 230 235
240Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr Leu
Gln 245 250 255Arg Gln Lys
Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 260
265 270Lys Leu Ala Leu Ala Glu Ala Arg Val Gln
Glu Glu Glu Gln Lys Ala 275 280
285Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe His Gln 290
295 300Asp Gln Asp Thr Ile Met Ala Lys
Leu Thr Asn Glu Asp Ser Gln Asn305 310
315 320Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg
Gln Ile Asp Glu 325 330
335Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu Leu Gln
340 345 350Asp Ile Lys Glu Lys Ile
Ser Lys Gly Glu Tyr Gly Asn Ala Gly Ile 355 360
365Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met
Glu Gly 370 375 380Lys Asp Glu Glu Leu
Ile Lys Met Glu Glu Gln Cys Arg Asp Leu Asn385 390
395 400Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser
Lys Asp Phe Lys Leu Glu 405 410
415Val Glu Lys Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu Glu Asp
420 425 430Ala Phe Asn Lys Ser
Lys Gln Glu Cys Tyr Ser Leu Lys Cys Asn Leu 435
440 445Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln
Glu Leu Glu Ser 450 455 460Leu Lys Val
Arg Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg Leu Glu465
470 475 480Lys Thr Glu Phe Thr Leu Lys
Glu Asp Leu Thr Lys Leu Lys Thr Leu 485
490 495Thr Val Met Phe Val Asp Glu Arg Lys Thr Met Ser
Glu Lys Leu Lys 500 505 510Lys
Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln Leu Gln Val Glu 515
520 525Gln Asn Lys Val Thr Thr Val Thr Glu
Lys Leu Ile Glu Glu Thr Lys 530 535
540Arg Ala Leu Lys Ser Lys Thr Asp Val Glu Glu Lys Met Tyr Ser Val545
550 555 560Thr Lys Glu Arg
Asp Asp Leu Lys Asn Lys Leu Lys Ala Glu Glu Glu 565
570 575Lys Gly Asn Asp Leu Leu Ser Arg Val Asn
Met Leu Lys Asn Arg Leu 580 585
590Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu Lys Asn Lys Leu Asn
595 600 605Gln Asp Ser Gly Lys Ser Thr
Thr Ala Leu His Gln Glu Asn Asn Lys 610 615
620Ile Lys Glu Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys Leu
Lys625 630 635 640Asp Met
Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu Asp Glu Tyr
645 650 655Glu Thr Leu Glu Arg Arg Tyr
Ala Asn Glu Arg Asp Lys Ala Gln Phe 660 665
670Leu Ser Lys Glu Leu Glu His Val Lys Met Glu Leu Ala Lys
Tyr Lys 675 680 685Leu Ala Glu Lys
Thr Glu Thr Ser His Glu Gln Trp Leu Phe Lys Arg 690
695 700Leu Gln Glu Glu Glu Ala Lys Ser Gly His Leu Ser
Arg Glu Val Asp705 710 715
720Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr Glu Asp Leu Ile
725 730 735Cys His Leu Gln Gly
Asp His Ser Val Leu Gln Lys Lys Thr Lys Ser 740
745 750Thr Arg Lys Gln Glu Gln Arg Phe Arg Lys Arg Asp
755 760113430DNAHomo sapiensmisc_featureGIP130a
11tttaaaga atg cgt tcc aga ggc agt gat acc gag ggc tca gcc caa aag
50 Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys
1 5 10aaa ttt cca aga cat
act aaa ggc cac agt ttc caa ggg cct aaa aac 98Lys Phe Pro Arg His
Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn15 20
25 30atg aag cat aga cag caa gac aaa gac tcc
ccc agt gag tcg gat gta 146Met Lys His Arg Gln Gln Asp Lys Asp Ser
Pro Ser Glu Ser Asp Val 35 40
45ata ctt ccg tgt ccc aag gca gag aag cca cac agt ggt aat ggc cac
194Ile Leu Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His
50 55 60caa gca gaa gac ctc tca
aga gat gac ctg tta ttt ctc ctc agc att 242Gln Ala Glu Asp Leu Ser
Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile 65 70
75ctg gag gga gaa ctg cag gct cga gat gag gtc ata ggc att
tta aag 290Leu Glu Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile
Leu Lys 80 85 90gct gaa aaa atg gac
ctg gct ttg ctg gaa gct cag tat ggg ttt gtc 338Ala Glu Lys Met Asp
Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val95 100
105 110act cca aaa aag gtg tta gag gct ctc cag
aga gat gct ttt caa gcg 386Thr Pro Lys Lys Val Leu Glu Ala Leu Gln
Arg Asp Ala Phe Gln Ala 115 120
125aaa tct acc cct tgg cag gag gac atc tat gag aaa cca atg aat gag
434Lys Ser Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu
130 135 140ttg gac aaa gtt gtg gaa
aaa cat aaa gaa tct tac aga cga atc ctg 482Leu Asp Lys Val Val Glu
Lys His Lys Glu Ser Tyr Arg Arg Ile Leu 145 150
155gga cag ctt tta gtg gca gaa aaa tcc cgt agg caa acc ata
ttg gag 530Gly Gln Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr Ile
Leu Glu 160 165 170ttg gag gaa gaa aag
aga aaa cat aaa gaa tac atg gag aag agt gat 578Leu Glu Glu Glu Lys
Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp175 180
185 190gaa ttc ata tgc cta cta gaa cag gaa tgt
gaa aga tta aag aag cta 626Glu Phe Ile Cys Leu Leu Glu Gln Glu Cys
Glu Arg Leu Lys Lys Leu 195 200
205att gat caa gaa atc aag tct cag gag gag aag gag caa gaa aag gag
674Ile Asp Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu
210 215 220aaa agg gtc acc acc ctg
aaa gag gag ctg acc aag ctg aag tct ttt 722Lys Arg Val Thr Thr Leu
Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe 225 230
235gct ttg atg gtg gtg gat gaa cag caa agg ctg acg gca cag
ctc acc 770Ala Leu Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln
Leu Thr 240 245 250ctt caa aga cag aaa
atc caa gag ctg acc aca aat gca aag gaa aca 818Leu Gln Arg Gln Lys
Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr255 260
265 270cat acc aaa cta gcc ctt gct gaa gcc aga
gtt cag gag gaa gag cag 866His Thr Lys Leu Ala Leu Ala Glu Ala Arg
Val Gln Glu Glu Glu Gln 275 280
285aag gca acc aga cta gag aag gaa ctg caa acg cag acc aca aag ttt
914Lys Ala Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe
290 295 300cac caa gac caa gac aca
att atg gcg aag ctc acc aat gag gac agt 962His Gln Asp Gln Asp Thr
Ile Met Ala Lys Leu Thr Asn Glu Asp Ser 305 310
315caa aat cgc cag ctt caa caa aag ctg gca gca ctc agc cgg
cag att 1010Gln Asn Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg
Gln Ile 320 325 330gat gag tta gaa gag
aca aac agg tct tta cga aaa gca gaa gag gag 1058Asp Glu Leu Glu Glu
Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu335 340
345 350ctg caa gat ata aaa gaa aaa atc agt aag
gga gaa tat gga aac gct 1106Leu Gln Asp Ile Lys Glu Lys Ile Ser Lys
Gly Glu Tyr Gly Asn Ala 355 360
365ggt atc atg gct gaa gtg gaa gag ctc agg aaa cgt gtg cta gat atg
1154Gly Ile Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met
370 375 380gaa ggg aaa gat gaa gag
ctc ata aaa atg gag gag cag tgc aga gat 1202Glu Gly Lys Asp Glu Glu
Leu Ile Lys Met Glu Glu Gln Cys Arg Asp 385 390
395ctc aat aag agg ctt gaa agg gag acg tta cag agt aaa gac
ttt aaa 1250Leu Asn Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp
Phe Lys 400 405 410cta gag gtt gaa aaa
ctc agt aaa aga att atg gct ctg gaa aag tta 1298Leu Glu Val Glu Lys
Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu415 420
425 430gaa gac gct ttc aac aaa agc aaa caa gaa
tgc tac tct ctg aaa tgc 1346Glu Asp Ala Phe Asn Lys Ser Lys Gln Glu
Cys Tyr Ser Leu Lys Cys 435 440
445aat tta gaa aaa gaa agg atg acc aca aag cag ttg tct caa gaa ctg
1394Asn Leu Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu
450 455 460gag agt tta aaa gta agg
atc aaa gag cta gaa gcc att gaa agt cgg 1442Glu Ser Leu Lys Val Arg
Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg 465 470
475cta gaa aag aca gaa ttc act cta aaa gag gat tta act aaa
ctg aaa 1490Leu Glu Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys
Leu Lys 480 485 490aca tta act gtg atg
ttt gta gat gaa cgg aaa aca atg agt gaa aaa 1538Thr Leu Thr Val Met
Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys495 500
505 510tta aag aaa act gaa gat aaa tta caa gct
gct tct tct cag ctt caa 1586Leu Lys Lys Thr Glu Asp Lys Leu Gln Ala
Ala Ser Ser Gln Leu Gln 515 520
525gtg gag caa aat aaa gta aca aca gtt act gag aag tta att gag gaa
1634Val Glu Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu
530 535 540act aaa agg gcg ctc aag
tcc aaa acc gat gta gaa gaa aag atg tac 1682Thr Lys Arg Ala Leu Lys
Ser Lys Thr Asp Val Glu Glu Lys Met Tyr 545 550
555agc gta acc aag gag aga gat gat tta aaa aac aaa ttg aaa
gcg gaa 1730Ser Val Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys
Ala Glu 560 565 570gaa gag aaa gga aat
gat ctc ctg tca aga gtt aat atg ttg aaa aat 1778Glu Glu Lys Gly Asn
Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn575 580
585 590agg ctt caa tca ttg gaa gca att gag aaa
gat ttc cta aaa aac aaa 1826Arg Leu Gln Ser Leu Glu Ala Ile Glu Lys
Asp Phe Leu Lys Asn Lys 595 600
605tta aat caa gac tct ggg aaa tcc aca aca gca tta cac caa gaa aac
1874Leu Asn Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn
610 615 620aat aag att aag gag ctc
tct caa gaa gtg gaa aga ctg aaa ctg aag 1922Asn Lys Ile Lys Glu Leu
Ser Gln Glu Val Glu Arg Leu Lys Leu Lys 625 630
635cta aag gac atg aaa gcc att gag gat gac ctc atg aaa aca
gaa gat 1970Leu Lys Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr
Glu Asp 640 645 650gaa tat gag act cta
gaa cga agg tat gct aat gaa cga gac aaa gct 2018Glu Tyr Glu Thr Leu
Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala655 660
665 670caa ttt tta tct aaa gag cta gaa cat gtt
aaa atg gaa ctt gct aag 2066Gln Phe Leu Ser Lys Glu Leu Glu His Val
Lys Met Glu Leu Ala Lys 675 680
685tac aag tta gca gaa aag aca gag acc agc cat gaa caa tgg ctt ttc
2114Tyr Lys Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe
690 695 700aaa agg ctt caa gaa gaa
gaa gct aag tca ggg cac ctc tca aga gaa 2162Lys Arg Leu Gln Glu Glu
Glu Ala Lys Ser Gly His Leu Ser Arg Glu 705 710
715gtg gat gca tta aaa gag aaa att cat gaa tac atg gca act
gaa gac 2210Val Asp Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr
Glu Asp 720 725 730cta ata tgt cac ctc
cag gga gat cac tca gtc ctg caa aaa aaa cta 2258Leu Ile Cys His Leu
Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu735 740
745 750aat caa caa gaa aac agg aac aga gat tta
gga aga gag att gaa aac 2306Asn Gln Gln Glu Asn Arg Asn Arg Asp Leu
Gly Arg Glu Ile Glu Asn 755 760
765ctc act aag gag tta gag agg tac cgg cat ttc agt aag agc ctc agg
2354Leu Thr Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg
770 775 780cct agt ctc aat gga aga
aga att tcc gat cct caa gta ttt tct aaa 2402Pro Ser Leu Asn Gly Arg
Arg Ile Ser Asp Pro Gln Val Phe Ser Lys 785 790
795gaa gtt cag aca gaa gca gta gac aat gaa cca cct gat tac
aag agc 2450Glu Val Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr
Lys Ser 800 805 810ctc att cct ctg gaa
cgt gca gtc atc aat ggt cag tta tat gag gag 2498Leu Ile Pro Leu Glu
Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu815 820
825 830agt gag aat caa gac gag gac cct aat gat
gag gga tct gtg ctg tcc 2546Ser Glu Asn Gln Asp Glu Asp Pro Asn Asp
Glu Gly Ser Val Leu Ser 835 840
845ttc aaa tgc agc cag tct act cca tgt cct gtt aac aga aag cta tgg
2594Phe Lys Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu Trp
850 855 860att ccc tgg atg aaa tcc
aag gag ggc cat ctt cag aat gga aaa atg 2642Ile Pro Trp Met Lys Ser
Lys Glu Gly His Leu Gln Asn Gly Lys Met 865 870
875caa act aaa ccc aat gcc aac ttt gtg caa cct gga gat cta
gtc cta 2690Gln Thr Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu
Val Leu 880 885 890agc cac aca cct ggg
cag cca ctt cat ata aag gtt act cca gac cat 2738Ser His Thr Pro Gly
Gln Pro Leu His Ile Lys Val Thr Pro Asp His895 900
905 910gta caa aac aca gcc act ctt gaa atc aca
agt cca acc aca gag agt 2786Val Gln Asn Thr Ala Thr Leu Glu Ile Thr
Ser Pro Thr Thr Glu Ser 915 920
925cct cac tct tac acg agt act gca gtg ata ccg aac tgt ggc acg cca
2834Pro His Ser Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro
930 935 940aag caa agg ata acc atc
ctc caa aac gcc tcc ata aca cca gta aag 2882Lys Gln Arg Ile Thr Ile
Leu Gln Asn Ala Ser Ile Thr Pro Val Lys 945 950
955tcc aaa acc tct acc gaa gac ctc atg aat tta gaa caa ggc
atg tcc 2930Ser Lys Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly
Met Ser 960 965 970cca att acc atg gca
acc ttt gcc aga gca cag acc cca gag tct tgt 2978Pro Ile Thr Met Ala
Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys975 980
985 990ggt tct cta act cca gaa agg aca atg tcc
cct att cag gtt ttg gct 3026Gly Ser Leu Thr Pro Glu Arg Thr Met Ser
Pro Ile Gln Val Leu Ala 995 1000
1005gtg act ggt tca gct agc tct cct gag cag gga cgc tcc cca gaa
3071Val Thr Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu
1010 1015 1020cca aca gaa atc
agt gcc aag cat gcg ata ttc aga gtc tcc cca 3116Pro Thr Glu Ile
Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro 1025
1030 1035gac cgg cag tca tca tgg cag ttt cag cgt
tca aac agc aat agc 3161Asp Arg Gln Ser Ser Trp Gln Phe Gln Arg
Ser Asn Ser Asn Ser 1040 1045
1050tca agt gtg ata act act gag gat aat aaa atc cac att cac tta
3206Ser Ser Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu
1055 1060 1065gga agt cct tac atg
caa gct gta gcc agc cct gtg aga cct gcc 3251Gly Ser Pro Tyr Met
Gln Ala Val Ala Ser Pro Val Arg Pro Ala 1070
1075 1080agc cct tca gca cca ctg cag gat aac cga act
caa ggc tta att 3296Ser Pro Ser Ala Pro Leu Gln Asp Asn Arg Thr
Gln Gly Leu Ile 1085 1090
1095aac ggg gca cta aac aaa aca acc aat aaa gtc acc agc agt att
3341Asn Gly Ala Leu Asn Lys Thr Thr Asn Lys Val Thr Ser Ser Ile
1100 1105 1110act atc aca cca aca
gcc aca cct ctt cct cga caa tca caa att 3386Thr Ile Thr Pro Thr
Ala Thr Pro Leu Pro Arg Gln Ser Gln Ile 1115
1120 1125aca gtg gaa cca ctt ctt ctg cct cat tgaactcaac
atccttc 3430Thr Val Glu Pro Leu Leu Leu Pro His
1130 1135121135PRTHomo sapiens 12Met Arg Ser Arg Gly Ser
Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1 5
10 15Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro
Lys Asn Met Lys 20 25 30His
Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp Val Ile Leu 35
40 45Pro Cys Pro Lys Ala Glu Lys Pro His
Ser Gly Asn Gly His Gln Ala 50 55
60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65
70 75 80Gly Glu Leu Gln Ala
Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu 85
90 95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr
Gly Phe Val Thr Pro 100 105
110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser
115 120 125Thr Pro Trp Gln Glu Asp Ile
Tyr Glu Lys Pro Met Asn Glu Leu Asp 130 135
140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu Gly
Gln145 150 155 160Leu Leu
Val Ala Glu Lys Ser Arg Arg Gln Thr Ile Leu Glu Leu Glu
165 170 175Glu Glu Lys Arg Lys His Lys
Glu Tyr Met Glu Lys Ser Asp Glu Phe 180 185
190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys Lys Leu
Ile Asp 195 200 205Gln Glu Ile Lys
Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210
215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys Leu Lys
Ser Phe Ala Leu225 230 235
240Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr Leu Gln
245 250 255Arg Gln Lys Ile Gln
Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 260
265 270Lys Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu
Glu Gln Lys Ala 275 280 285Thr Arg
Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe His Gln 290
295 300Asp Gln Asp Thr Ile Met Ala Lys Leu Thr Asn
Glu Asp Ser Gln Asn305 310 315
320Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu
325 330 335Leu Glu Glu Thr
Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu Leu Gln 340
345 350Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr
Gly Asn Ala Gly Ile 355 360 365Met
Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met Glu Gly 370
375 380Lys Asp Glu Glu Leu Ile Lys Met Glu Glu
Gln Cys Arg Asp Leu Asn385 390 395
400Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys Leu
Glu 405 410 415Val Glu Lys
Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu Glu Asp 420
425 430Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr
Ser Leu Lys Cys Asn Leu 435 440
445Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu Glu Ser 450
455 460Leu Lys Val Arg Ile Lys Glu Leu
Glu Ala Ile Glu Ser Arg Leu Glu465 470
475 480Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys
Leu Lys Thr Leu 485 490
495Thr Val Met Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys
500 505 510Lys Thr Glu Asp Lys Leu
Gln Ala Ala Ser Ser Gln Leu Gln Val Glu 515 520
525Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu
Thr Lys 530 535 540Arg Ala Leu Lys Ser
Lys Thr Asp Val Glu Glu Lys Met Tyr Ser Val545 550
555 560Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys
Leu Lys Ala Glu Glu Glu 565 570
575Lys Gly Asn Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu
580 585 590Gln Ser Leu Glu Ala
Ile Glu Lys Asp Phe Leu Lys Asn Lys Leu Asn 595
600 605Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln
Glu Asn Asn Lys 610 615 620Ile Lys Glu
Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys Leu Lys625
630 635 640Asp Met Lys Ala Ile Glu Asp
Asp Leu Met Lys Thr Glu Asp Glu Tyr 645
650 655Glu Thr Leu Glu Arg Arg Tyr Ala Asn Glu Arg Asp
Lys Ala Gln Phe 660 665 670Leu
Ser Lys Glu Leu Glu His Val Lys Met Glu Leu Ala Lys Tyr Lys 675
680 685Leu Ala Glu Lys Thr Glu Thr Ser His
Glu Gln Trp Leu Phe Lys Arg 690 695
700Leu Gln Glu Glu Glu Ala Lys Ser Gly His Leu Ser Arg Glu Val Asp705
710 715 720Ala Leu Lys Glu
Lys Ile His Glu Tyr Met Ala Thr Glu Asp Leu Ile 725
730 735Cys His Leu Gln Gly Asp His Ser Val Leu
Gln Lys Lys Leu Asn Gln 740 745
750Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu Asn Leu Thr
755 760 765Lys Glu Leu Glu Arg Tyr Arg
His Phe Ser Lys Ser Leu Arg Pro Ser 770 775
780Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser Lys Glu
Val785 790 795 800Gln Thr
Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr Lys Ser Leu Ile
805 810 815Pro Leu Glu Arg Ala Val Ile
Asn Gly Gln Leu Tyr Glu Glu Ser Glu 820 825
830Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu Ser
Phe Lys 835 840 845Cys Ser Gln Ser
Thr Pro Cys Pro Val Asn Arg Lys Leu Trp Ile Pro 850
855 860Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly
Lys Met Gln Thr865 870 875
880Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val Leu Ser His
885 890 895Thr Pro Gly Gln Pro
Leu His Ile Lys Val Thr Pro Asp His Val Gln 900
905 910Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr
Glu Ser Pro His 915 920 925Ser Tyr
Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro Lys Gln 930
935 940Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr
Pro Val Lys Ser Lys945 950 955
960Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met Ser Pro Ile
965 970 975Thr Met Ala Thr
Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys Gly Ser 980
985 990Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln
Val Leu Ala Val Thr 995 1000
1005Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu Pro Thr
1010 1015 1020Glu Ile Ser Ala Lys His
Ala Ile Phe Arg Val Ser Pro Asp Arg 1025 1030
1035Gln Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser
Ser 1040 1045 1050Val Ile Thr Thr Glu
Asp Asn Lys Ile His Ile His Leu Gly Ser 1055 1060
1065Pro Tyr Met Gln Ala Val Ala Ser Pro Val Arg Pro Ala
Ser Pro 1070 1075 1080Ser Ala Pro Leu
Gln Asp Asn Arg Thr Gln Gly Leu Ile Asn Gly 1085
1090 1095Ala Leu Asn Lys Thr Thr Asn Lys Val Thr Ser
Ser Ile Thr Ile 1100 1105 1110Thr Pro
Thr Ala Thr Pro Leu Pro Arg Gln Ser Gln Ile Thr Val 1115
1120 1125Glu Pro Leu Leu Leu Pro His 1130
1135133415DNAHomo sapiensmisc_featureGIP130b 13ggctttaaag a atg
cgt tcc aga ggc agt gat acc gag ggc tca gcc caa 50 Met
Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln 1
5 10aag aaa ttt cca aga cat act aaa ggc cac agt ttc
caa ggg cct aaa 98Lys Lys Phe Pro Arg His Thr Lys Gly His Ser Phe
Gln Gly Pro Lys 15 20 25aac atg aag
cat aga cag caa gac aaa gac tcc ccc agt gag tcg gat 146Asn Met Lys
His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp30 35
40 45gta ata ctt ccg tgt ccc aag gca
gag aag cca cac agt ggt aat ggc 194Val Ile Leu Pro Cys Pro Lys Ala
Glu Lys Pro His Ser Gly Asn Gly 50 55
60cac caa gca gaa gac ctc tca aga gat gac ctg tta ttt ctc
ctc agc 242His Gln Ala Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu
Leu Ser 65 70 75att ctg gag
gga gaa ctg cag gct cga gat gag gtc ata ggc att tta 290Ile Leu Glu
Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu 80
85 90aag gct gaa aaa atg gac ctg gct ttg ctg gaa
gct cag tat ggg ttt 338Lys Ala Glu Lys Met Asp Leu Ala Leu Leu Glu
Ala Gln Tyr Gly Phe 95 100 105gtc act
cca aaa aag gtg tta gag gct ctc cag aga gat gct ttt caa 386Val Thr
Pro Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln110
115 120 125gcg aaa tct acc cct tgg cag
gag gac atc tat gag aaa cca atg aat 434Ala Lys Ser Thr Pro Trp Gln
Glu Asp Ile Tyr Glu Lys Pro Met Asn 130
135 140gag ttg gac aaa gtt gtg gaa aaa cat aaa gaa tct
tac aga cga atc 482Glu Leu Asp Lys Val Val Glu Lys His Lys Glu Ser
Tyr Arg Arg Ile 145 150 155ctg
gga cag ctt tta gtg gca gaa aaa tcc cat agg caa acc ata ttg 530Leu
Gly Gln Leu Leu Val Ala Glu Lys Ser His Arg Gln Thr Ile Leu 160
165 170gag ttg gag gaa gaa aag aga aaa cat
aaa gaa tac atg gag aag agt 578Glu Leu Glu Glu Glu Lys Arg Lys His
Lys Glu Tyr Met Glu Lys Ser 175 180
185gat gaa ttc ata tgc cta cta gaa cag gaa tgt gaa aga tta aag aag
626Asp Glu Phe Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys Lys190
195 200 205cta att gat caa
gaa atc aag tct cag gag gag aag gag caa gaa aag 674Leu Ile Asp Gln
Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys 210
215 220gag aaa agg gtc acc acc ctg aaa gag gag
ctg acc aag ctg aag tct 722Glu Lys Arg Val Thr Thr Leu Lys Glu Glu
Leu Thr Lys Leu Lys Ser 225 230
235ttt gct ttg atg gtg gtg gat gaa cag caa agg ctg acg gca cag ctc
770Phe Ala Leu Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu
240 245 250acc ctt caa aga cag aaa atc
caa gag ctg acc aca aat gca aag gaa 818Thr Leu Gln Arg Gln Lys Ile
Gln Glu Leu Thr Thr Asn Ala Lys Glu 255 260
265aca cat acc aaa cta gcc ctt gct gaa gcc aga gtt cag gag gaa gag
866Thr His Thr Lys Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu270
275 280 285cag aag gca acc
aga cta gag aag gaa ctg caa acg cag acc aca aag 914Gln Lys Ala Thr
Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys 290
295 300ttt cac caa gac caa gac aca att atg gcg
aag ctc acc aat gag gac 962Phe His Gln Asp Gln Asp Thr Ile Met Ala
Lys Leu Thr Asn Glu Asp 305 310
315agt caa aat cgc cag ctt caa caa aag ctg gca gca ctc agc cgg cag
1010Ser Gln Asn Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg Gln
320 325 330att gat gag tta gaa gag aca
aac agg tct tta cga aaa gca gaa gag 1058Ile Asp Glu Leu Glu Glu Thr
Asn Arg Ser Leu Arg Lys Ala Glu Glu 335 340
345gag ctg caa gat ata aaa gaa aaa atc agt aag gga gaa tat gga aac
1106Glu Leu Gln Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn350
355 360 365gct ggt atc atg
gct gaa gtg gaa gag ctc agg aaa cgt gtg cta gat 1154Ala Gly Ile Met
Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp 370
375 380atg gaa ggg aaa gat gaa gag ctc ata aaa
atg gag gag cag tgc aga 1202Met Glu Gly Lys Asp Glu Glu Leu Ile Lys
Met Glu Glu Gln Cys Arg 385 390
395gat ctc aat aag agg ctt gaa agg gag acg tta cag agt aaa gac ttt
1250Asp Leu Asn Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe
400 405 410aaa cta gag gtt gaa aaa ctc
agt aaa aga att atg gct ctg gaa aag 1298Lys Leu Glu Val Glu Lys Leu
Ser Lys Arg Ile Met Ala Leu Glu Lys 415 420
425tta gaa gac gct ttc aac aaa agc aaa caa gaa tgc tac tct ctg aaa
1346Leu Glu Asp Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu Lys430
435 440 445tgc aat tta gaa
aaa gaa agg atg acc aca aag cag ttg tct caa gaa 1394Cys Asn Leu Glu
Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu 450
455 460ctg gag agt tta aaa gta agg atc aaa gag
cta gaa gcc att gaa agt 1442Leu Glu Ser Leu Lys Val Arg Ile Lys Glu
Leu Glu Ala Ile Glu Ser 465 470
475cgg cta gaa aag aca gaa ttc act cta aaa gag gat tta act aaa ctg
1490Arg Leu Glu Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu
480 485 490aaa aca tta act gtg atg ttt
gta gat gaa cgg aaa aca atg agt gaa 1538Lys Thr Leu Thr Val Met Phe
Val Asp Glu Arg Lys Thr Met Ser Glu 495 500
505aaa tta aag aaa act gaa gat aaa tta caa gct gct tct tct cag ctt
1586Lys Leu Lys Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln Leu510
515 520 525caa gtg gag caa
aat aaa gta aca aca gtt act gag aag tta att gag 1634Gln Val Glu Gln
Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu 530
535 540gaa act aaa agg gcg ctc aag tcc aaa acc
gat gta gaa gaa aag atg 1682Glu Thr Lys Arg Ala Leu Lys Ser Lys Thr
Asp Val Glu Glu Lys Met 545 550
555tac agc gta acc aag gag aga gat gat tta aaa aac aaa ttg aaa gcg
1730Tyr Ser Val Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys Ala
560 565 570gaa gaa gag aaa gga aat gat
ctc ctg tca aga gtt aat atg ttg aaa 1778Glu Glu Glu Lys Gly Asn Asp
Leu Leu Ser Arg Val Asn Met Leu Lys 575 580
585aat agg ctt caa tca ttg gaa gca att gag aaa gat ttc cta aaa aac
1826Asn Arg Leu Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu Lys Asn590
595 600 605aaa tta aat caa
gac tct ggg aaa tcc aca aca gca tta cac caa gaa 1874Lys Leu Asn Gln
Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu 610
615 620aac aat aag att aag gag ctc tct caa gaa
gtg gaa aga ctg aaa ctg 1922Asn Asn Lys Ile Lys Glu Leu Ser Gln Glu
Val Glu Arg Leu Lys Leu 625 630
635aag cta aag gac atg aaa gcc att gag gat gac ctc atg aaa aca gaa
1970Lys Leu Lys Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu
640 645 650gat gaa tat gag act cta gaa
cga agg tat gct aat gaa cga gac aaa 2018Asp Glu Tyr Glu Thr Leu Glu
Arg Arg Tyr Ala Asn Glu Arg Asp Lys 655 660
665gct caa ttt tta tct aaa gag cta gaa cat gtt aaa atg gaa ctt gct
2066Ala Gln Phe Leu Ser Lys Glu Leu Glu His Val Lys Met Glu Leu Ala670
675 680 685aag tac aag tta
gca gaa aag aca gag acc agc cat gaa caa tgg ctt 2114Lys Tyr Lys Leu
Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu 690
695 700ttc aaa agg ctt caa gaa gaa gaa gct aag
tca ggg cac ctc tca aga 2162Phe Lys Arg Leu Gln Glu Glu Glu Ala Lys
Ser Gly His Leu Ser Arg 705 710
715gaa gtg gat gca tta aaa gag aaa att cat gaa tac atg gca act gaa
2210Glu Val Asp Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr Glu
720 725 730gac cta ata tgt cac ctc cag
gga gat cac tca gtc ctg caa aaa aaa 2258Asp Leu Ile Cys His Leu Gln
Gly Asp His Ser Val Leu Gln Lys Lys 735 740
745cta aat caa caa gaa aac agg aac aga gat tta gga aga gag att gaa
2306Leu Asn Gln Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu750
755 760 765aac ctc act aag
gag tta gag agg tac cgg cat ttc agt aag agc ctc 2354Asn Leu Thr Lys
Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu 770
775 780agg cct agt ctc aat gga aga aga att tcc
gat cct caa gta ttt tct 2402Arg Pro Ser Leu Asn Gly Arg Arg Ile Ser
Asp Pro Gln Val Phe Ser 785 790
795aaa gaa gtt cag aca gaa gca gta gac aat gaa cca cct gat tac aag
2450Lys Glu Val Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr Lys
800 805 810agc ctc att cct ctg gaa cgt
gca gtc atc aat ggt cag tta tat gag 2498Ser Leu Ile Pro Leu Glu Arg
Ala Val Ile Asn Gly Gln Leu Tyr Glu 815 820
825gag agt gag aat caa gac gag gac cct aat gat gag gga tct gtg ctg
2546Glu Ser Glu Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu830
835 840 845tcc ttc aaa tgc
agc cag tct act cca tgt cct gtt aac aga aag cta 2594Ser Phe Lys Cys
Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu 850
855 860tgg att ccc tgg atg aaa tcc aag gag ggc
cat ctt cag aat gga aaa 2642Trp Ile Pro Trp Met Lys Ser Lys Glu Gly
His Leu Gln Asn Gly Lys 865 870
875atg caa act aaa ccc aat gcc aac ttt gtg caa cct gga gat cta gtc
2690Met Gln Thr Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val
880 885 890cta agc cac aca cct ggg cag
cca ctt cat ata aag gtt act cca gac 2738Leu Ser His Thr Pro Gly Gln
Pro Leu His Ile Lys Val Thr Pro Asp 895 900
905cat gta caa aac aca gcc act ctt gaa atc aca agt cca acc aca gag
2786His Val Gln Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu910
915 920 925agt cct cac tct
tac acg agt act gca gtg ata ccg aac tgt ggc acg 2834Ser Pro His Ser
Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr 930
935 940cca aag caa agg ata acc atc ctc caa aac
gcc tcc ata aca cca gta 2882Pro Lys Gln Arg Ile Thr Ile Leu Gln Asn
Ala Ser Ile Thr Pro Val 945 950
955aag tcc aaa acc tct acc gaa gac ctc atg aat tta gaa caa ggc atg
2930Lys Ser Lys Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met
960 965 970tcc cca att acc atg gca acc
ttt gcc aga gca cag acc cca gag tct 2978Ser Pro Ile Thr Met Ala Thr
Phe Ala Arg Ala Gln Thr Pro Glu Ser 975 980
985tgt ggt tct cta act cca gaa agg aca atg tcc cct att cag gtt ttg
3026Cys Gly Ser Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu990
995 1000 1005gct gtg act
ggt tca gct agc tct cct gag cag gga cgc tcc cca 3071Ala Val Thr
Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro 1010
1015 1020gaa cca aca gaa atc agt gcc aag cat
gcg ata ttc aga gtc tcc 3116Glu Pro Thr Glu Ile Ser Ala Lys His
Ala Ile Phe Arg Val Ser 1025 1030
1035cca gac cgg cag tca tca tgg cag ttt cag cgt tca aac agc aat
3161Pro Asp Arg Gln Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn
1040 1045 1050agc tca agt
gtg ata act act gag gat aat aaa atc cac att cac 3206Ser Ser Ser
Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His 1055
1060 1065tta gga agt cct tac atg caa gct gta
gcc agc cct gtg aga cct 3251Leu Gly Ser Pro Tyr Met Gln Ala Val
Ala Ser Pro Val Arg Pro 1070 1075
1080gcc agc cct tca gca cca ctg cag gat aac cga act caa ggc tta
3296Ala Ser Pro Ser Ala Pro Leu Gln Asp Asn Arg Thr Gln Gly Leu
1085 1090 1095att aac ggg
gca cta aac aaa aca acc aat aaa gtc acc agc agt 3341Ile Asn Gly
Ala Leu Asn Lys Thr Thr Asn Lys Val Thr Ser Ser 1100
1105 1110att act atc aca cca aca gcc aca cct
ctt cct cga caa tca caa 3386Ile Thr Ile Thr Pro Thr Ala Thr Pro
Leu Pro Arg Gln Ser Gln 1115 1120
1125att aca gta agt aat ata tat aac tgacc
3415Ile Thr Val Ser Asn Ile Tyr Asn
1130141133PRTHomo sapiens 14Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser
Ala Gln Lys Lys Phe1 5 10
15Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys
20 25 30His Arg Gln Gln Asp Lys Asp
Ser Pro Ser Glu Ser Asp Val Ile Leu 35 40
45Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln
Ala 50 55 60Glu Asp Leu Ser Arg Asp
Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65 70
75 80Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly
Ile Leu Lys Ala Glu 85 90
95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro
100 105 110Lys Lys Val Leu Glu Ala
Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120
125Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu
Leu Asp 130 135 140Lys Val Val Glu Lys
His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150
155 160Leu Leu Val Ala Glu Lys Ser His Arg Gln
Thr Ile Leu Glu Leu Glu 165 170
175Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
180 185 190Ile Cys Leu Leu Glu
Gln Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195
200 205Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu
Lys Glu Lys Arg 210 215 220Val Thr Thr
Leu Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225
230 235 240Met Val Val Asp Glu Gln Gln
Arg Leu Thr Ala Gln Leu Thr Leu Gln 245
250 255Arg Gln Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys
Glu Thr His Thr 260 265 270Lys
Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala 275
280 285Thr Arg Leu Glu Lys Glu Leu Gln Thr
Gln Thr Thr Lys Phe His Gln 290 295
300Asp Gln Asp Thr Ile Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn305
310 315 320Arg Gln Leu Gln
Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu 325
330 335Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys
Ala Glu Glu Glu Leu Gln 340 345
350Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn Ala Gly Ile
355 360 365Met Ala Glu Val Glu Glu Leu
Arg Lys Arg Val Leu Asp Met Glu Gly 370 375
380Lys Asp Glu Glu Leu Ile Lys Met Glu Glu Gln Cys Arg Asp Leu
Asn385 390 395 400Lys Arg
Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys Leu Glu
405 410 415Val Glu Lys Leu Ser Lys Arg
Ile Met Ala Leu Glu Lys Leu Glu Asp 420 425
430Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu Lys Cys
Asn Leu 435 440 445Glu Lys Glu Arg
Met Thr Thr Lys Gln Leu Ser Gln Glu Leu Glu Ser 450
455 460Leu Lys Val Arg Ile Lys Glu Leu Glu Ala Ile Glu
Ser Arg Leu Glu465 470 475
480Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu Lys Thr Leu
485 490 495Thr Val Met Phe Val
Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys 500
505 510Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln
Leu Gln Val Glu 515 520 525Gln Asn
Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu Thr Lys 530
535 540Arg Ala Leu Lys Ser Lys Thr Asp Val Glu Glu
Lys Met Tyr Ser Val545 550 555
560Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys Ala Glu Glu Glu
565 570 575Lys Gly Asn Asp
Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu 580
585 590Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu
Lys Asn Lys Leu Asn 595 600 605Gln
Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn Asn Lys 610
615 620Ile Lys Glu Leu Ser Gln Glu Val Glu Arg
Leu Lys Leu Lys Leu Lys625 630 635
640Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu Asp Glu
Tyr 645 650 655Glu Thr Leu
Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala Gln Phe 660
665 670Leu Ser Lys Glu Leu Glu His Val Lys Met
Glu Leu Ala Lys Tyr Lys 675 680
685Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe Lys Arg 690
695 700Leu Gln Glu Glu Glu Ala Lys Ser
Gly His Leu Ser Arg Glu Val Asp705 710
715 720Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr
Glu Asp Leu Ile 725 730
735Cys His Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu Asn Gln
740 745 750Gln Glu Asn Arg Asn Arg
Asp Leu Gly Arg Glu Ile Glu Asn Leu Thr 755 760
765Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg
Pro Ser 770 775 780Leu Asn Gly Arg Arg
Ile Ser Asp Pro Gln Val Phe Ser Lys Glu Val785 790
795 800Gln Thr Glu Ala Val Asp Asn Glu Pro Pro
Asp Tyr Lys Ser Leu Ile 805 810
815Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu Ser Glu
820 825 830Asn Gln Asp Glu Asp
Pro Asn Asp Glu Gly Ser Val Leu Ser Phe Lys 835
840 845Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys
Leu Trp Ile Pro 850 855 860Trp Met Lys
Ser Lys Glu Gly His Leu Gln Asn Gly Lys Met Gln Thr865
870 875 880Lys Pro Asn Ala Asn Phe Val
Gln Pro Gly Asp Leu Val Leu Ser His 885
890 895Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro
Asp His Val Gln 900 905 910Asn
Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu Ser Pro His 915
920 925Ser Tyr Thr Ser Thr Ala Val Ile Pro
Asn Cys Gly Thr Pro Lys Gln 930 935
940Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val Lys Ser Lys945
950 955 960Thr Ser Thr Glu
Asp Leu Met Asn Leu Glu Gln Gly Met Ser Pro Ile 965
970 975Thr Met Ala Thr Phe Ala Arg Ala Gln Thr
Pro Glu Ser Cys Gly Ser 980 985
990Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu Ala Val Thr
995 1000 1005Gly Ser Ala Ser Ser Pro
Glu Gln Gly Arg Ser Pro Glu Pro Thr 1010 1015
1020Glu Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp
Arg 1025 1030 1035Gln Ser Ser Trp Gln
Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser 1040 1045
1050Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu
Gly Ser 1055 1060 1065Pro Tyr Met Gln
Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro 1070
1075 1080Ser Ala Pro Leu Gln Asp Asn Arg Thr Gln Gly
Leu Ile Asn Gly 1085 1090 1095Ala Leu
Asn Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile 1100
1105 1110Thr Pro Thr Ala Thr Pro Leu Pro Arg Gln
Ser Gln Ile Thr Val 1115 1120 1125Ser
Asn Ile Tyr Asn 1130153416DNAHomo sapiensmisc_featureGIP130c
15tttaaaga atg cgt tcc aga ggc agt gat acc gag ggc tca gcc caa aag
50 Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys
1 5 10aaa ttt cca aga cat act aaa ggc
cac agt ttc caa ggg cct aaa aac 98Lys Phe Pro Arg His Thr Lys Gly
His Ser Phe Gln Gly Pro Lys Asn15 20 25
30atg aag cat aga cag caa gac aaa gac tcc ccc agt gag
tcg gat gta 146Met Lys His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu
Ser Asp Val 35 40 45ata
ctt ccg tgt ccc aag gca gag aag cca cac agt ggt aat ggc cac 194Ile
Leu Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His 50
55 60caa gca gaa gac ctc tca aga gat
gac ctg tta ttt ctc ctc agc att 242Gln Ala Glu Asp Leu Ser Arg Asp
Asp Leu Leu Phe Leu Leu Ser Ile 65 70
75ctg gag gga gaa ctg cag gct cga gat gag gtc ata ggc att tta aag
290Leu Glu Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly Ile Leu Lys
80 85 90gct gaa aaa atg gac ctg gct ttg
ctg gaa gct cag tat ggg ttt gtc 338Ala Glu Lys Met Asp Leu Ala Leu
Leu Glu Ala Gln Tyr Gly Phe Val95 100
105 110act cca aaa aag gtg tta gag gct ctc cag aga gat
gct ttt caa gcg 386Thr Pro Lys Lys Val Leu Glu Ala Leu Gln Arg Asp
Ala Phe Gln Ala 115 120
125aaa tct acc cct tgg cag gag gac atc tat gag aaa cca atg aat gag
434Lys Ser Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu
130 135 140ttg gac aaa gtt gtg gaa
aaa cat aaa gaa tct tac aga cga atc ctg 482Leu Asp Lys Val Val Glu
Lys His Lys Glu Ser Tyr Arg Arg Ile Leu 145 150
155gga cag ctt tta gtg gca gaa aaa tcc cgt agg caa acc ata
ttg gag 530Gly Gln Leu Leu Val Ala Glu Lys Ser Arg Arg Gln Thr Ile
Leu Glu 160 165 170ttg gag gaa gaa aag
aga aaa cat aaa gaa tac atg gag aag agt gat 578Leu Glu Glu Glu Lys
Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp175 180
185 190gaa ttc ata tgc cta cta gaa cag gaa tgt
gaa aga tta aag aag cta 626Glu Phe Ile Cys Leu Leu Glu Gln Glu Cys
Glu Arg Leu Lys Lys Leu 195 200
205att gat caa gaa atc aag tct cag gag gag aag gag caa gaa aag gag
674Ile Asp Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu
210 215 220aaa agg gtc acc acc ctg
aaa gag gag ctg acc aag ctg aag tct ttt 722Lys Arg Val Thr Thr Leu
Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe 225 230
235gct ttg atg gtg gtg gat gaa cag caa agg ctg acg gca cag
ctc acc 770Ala Leu Met Val Val Asp Glu Gln Gln Arg Leu Thr Ala Gln
Leu Thr 240 245 250ctt caa aga cag aaa
atc caa gag ctg acc aca aat gca aag gaa aca 818Leu Gln Arg Gln Lys
Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr255 260
265 270cat acc aaa cta gcc ctt gct gaa gcc aga
gtt cag gag gaa gag cag 866His Thr Lys Leu Ala Leu Ala Glu Ala Arg
Val Gln Glu Glu Glu Gln 275 280
285aag gca acc aga cta gag aag gaa ctg caa acg cag acc aca aag ttt
914Lys Ala Thr Arg Leu Glu Lys Glu Leu Gln Thr Gln Thr Thr Lys Phe
290 295 300cac caa gac caa gac aca
att atg gcg aag ctc acc aat gag gac agt 962His Gln Asp Gln Asp Thr
Ile Met Ala Lys Leu Thr Asn Glu Asp Ser 305 310
315caa aat cgc cag ctt caa caa aag ctg gca gca ctc agc cgg
cag att 1010Gln Asn Arg Gln Leu Gln Gln Lys Leu Ala Ala Leu Ser Arg
Gln Ile 320 325 330gat gag tta gaa gag
aca aac agg tct tta cga aaa gca gaa gag gag 1058Asp Glu Leu Glu Glu
Thr Asn Arg Ser Leu Arg Lys Ala Glu Glu Glu335 340
345 350ctg caa gat ata aaa gaa aaa atc agt aag
gga gaa tat gga aac gct 1106Leu Gln Asp Ile Lys Glu Lys Ile Ser Lys
Gly Glu Tyr Gly Asn Ala 355 360
365ggt atc atg gct gaa gtg gaa gag ctc agg aaa cgt gtg cta gat atg
1154Gly Ile Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met
370 375 380gaa ggg aaa gat gaa gag
ctc ata aaa atg gag gag cag tgc aga gat 1202Glu Gly Lys Asp Glu Glu
Leu Ile Lys Met Glu Glu Gln Cys Arg Asp 385 390
395ctc aat aag agg ctt gaa agg gag acg tta cag agt aaa gac
ttt aaa 1250Leu Asn Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp
Phe Lys 400 405 410cta gag gtt gaa aaa
ctc agt aaa aga att atg gct ctg gaa aag tta 1298Leu Glu Val Glu Lys
Leu Ser Lys Arg Ile Met Ala Leu Glu Lys Leu415 420
425 430gaa gac gct ttc aac aaa agc aaa caa gaa
tgc tac tct ctg aaa tgc 1346Glu Asp Ala Phe Asn Lys Ser Lys Gln Glu
Cys Tyr Ser Leu Lys Cys 435 440
445aat tta gaa aaa gaa agg atg acc aca aag cag ttg tct caa gaa ctg
1394Asn Leu Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu
450 455 460gag agt tta aaa gta agg
atc aaa gag cta gaa gcc att gaa agt cgg 1442Glu Ser Leu Lys Val Arg
Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg 465 470
475cta gaa aag aca gaa ttc act cta aaa gag gat tta act aaa
ctg aaa 1490Leu Glu Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys
Leu Lys 480 485 490aca tta act gtg atg
ttt gta gat gaa cgg aaa aca atg agt gaa aaa 1538Thr Leu Thr Val Met
Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys495 500
505 510tta aag aaa act gaa gat aaa tta caa gct
gct tct tct cag ctt caa 1586Leu Lys Lys Thr Glu Asp Lys Leu Gln Ala
Ala Ser Ser Gln Leu Gln 515 520
525gtg gag caa aat aaa gta aca aca gtt act gag aag tta att gag gaa
1634Val Glu Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu
530 535 540act aaa agg gcg ctc aag
tcc aaa acc gat gta gaa gaa aag atg tac 1682Thr Lys Arg Ala Leu Lys
Ser Lys Thr Asp Val Glu Glu Lys Met Tyr 545 550
555agc gta acc aag gag aga gat gat tta aaa aac aaa ttg aaa
gcg gaa 1730Ser Val Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys
Ala Glu 560 565 570gaa gag aaa gga aat
gat ctc ctg tca aga gtt aat atg ttg aaa aat 1778Glu Glu Lys Gly Asn
Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn575 580
585 590agg ctt caa tca ttg gaa gca att gag aaa
gat ttc cta aaa aac aaa 1826Arg Leu Gln Ser Leu Glu Ala Ile Glu Lys
Asp Phe Leu Lys Asn Lys 595 600
605tta aat caa gac tct ggg aaa tcc aca aca gca tta cac caa gaa aac
1874Leu Asn Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn
610 615 620aat aag att aag gag ctc
tct caa gaa gtg gaa aga ctg aaa ctg aag 1922Asn Lys Ile Lys Glu Leu
Ser Gln Glu Val Glu Arg Leu Lys Leu Lys 625 630
635cta aag gac atg aaa gcc att gag gat gac ctc atg aaa aca
gaa gat 1970Leu Lys Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr
Glu Asp 640 645 650gaa tat gag act cta
gaa cga agg tat gct aat gaa cga gac aaa gct 2018Glu Tyr Glu Thr Leu
Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala655 660
665 670caa ttt tta tct aaa gag cta gaa cat gtt
aaa atg gaa ctt gct aag 2066Gln Phe Leu Ser Lys Glu Leu Glu His Val
Lys Met Glu Leu Ala Lys 675 680
685tac aag tta gca gaa aag aca gag acc agc cat gaa caa tgg ctt ttc
2114Tyr Lys Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe
690 695 700aaa agg ctt caa gaa gaa
gaa gct aag tca ggg cac ctc tca aga gaa 2162Lys Arg Leu Gln Glu Glu
Glu Ala Lys Ser Gly His Leu Ser Arg Glu 705 710
715gtg gat gca tta aaa gag aaa att cat gaa tac atg gca act
gaa gac 2210Val Asp Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr
Glu Asp 720 725 730cta ata tgt cac ctc
cag gga gat cac tca gtc ctg caa aaa aaa cta 2258Leu Ile Cys His Leu
Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu735 740
745 750aat caa caa gaa aac agg aac aga gat tta
gga aga gag att gaa aac 2306Asn Gln Gln Glu Asn Arg Asn Arg Asp Leu
Gly Arg Glu Ile Glu Asn 755 760
765ctc act aag gag tta gag agg tac cgg cat ttc agt aag agc ctc agg
2354Leu Thr Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg
770 775 780cct agt ctc aat gga aga
aga att tcc gat cct caa gta ttt tct aaa 2402Pro Ser Leu Asn Gly Arg
Arg Ile Ser Asp Pro Gln Val Phe Ser Lys 785 790
795gaa gtt cag aca gaa gca gta gac aat gaa cca cct gat tac
aag agc 2450Glu Val Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr
Lys Ser 800 805 810ctc att cct ctg gaa
cgt gca gtc atc aat ggt cag tta tat gag gag 2498Leu Ile Pro Leu Glu
Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu815 820
825 830agt gag aat caa gac gag gac cct aat gat
gag gga tct gtg ctg tcc 2546Ser Glu Asn Gln Asp Glu Asp Pro Asn Asp
Glu Gly Ser Val Leu Ser 835 840
845ttc aaa tgc agc cag tct act cca tgt cct gtt aac aga aag cta tgg
2594Phe Lys Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu Trp
850 855 860att ccc tgg atg aaa tcc
aag gag ggc cat ctt cag aat gga aaa atg 2642Ile Pro Trp Met Lys Ser
Lys Glu Gly His Leu Gln Asn Gly Lys Met 865 870
875caa act aaa ccc aat gcc aac ttt gtg caa cct gga gat cta
gtc cta 2690Gln Thr Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu
Val Leu 880 885 890agc cac aca cct ggg
cag cca ctt cat ata aag gtt act cca gac cat 2738Ser His Thr Pro Gly
Gln Pro Leu His Ile Lys Val Thr Pro Asp His895 900
905 910gta caa aac aca gcc act ctt gaa atc aca
agt cca acc aca gag agt 2786Val Gln Asn Thr Ala Thr Leu Glu Ile Thr
Ser Pro Thr Thr Glu Ser 915 920
925cct cac tct tac acg agt act gca gtg ata ccg aac tgt ggc acg cca
2834Pro His Ser Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro
930 935 940aag caa agg ata acc atc
ctc caa aac gcc tcc ata aca cca gta aag 2882Lys Gln Arg Ile Thr Ile
Leu Gln Asn Ala Ser Ile Thr Pro Val Lys 945 950
955tcc aaa acc tct acc gaa gac ctc atg aat tta gaa caa ggc
atg tcc 2930Ser Lys Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly
Met Ser 960 965 970cca att acc atg gca
acc ttt gcc aga gca cag acc cca gag tct tgt 2978Pro Ile Thr Met Ala
Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys975 980
985 990ggt tct cta act cca gaa agg aca atg tcc
cct att cag gtt ttg gct 3026Gly Ser Leu Thr Pro Glu Arg Thr Met Ser
Pro Ile Gln Val Leu Ala 995 1000
1005gtg act ggt tca gct agc tct cct gag cag gga cgc tcc cca gaa
3071Val Thr Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu
1010 1015 1020cca aca gaa atc
agt gcc aag cat gcg ata ttc aga gtc tcc cca 3116Pro Thr Glu Ile
Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro 1025
1030 1035gac cgg cag tca tca tgg cag ttt cag cgt
tca aac agc aat agc 3161Asp Arg Gln Ser Ser Trp Gln Phe Gln Arg
Ser Asn Ser Asn Ser 1040 1045
1050tca agt gtg ata act act gag gat aat aaa atc cac att cac tta
3206Ser Ser Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu
1055 1060 1065gga agt cct tac atg
caa gct gta gcc agc cct gtg aga cct gcc 3251Gly Ser Pro Tyr Met
Gln Ala Val Ala Ser Pro Val Arg Pro Ala 1070
1075 1080agc cct tca gca cca ctg cag gat aac cga act
caa ggc tta att 3296Ser Pro Ser Ala Pro Leu Gln Asp Asn Arg Thr
Gln Gly Leu Ile 1085 1090
1095aac ggg gca cta aac aaa aca acc aat aaa gtc acc agc agt att
3341Asn Gly Ala Leu Asn Lys Thr Thr Asn Lys Val Thr Ser Ser Ile
1100 1105 1110act atc aca cca aca
gcc aca cct ctt cct cga caa tca caa att 3386Thr Ile Thr Pro Thr
Ala Thr Pro Leu Pro Arg Gln Ser Gln Ile 1115
1120 1125aca gta agt aat ata tat aac tgaccacgc
3416Thr Val Ser Asn Ile Tyr Asn
1130161133PRTHomo sapiens 16Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser
Ala Gln Lys Lys Phe1 5 10
15Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys
20 25 30His Arg Gln Gln Asp Lys Asp
Ser Pro Ser Glu Ser Asp Val Ile Leu 35 40
45Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln
Ala 50 55 60Glu Asp Leu Ser Arg Asp
Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65 70
75 80Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly
Ile Leu Lys Ala Glu 85 90
95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro
100 105 110Lys Lys Val Leu Glu Ala
Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120
125Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu
Leu Asp 130 135 140Lys Val Val Glu Lys
His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150
155 160Leu Leu Val Ala Glu Lys Ser Arg Arg Gln
Thr Ile Leu Glu Leu Glu 165 170
175Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
180 185 190Ile Cys Leu Leu Glu
Gln Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195
200 205Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu
Lys Glu Lys Arg 210 215 220Val Thr Thr
Leu Lys Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225
230 235 240Met Val Val Asp Glu Gln Gln
Arg Leu Thr Ala Gln Leu Thr Leu Gln 245
250 255Arg Gln Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys
Glu Thr His Thr 260 265 270Lys
Leu Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala 275
280 285Thr Arg Leu Glu Lys Glu Leu Gln Thr
Gln Thr Thr Lys Phe His Gln 290 295
300Asp Gln Asp Thr Ile Met Ala Lys Leu Thr Asn Glu Asp Ser Gln Asn305
310 315 320Arg Gln Leu Gln
Gln Lys Leu Ala Ala Leu Ser Arg Gln Ile Asp Glu 325
330 335Leu Glu Glu Thr Asn Arg Ser Leu Arg Lys
Ala Glu Glu Glu Leu Gln 340 345
350Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn Ala Gly Ile
355 360 365Met Ala Glu Val Glu Glu Leu
Arg Lys Arg Val Leu Asp Met Glu Gly 370 375
380Lys Asp Glu Glu Leu Ile Lys Met Glu Glu Gln Cys Arg Asp Leu
Asn385 390 395 400Lys Arg
Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys Leu Glu
405 410 415Val Glu Lys Leu Ser Lys Arg
Ile Met Ala Leu Glu Lys Leu Glu Asp 420 425
430Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu Lys Cys
Asn Leu 435 440 445Glu Lys Glu Arg
Met Thr Thr Lys Gln Leu Ser Gln Glu Leu Glu Ser 450
455 460Leu Lys Val Arg Ile Lys Glu Leu Glu Ala Ile Glu
Ser Arg Leu Glu465 470 475
480Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu Lys Thr Leu
485 490 495Thr Val Met Phe Val
Asp Glu Arg Lys Thr Met Ser Glu Lys Leu Lys 500
505 510Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser Ser Gln
Leu Gln Val Glu 515 520 525Gln Asn
Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu Thr Lys 530
535 540Arg Ala Leu Lys Ser Lys Thr Asp Val Glu Glu
Lys Met Tyr Ser Val545 550 555
560Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys Ala Glu Glu Glu
565 570 575Lys Gly Asn Asp
Leu Leu Ser Arg Val Asn Met Leu Lys Asn Arg Leu 580
585 590Gln Ser Leu Glu Ala Ile Glu Lys Asp Phe Leu
Lys Asn Lys Leu Asn 595 600 605Gln
Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn Asn Lys 610
615 620Ile Lys Glu Leu Ser Gln Glu Val Glu Arg
Leu Lys Leu Lys Leu Lys625 630 635
640Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr Glu Asp Glu
Tyr 645 650 655Glu Thr Leu
Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala Gln Phe 660
665 670Leu Ser Lys Glu Leu Glu His Val Lys Met
Glu Leu Ala Lys Tyr Lys 675 680
685Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe Lys Arg 690
695 700Leu Gln Glu Glu Glu Ala Lys Ser
Gly His Leu Ser Arg Glu Val Asp705 710
715 720Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr
Glu Asp Leu Ile 725 730
735Cys His Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu Asn Gln
740 745 750Gln Glu Asn Arg Asn Arg
Asp Leu Gly Arg Glu Ile Glu Asn Leu Thr 755 760
765Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg
Pro Ser 770 775 780Leu Asn Gly Arg Arg
Ile Ser Asp Pro Gln Val Phe Ser Lys Glu Val785 790
795 800Gln Thr Glu Ala Val Asp Asn Glu Pro Pro
Asp Tyr Lys Ser Leu Ile 805 810
815Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu Ser Glu
820 825 830Asn Gln Asp Glu Asp
Pro Asn Asp Glu Gly Ser Val Leu Ser Phe Lys 835
840 845Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys
Leu Trp Ile Pro 850 855 860Trp Met Lys
Ser Lys Glu Gly His Leu Gln Asn Gly Lys Met Gln Thr865
870 875 880Lys Pro Asn Ala Asn Phe Val
Gln Pro Gly Asp Leu Val Leu Ser His 885
890 895Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro
Asp His Val Gln 900 905 910Asn
Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu Ser Pro His 915
920 925Ser Tyr Thr Ser Thr Ala Val Ile Pro
Asn Cys Gly Thr Pro Lys Gln 930 935
940Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val Lys Ser Lys945
950 955 960Thr Ser Thr Glu
Asp Leu Met Asn Leu Glu Gln Gly Met Ser Pro Ile 965
970 975Thr Met Ala Thr Phe Ala Arg Ala Gln Thr
Pro Glu Ser Cys Gly Ser 980 985
990Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu Ala Val Thr
995 1000 1005Gly Ser Ala Ser Ser Pro
Glu Gln Gly Arg Ser Pro Glu Pro Thr 1010 1015
1020Glu Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp
Arg 1025 1030 1035Gln Ser Ser Trp Gln
Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser 1040 1045
1050Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu
Gly Ser 1055 1060 1065Pro Tyr Met Gln
Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro 1070
1075 1080Ser Ala Pro Leu Gln Asp Asn Arg Thr Gln Gly
Leu Ile Asn Gly 1085 1090 1095Ala Leu
Asn Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile 1100
1105 1110Thr Pro Thr Ala Thr Pro Leu Pro Arg Gln
Ser Gln Ile Thr Val 1115 1120 1125Ser
Asn Ile Tyr Asn 11301745DNAHomo sapiensCDS(1)..(45) 17act aaa tca aca
aga aaa cag gaa cag aga ttt agg aag aga gat 45Thr Lys Ser Thr
Arg Lys Gln Glu Gln Arg Phe Arg Lys Arg Asp1 5
10 151815PRTHomo sapiens 18Thr Lys Ser Thr Arg Lys
Gln Glu Gln Arg Phe Arg Lys Arg Asp1 5 10
151990DNAHomo sapiensCDS(1)..(90) 19gtg gat gaa cag caa
agg ctg acg gca cag ctc acc ctt caa aga cag 48Val Asp Glu Gln Gln
Arg Leu Thr Ala Gln Leu Thr Leu Gln Arg Gln1 5
10 15aaa atc caa gag ctg acc aca aat gca aag gaa
aca cat acc 90Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu
Thr His Thr 20 25
302030PRTHomo sapiens 20Val Asp Glu Gln Gln Arg Leu Thr Ala Gln Leu Thr
Leu Gln Arg Gln1 5 10
15Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr 20
25 30211158DNAHomo sapiensCDS(1)..(1158)
21cta aat caa caa gaa aac agg aac aga gat tta gga aga gag att gaa
48Leu Asn Gln Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu1
5 10 15aac ctc act aag gag tta
gag agg tac cgg cat ttc agt aag agc ctc 96Asn Leu Thr Lys Glu Leu
Glu Arg Tyr Arg His Phe Ser Lys Ser Leu 20 25
30agg cct agt ctc aat gga aga aga att tcc gat cct caa
gta ttt tct 144Arg Pro Ser Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln
Val Phe Ser 35 40 45aaa gaa gtt
cag aca gaa gca gta gac aat gaa cca cct gat tac aag 192Lys Glu Val
Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr Lys 50
55 60agc ctc att cct ctg gaa cgt gca gtc atc aat ggt
cag tta tat gag 240Ser Leu Ile Pro Leu Glu Arg Ala Val Ile Asn Gly
Gln Leu Tyr Glu65 70 75
80gag agt gag aat caa gac gag gac cct aat gat gag gga tct gtg ctg
288Glu Ser Glu Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu
85 90 95tcc ttc aaa tgc agc cag
tct act cca tgt cct gtt aac aga aag cta 336Ser Phe Lys Cys Ser Gln
Ser Thr Pro Cys Pro Val Asn Arg Lys Leu 100
105 110tgg att ccc tgg atg aaa tcc aag gag ggc cat ctt
cag aat gga aaa 384Trp Ile Pro Trp Met Lys Ser Lys Glu Gly His Leu
Gln Asn Gly Lys 115 120 125atg caa
act aaa ccc aat gcc aac ttt gtg caa cct gga gat cta gtc 432Met Gln
Thr Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val 130
135 140cta agc cac aca cct ggg cag cca ctt cat ata
aag gtt act cca gac 480Leu Ser His Thr Pro Gly Gln Pro Leu His Ile
Lys Val Thr Pro Asp145 150 155
160cat gta caa aac aca gcc act ctt gaa atc aca agt cca acc aca gag
528His Val Gln Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu
165 170 175agt cct cac tct tac
acg agt act gca gtg ata ccg aac tgt ggc acg 576Ser Pro His Ser Tyr
Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr 180
185 190cca aag caa agg ata acc atc ctc caa aac gcc tcc
ata aca cca gta 624Pro Lys Gln Arg Ile Thr Ile Leu Gln Asn Ala Ser
Ile Thr Pro Val 195 200 205aag tcc
aaa acc tct acc gaa gac ctc atg aat tta gaa caa ggc atg 672Lys Ser
Lys Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met 210
215 220tcc cca att acc atg gca acc ttt gcc aga gca
cag acc cca gag tct 720Ser Pro Ile Thr Met Ala Thr Phe Ala Arg Ala
Gln Thr Pro Glu Ser225 230 235
240tgt ggt tct cta act cca gaa agg aca atg tcc cct att cag gtt ttg
768Cys Gly Ser Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu
245 250 255gct gtg act ggt tca
gct agc tct cct gag cag gga cgc tcc cca gaa 816Ala Val Thr Gly Ser
Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu 260
265 270cca aca gaa atc agt gcc aag cat gcg ata ttc aga
gtc tcc cca gac 864Pro Thr Glu Ile Ser Ala Lys His Ala Ile Phe Arg
Val Ser Pro Asp 275 280 285cgg cag
tca tca tgg cag ttt cag cgt tca aac agc aat agc tca agt 912Arg Gln
Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser 290
295 300gtg ata act act gag gat aat aaa atc cac att
cac tta gga agt cct 960Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile
His Leu Gly Ser Pro305 310 315
320tac atg caa gct gta gcc agc cct gtg aga cct gcc agc cct tca gca
1008Tyr Met Gln Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro Ser Ala
325 330 335cca ctg cag gat aac
cga act caa ggc tta att aac ggg gca cta aac 1056Pro Leu Gln Asp Asn
Arg Thr Gln Gly Leu Ile Asn Gly Ala Leu Asn 340
345 350aaa aca acc aat aaa gtc acc agc agt att act atc
aca cca aca gcc 1104Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile
Thr Pro Thr Ala 355 360 365aca cct
ctt cct cga caa tca caa att aca gtg gaa cca ctt ctt ctg 1152Thr Pro
Leu Pro Arg Gln Ser Gln Ile Thr Val Glu Pro Leu Leu Leu 370
375 380cct cat
1158Pro His38522386PRTHomo sapiens 22Leu Asn Gln
Gln Glu Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu1 5
10 15Asn Leu Thr Lys Glu Leu Glu Arg Tyr
Arg His Phe Ser Lys Ser Leu 20 25
30Arg Pro Ser Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser
35 40 45Lys Glu Val Gln Thr Glu Ala
Val Asp Asn Glu Pro Pro Asp Tyr Lys 50 55
60Ser Leu Ile Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu65
70 75 80Glu Ser Glu Asn
Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu 85
90 95Ser Phe Lys Cys Ser Gln Ser Thr Pro Cys
Pro Val Asn Arg Lys Leu 100 105
110Trp Ile Pro Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly Lys
115 120 125Met Gln Thr Lys Pro Asn Ala
Asn Phe Val Gln Pro Gly Asp Leu Val 130 135
140Leu Ser His Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro
Asp145 150 155 160His Val
Gln Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu
165 170 175Ser Pro His Ser Tyr Thr Ser
Thr Ala Val Ile Pro Asn Cys Gly Thr 180 185
190Pro Lys Gln Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr
Pro Val 195 200 205Lys Ser Lys Thr
Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met 210
215 220Ser Pro Ile Thr Met Ala Thr Phe Ala Arg Ala Gln
Thr Pro Glu Ser225 230 235
240Cys Gly Ser Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu
245 250 255Ala Val Thr Gly Ser
Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu 260
265 270Pro Thr Glu Ile Ser Ala Lys His Ala Ile Phe Arg
Val Ser Pro Asp 275 280 285Arg Gln
Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser 290
295 300Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile
His Leu Gly Ser Pro305 310 315
320Tyr Met Gln Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro Ser Ala
325 330 335Pro Leu Gln Asp
Asn Arg Thr Gln Gly Leu Ile Asn Gly Ala Leu Asn 340
345 350Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr
Ile Thr Pro Thr Ala 355 360 365Thr
Pro Leu Pro Arg Gln Ser Gln Ile Thr Val Glu Pro Leu Leu Leu 370
375 380Pro His385232355DNAHomo
sapiensCDS(1)..(2355) 23ctg caa gat ata aaa gaa aaa atc agt aag gga gaa
tat gga aac gct 48Leu Gln Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu
Tyr Gly Asn Ala1 5 10
15ggt atc atg gct gaa gtg gaa gag ctc agg aaa cgt gtg cta gat atg
96Gly Ile Met Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met
20 25 30gaa ggg aaa gat gaa gag ctc
ata aaa atg gag gag cag tgc aga gat 144Glu Gly Lys Asp Glu Glu Leu
Ile Lys Met Glu Glu Gln Cys Arg Asp 35 40
45ctc aat aag agg ctt gaa agg gag acg tta cag agt aaa gac ttt
aaa 192Leu Asn Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe
Lys 50 55 60cta gag gtt gaa aaa ctc
agt aaa aga att atg gct ctg gaa aag tta 240Leu Glu Val Glu Lys Leu
Ser Lys Arg Ile Met Ala Leu Glu Lys Leu65 70
75 80gaa gac gct ttc aac aaa agc aaa caa gaa tgc
tac tct ctg aaa tgc 288Glu Asp Ala Phe Asn Lys Ser Lys Gln Glu Cys
Tyr Ser Leu Lys Cys 85 90
95aat tta gaa aaa gaa agg atg acc aca aag cag ttg tct caa gaa ctg
336Asn Leu Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu
100 105 110gag agt tta aaa gta agg
atc aaa gag cta gaa gcc att gaa agt cgg 384Glu Ser Leu Lys Val Arg
Ile Lys Glu Leu Glu Ala Ile Glu Ser Arg 115 120
125cta gaa aag aca gaa ttc act cta aaa gag gat tta act aaa
ctg aaa 432Leu Glu Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys
Leu Lys 130 135 140aca tta act gtg atg
ttt gta gat gaa cgg aaa aca atg agt gaa aaa 480Thr Leu Thr Val Met
Phe Val Asp Glu Arg Lys Thr Met Ser Glu Lys145 150
155 160tta aag aaa act gaa gat aaa tta caa gct
gct tct tct cag ctt caa 528Leu Lys Lys Thr Glu Asp Lys Leu Gln Ala
Ala Ser Ser Gln Leu Gln 165 170
175gtg gag caa aat aaa gta aca aca gtt act gag aag tta att gag gaa
576Val Glu Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu
180 185 190act aaa agg gcg ctc aag
tcc aaa acc gat gta gaa gaa aag atg tac 624Thr Lys Arg Ala Leu Lys
Ser Lys Thr Asp Val Glu Glu Lys Met Tyr 195 200
205agc gta acc aag gag aga gat gat tta aaa aac aaa ttg aaa
gcg gaa 672Ser Val Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys
Ala Glu 210 215 220gaa gag aaa gga aat
gat ctc ctg tca aga gtt aat atg ttg aaa aat 720Glu Glu Lys Gly Asn
Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn225 230
235 240agg ctt caa tca ttg gaa gca att gag aaa
gat ttc cta aaa aac aaa 768Arg Leu Gln Ser Leu Glu Ala Ile Glu Lys
Asp Phe Leu Lys Asn Lys 245 250
255tta aat caa gac tct ggg aaa tcc aca aca gca tta cac caa gaa aac
816Leu Asn Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn
260 265 270aat aag att aag gag ctc
tct caa gaa gtg gaa aga ctg aaa ctg aag 864Asn Lys Ile Lys Glu Leu
Ser Gln Glu Val Glu Arg Leu Lys Leu Lys 275 280
285cta aag gac atg aaa gcc att gag gat gac ctc atg aaa aca
gaa gat 912Leu Lys Asp Met Lys Ala Ile Glu Asp Asp Leu Met Lys Thr
Glu Asp 290 295 300gaa tat gag act cta
gaa cga agg tat gct aat gaa cga gac aaa gct 960Glu Tyr Glu Thr Leu
Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala305 310
315 320caa ttt tta tct aaa gag cta gaa cat gtt
aaa atg gaa ctt gct aag 1008Gln Phe Leu Ser Lys Glu Leu Glu His Val
Lys Met Glu Leu Ala Lys 325 330
335tac aag tta gca gaa aag aca gag acc agc cat gaa caa tgg ctt ttc
1056Tyr Lys Leu Ala Glu Lys Thr Glu Thr Ser His Glu Gln Trp Leu Phe
340 345 350aaa agg ctt caa gaa gaa
gaa gct aag tca ggg cac ctc tca aga gaa 1104Lys Arg Leu Gln Glu Glu
Glu Ala Lys Ser Gly His Leu Ser Arg Glu 355 360
365gtg gat gca tta aaa gag aaa att cat gaa tac atg gca act
gaa gac 1152Val Asp Ala Leu Lys Glu Lys Ile His Glu Tyr Met Ala Thr
Glu Asp 370 375 380cta ata tgt cac ctc
cag gga gat cac tca gtc ctg caa aaa aaa cta 1200Leu Ile Cys His Leu
Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu385 390
395 400aat caa caa gaa aac agg aac aga gat tta
gga aga gag att gaa aac 1248Asn Gln Gln Glu Asn Arg Asn Arg Asp Leu
Gly Arg Glu Ile Glu Asn 405 410
415ctc act aag gag tta gag agg tac cgg cat ttc agt aag agc ctc agg
1296Leu Thr Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu Arg
420 425 430cct agt ctc aat gga aga
aga att tcc gat cct caa gta ttt tct aaa 1344Pro Ser Leu Asn Gly Arg
Arg Ile Ser Asp Pro Gln Val Phe Ser Lys 435 440
445gaa gtt cag aca gaa gca gta gac aat gaa cca cct gat tac
aag agc 1392Glu Val Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp Tyr
Lys Ser 450 455 460ctc att cct ctg gaa
cgt gca gtc atc aat ggt cag tta tat gag gag 1440Leu Ile Pro Leu Glu
Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu Glu465 470
475 480agt gag aat caa gac gag gac cct aat gat
gag gga tct gtg ctg tcc 1488Ser Glu Asn Gln Asp Glu Asp Pro Asn Asp
Glu Gly Ser Val Leu Ser 485 490
495ttc aaa tgc agc cag tct act cca tgt cct gtt aac aga aag cta tgg
1536Phe Lys Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu Trp
500 505 510att ccc tgg atg aaa tcc
aag gag ggc cat ctt cag aat gga aaa atg 1584Ile Pro Trp Met Lys Ser
Lys Glu Gly His Leu Gln Asn Gly Lys Met 515 520
525caa act aaa ccc aat gcc aac ttt gtg caa cct gga gat cta
gtc cta 1632Gln Thr Lys Pro Asn Ala Asn Phe Val Gln Pro Gly Asp Leu
Val Leu 530 535 540agc cac aca cct ggg
cag cca ctt cat ata aag gtt act cca gac cat 1680Ser His Thr Pro Gly
Gln Pro Leu His Ile Lys Val Thr Pro Asp His545 550
555 560gta caa aac aca gcc act ctt gaa atc aca
agt cca acc aca gag agt 1728Val Gln Asn Thr Ala Thr Leu Glu Ile Thr
Ser Pro Thr Thr Glu Ser 565 570
575cct cac tct tac acg agt act gca gtg ata ccg aac tgt ggc acg cca
1776Pro His Ser Tyr Thr Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro
580 585 590aag caa agg ata acc atc
ctc caa aac gcc tcc ata aca cca gta aag 1824Lys Gln Arg Ile Thr Ile
Leu Gln Asn Ala Ser Ile Thr Pro Val Lys 595 600
605tcc aaa acc tct acc gaa gac ctc atg aat tta gaa caa ggc
atg tcc 1872Ser Lys Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly
Met Ser 610 615 620cca att acc atg gca
acc ttt gcc aga gca cag acc cca gag tct tgt 1920Pro Ile Thr Met Ala
Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser Cys625 630
635 640ggt tct cta act cca gaa agg aca atg tcc
cct att cag gtt ttg gct 1968Gly Ser Leu Thr Pro Glu Arg Thr Met Ser
Pro Ile Gln Val Leu Ala 645 650
655gtg act ggt tca gct agc tct cct gag cag gga cgc tcc cca gaa cca
2016Val Thr Gly Ser Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu Pro
660 665 670aca gaa atc agt gcc aag
cat gcg ata ttc aga gtc tcc cca gac cgg 2064Thr Glu Ile Ser Ala Lys
His Ala Ile Phe Arg Val Ser Pro Asp Arg 675 680
685cag tca tca tgg cag ttt cag cgt tca aac agc aat agc tca
agt gtg 2112Gln Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser
Ser Val 690 695 700ata act act gag gat
aat aaa atc cac att cac tta gga agt cct tac 2160Ile Thr Thr Glu Asp
Asn Lys Ile His Ile His Leu Gly Ser Pro Tyr705 710
715 720atg caa gct gta gcc agc cct gtg aga cct
gcc agc cct tca gca cca 2208Met Gln Ala Val Ala Ser Pro Val Arg Pro
Ala Ser Pro Ser Ala Pro 725 730
735ctg cag gat aac cga act caa ggc tta att aac ggg gca cta aac aaa
2256Leu Gln Asp Asn Arg Thr Gln Gly Leu Ile Asn Gly Ala Leu Asn Lys
740 745 750aca acc aat aaa gtc acc
agc agt att act atc aca cca aca gcc aca 2304Thr Thr Asn Lys Val Thr
Ser Ser Ile Thr Ile Thr Pro Thr Ala Thr 755 760
765cct ctt cct cga caa tca caa att aca gtg gaa cca ctt ctt
ctg cct 2352Pro Leu Pro Arg Gln Ser Gln Ile Thr Val Glu Pro Leu Leu
Leu Pro 770 775 780cat
2355His78524785PRTHomo
sapiens 24Leu Gln Asp Ile Lys Glu Lys Ile Ser Lys Gly Glu Tyr Gly Asn
Ala1 5 10 15Gly Ile Met
Ala Glu Val Glu Glu Leu Arg Lys Arg Val Leu Asp Met 20
25 30Glu Gly Lys Asp Glu Glu Leu Ile Lys Met
Glu Glu Gln Cys Arg Asp 35 40
45Leu Asn Lys Arg Leu Glu Arg Glu Thr Leu Gln Ser Lys Asp Phe Lys 50
55 60Leu Glu Val Glu Lys Leu Ser Lys Arg
Ile Met Ala Leu Glu Lys Leu65 70 75
80Glu Asp Ala Phe Asn Lys Ser Lys Gln Glu Cys Tyr Ser Leu
Lys Cys 85 90 95Asn Leu
Glu Lys Glu Arg Met Thr Thr Lys Gln Leu Ser Gln Glu Leu 100
105 110Glu Ser Leu Lys Val Arg Ile Lys Glu
Leu Glu Ala Ile Glu Ser Arg 115 120
125Leu Glu Lys Thr Glu Phe Thr Leu Lys Glu Asp Leu Thr Lys Leu Lys
130 135 140Thr Leu Thr Val Met Phe Val
Asp Glu Arg Lys Thr Met Ser Glu Lys145 150
155 160Leu Lys Lys Thr Glu Asp Lys Leu Gln Ala Ala Ser
Ser Gln Leu Gln 165 170
175Val Glu Gln Asn Lys Val Thr Thr Val Thr Glu Lys Leu Ile Glu Glu
180 185 190Thr Lys Arg Ala Leu Lys
Ser Lys Thr Asp Val Glu Glu Lys Met Tyr 195 200
205Ser Val Thr Lys Glu Arg Asp Asp Leu Lys Asn Lys Leu Lys
Ala Glu 210 215 220Glu Glu Lys Gly Asn
Asp Leu Leu Ser Arg Val Asn Met Leu Lys Asn225 230
235 240Arg Leu Gln Ser Leu Glu Ala Ile Glu Lys
Asp Phe Leu Lys Asn Lys 245 250
255Leu Asn Gln Asp Ser Gly Lys Ser Thr Thr Ala Leu His Gln Glu Asn
260 265 270Asn Lys Ile Lys Glu
Leu Ser Gln Glu Val Glu Arg Leu Lys Leu Lys 275
280 285Leu Lys Asp Met Lys Ala Ile Glu Asp Asp Leu Met
Lys Thr Glu Asp 290 295 300Glu Tyr Glu
Thr Leu Glu Arg Arg Tyr Ala Asn Glu Arg Asp Lys Ala305
310 315 320Gln Phe Leu Ser Lys Glu Leu
Glu His Val Lys Met Glu Leu Ala Lys 325
330 335Tyr Lys Leu Ala Glu Lys Thr Glu Thr Ser His Glu
Gln Trp Leu Phe 340 345 350Lys
Arg Leu Gln Glu Glu Glu Ala Lys Ser Gly His Leu Ser Arg Glu 355
360 365Val Asp Ala Leu Lys Glu Lys Ile His
Glu Tyr Met Ala Thr Glu Asp 370 375
380Leu Ile Cys His Leu Gln Gly Asp His Ser Val Leu Gln Lys Lys Leu385
390 395 400Asn Gln Gln Glu
Asn Arg Asn Arg Asp Leu Gly Arg Glu Ile Glu Asn 405
410 415Leu Thr Lys Glu Leu Glu Arg Tyr Arg His
Phe Ser Lys Ser Leu Arg 420 425
430Pro Ser Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser Lys
435 440 445Glu Val Gln Thr Glu Ala Val
Asp Asn Glu Pro Pro Asp Tyr Lys Ser 450 455
460Leu Ile Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu
Glu465 470 475 480Ser Glu
Asn Gln Asp Glu Asp Pro Asn Asp Glu Gly Ser Val Leu Ser
485 490 495Phe Lys Cys Ser Gln Ser Thr
Pro Cys Pro Val Asn Arg Lys Leu Trp 500 505
510Ile Pro Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly
Lys Met 515 520 525Gln Thr Lys Pro
Asn Ala Asn Phe Val Gln Pro Gly Asp Leu Val Leu 530
535 540Ser His Thr Pro Gly Gln Pro Leu His Ile Lys Val
Thr Pro Asp His545 550 555
560Val Gln Asn Thr Ala Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu Ser
565 570 575Pro His Ser Tyr Thr
Ser Thr Ala Val Ile Pro Asn Cys Gly Thr Pro 580
585 590Lys Gln Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile
Thr Pro Val Lys 595 600 605Ser Lys
Thr Ser Thr Glu Asp Leu Met Asn Leu Glu Gln Gly Met Ser 610
615 620Pro Ile Thr Met Ala Thr Phe Ala Arg Ala Gln
Thr Pro Glu Ser Cys625 630 635
640Gly Ser Leu Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu Ala
645 650 655Val Thr Gly Ser
Ala Ser Ser Pro Glu Gln Gly Arg Ser Pro Glu Pro 660
665 670Thr Glu Ile Ser Ala Lys His Ala Ile Phe Arg
Val Ser Pro Asp Arg 675 680 685Gln
Ser Ser Trp Gln Phe Gln Arg Ser Asn Ser Asn Ser Ser Ser Val 690
695 700Ile Thr Thr Glu Asp Asn Lys Ile His Ile
His Leu Gly Ser Pro Tyr705 710 715
720Met Gln Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro Ser Ala
Pro 725 730 735Leu Gln Asp
Asn Arg Thr Gln Gly Leu Ile Asn Gly Ala Leu Asn Lys 740
745 750Thr Thr Asn Lys Val Thr Ser Ser Ile Thr
Ile Thr Pro Thr Ala Thr 755 760
765Pro Leu Pro Arg Gln Ser Gln Ile Thr Val Glu Pro Leu Leu Leu Pro 770
775 780His7852521DNAHomo
sapiensCDS(1)..(21) 25gaa cca ctt ctt ctg cct cat
21Glu Pro Leu Leu Leu Pro His1
5267PRTHomo sapiens 26Glu Pro Leu Leu Leu Pro His1
52730DNAHomo sapiensCDS(1)..(30) 27ttg gac aaa gtt gtg gaa aaa cat aaa
gaa 30Leu Asp Lys Val Val Glu Lys His Lys
Glu1 5 102810PRTHomo sapiens 28Leu Asp
Lys Val Val Glu Lys His Lys Glu1 5
102930DNAHomo sapiensCDS(1)..(30) 29gag gaa gag cag aag gca acc aga cta
gag 30Glu Glu Glu Gln Lys Ala Thr Arg Leu
Glu1 5 103010PRTHomo sapiens 30Glu Glu
Glu Gln Lys Ala Thr Arg Leu Glu1 5
103160DNAHomo sapiensCDS(1)..(60) 31ttg gac aaa gtt gtg gaa aaa cat aaa
gaa tct tac aga cga atc ctg 48Leu Asp Lys Val Val Glu Lys His Lys
Glu Ser Tyr Arg Arg Ile Leu1 5 10
15gga cag ctt tta
60Gly Gln Leu Leu 203220PRTHomo sapiens 32Leu Asp Lys
Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu1 5
10 15Gly Gln Leu Leu
2033150DNAHomo sapiensCDS(1)..(150) 33gtg gat gaa cag caa agg ctg acg gca
cag ctc acc ctt caa aga cag 48Val Asp Glu Gln Gln Arg Leu Thr Ala
Gln Leu Thr Leu Gln Arg Gln1 5 10
15aaa atc caa gag ctg acc aca aat gca aag gaa aca cat acc aaa
cta 96Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys Glu Thr His Thr Lys
Leu 20 25 30gcc ctt gct gaa
gcc aga gtt cag gag gaa gag cag aag gca acc aga 144Ala Leu Ala Glu
Ala Arg Val Gln Glu Glu Glu Gln Lys Ala Thr Arg 35
40 45cta gag
150Leu Glu 503450PRTHomo sapiens 34Val Asp Glu Gln
Gln Arg Leu Thr Ala Gln Leu Thr Leu Gln Arg Gln1 5
10 15Lys Ile Gln Glu Leu Thr Thr Asn Ala Lys
Glu Thr His Thr Lys Leu 20 25
30Ala Leu Ala Glu Ala Arg Val Gln Glu Glu Glu Gln Lys Ala Thr Arg
35 40 45Leu Glu 5035720DNAHomo
sapiensCDS(1)..(720) 35atg cgt tcc aga ggc agt gat acc gag ggc tca gcc
caa aag aaa ttt 48Met Arg Ser Arg Gly Ser Asp Thr Glu Gly Ser Ala
Gln Lys Lys Phe1 5 10
15cca aga cat act aaa ggc cac agt ttc caa ggg cct aaa aac atg aag
96Pro Arg His Thr Lys Gly His Ser Phe Gln Gly Pro Lys Asn Met Lys
20 25 30cat aga cag caa gac aaa gac
tcc ccc agt gag tcg gat gta ata ctt 144His Arg Gln Gln Asp Lys Asp
Ser Pro Ser Glu Ser Asp Val Ile Leu 35 40
45ccg tgt ccc aag gca gag aag cca cac agt ggt aat ggc cac caa
gca 192Pro Cys Pro Lys Ala Glu Lys Pro His Ser Gly Asn Gly His Gln
Ala 50 55 60gaa gac ctc tca aga gat
gac ctg tta ttt ctc ctc agc att ctg gag 240Glu Asp Leu Ser Arg Asp
Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65 70
75 80gga gaa ctg cag gct cga gat gag gtc ata ggc
att tta aag gct gaa 288Gly Glu Leu Gln Ala Arg Asp Glu Val Ile Gly
Ile Leu Lys Ala Glu 85 90
95aaa atg gac ctg gct ttg ctg gaa gct cag tat ggg ttt gtc act cca
336Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr Gly Phe Val Thr Pro
100 105 110aaa aag gtg tta gag gct
ctc cag aga gat gct ttt caa gcg aaa tct 384Lys Lys Val Leu Glu Ala
Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser 115 120
125acc cct tgg cag gag gac atc tat gag aaa cca atg aat gag
ttg gac 432Thr Pro Trp Gln Glu Asp Ile Tyr Glu Lys Pro Met Asn Glu
Leu Asp 130 135 140aaa gtt gtg gaa aaa
cat aaa gaa tct tac aga cga atc ctg gga cag 480Lys Val Val Glu Lys
His Lys Glu Ser Tyr Arg Arg Ile Leu Gly Gln145 150
155 160ctt tta gtg gca gaa aaa tcc cat agg caa
acc ata ttg gag ttg gag 528Leu Leu Val Ala Glu Lys Ser His Arg Gln
Thr Ile Leu Glu Leu Glu 165 170
175gaa gaa aag aga aaa cat aaa gaa tac atg gag aag agt gat gaa ttc
576Glu Glu Lys Arg Lys His Lys Glu Tyr Met Glu Lys Ser Asp Glu Phe
180 185 190ata tgc cta cta gaa cag
gaa tgt gaa aga tta aag aag cta att gat 624Ile Cys Leu Leu Glu Gln
Glu Cys Glu Arg Leu Lys Lys Leu Ile Asp 195 200
205caa gaa atc aag tct cag gag gag aag gag caa gaa aag gag
aaa agg 672Gln Glu Ile Lys Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu
Lys Arg 210 215 220gtc acc acc ctg aaa
gag gag ctg acc aag ctg aag tct ttt gct ttg 720Val Thr Thr Leu Lys
Glu Glu Leu Thr Lys Leu Lys Ser Phe Ala Leu225 230
235 24036240PRTHomo sapiens 36Met Arg Ser Arg
Gly Ser Asp Thr Glu Gly Ser Ala Gln Lys Lys Phe1 5
10 15Pro Arg His Thr Lys Gly His Ser Phe Gln
Gly Pro Lys Asn Met Lys 20 25
30His Arg Gln Gln Asp Lys Asp Ser Pro Ser Glu Ser Asp Val Ile Leu
35 40 45Pro Cys Pro Lys Ala Glu Lys Pro
His Ser Gly Asn Gly His Gln Ala 50 55
60Glu Asp Leu Ser Arg Asp Asp Leu Leu Phe Leu Leu Ser Ile Leu Glu65
70 75 80Gly Glu Leu Gln Ala
Arg Asp Glu Val Ile Gly Ile Leu Lys Ala Glu 85
90 95Lys Met Asp Leu Ala Leu Leu Glu Ala Gln Tyr
Gly Phe Val Thr Pro 100 105
110Lys Lys Val Leu Glu Ala Leu Gln Arg Asp Ala Phe Gln Ala Lys Ser
115 120 125Thr Pro Trp Gln Glu Asp Ile
Tyr Glu Lys Pro Met Asn Glu Leu Asp 130 135
140Lys Val Val Glu Lys His Lys Glu Ser Tyr Arg Arg Ile Leu Gly
Gln145 150 155 160Leu Leu
Val Ala Glu Lys Ser His Arg Gln Thr Ile Leu Glu Leu Glu
165 170 175Glu Glu Lys Arg Lys His Lys
Glu Tyr Met Glu Lys Ser Asp Glu Phe 180 185
190Ile Cys Leu Leu Glu Gln Glu Cys Glu Arg Leu Lys Lys Leu
Ile Asp 195 200 205Gln Glu Ile Lys
Ser Gln Glu Glu Lys Glu Gln Glu Lys Glu Lys Arg 210
215 220Val Thr Thr Leu Lys Glu Glu Leu Thr Lys Leu Lys
Ser Phe Ala Leu225 230 235
240371152DNAHomo sapiensCDS(1)..(1152) 37cta aat caa caa gaa aac agg aac
aga gat tta gga aga gag att gaa 48Leu Asn Gln Gln Glu Asn Arg Asn
Arg Asp Leu Gly Arg Glu Ile Glu1 5 10
15aac ctc act aag gag tta gag agg tac cgg cat ttc agt aag
agc ctc 96Asn Leu Thr Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys
Ser Leu 20 25 30agg cct agt
ctc aat gga aga aga att tcc gat cct caa gta ttt tct 144Arg Pro Ser
Leu Asn Gly Arg Arg Ile Ser Asp Pro Gln Val Phe Ser 35
40 45aaa gaa gtt cag aca gaa gca gta gac aat gaa
cca cct gat tac aag 192Lys Glu Val Gln Thr Glu Ala Val Asp Asn Glu
Pro Pro Asp Tyr Lys 50 55 60agc ctc
att cct ctg gaa cgt gca gtc atc aat ggt cag tta tat gag 240Ser Leu
Ile Pro Leu Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu65
70 75 80gag agt gag aat caa gac gag
gac cct aat gat gag gga tct gtg ctg 288Glu Ser Glu Asn Gln Asp Glu
Asp Pro Asn Asp Glu Gly Ser Val Leu 85 90
95tcc ttc aaa tgc agc cag tct act cca tgt cct gtt aac
aga aag cta 336Ser Phe Lys Cys Ser Gln Ser Thr Pro Cys Pro Val Asn
Arg Lys Leu 100 105 110tgg att
ccc tgg atg aaa tcc aag gag ggc cat ctt cag aat gga aaa 384Trp Ile
Pro Trp Met Lys Ser Lys Glu Gly His Leu Gln Asn Gly Lys 115
120 125atg caa act aaa ccc aat gcc aac ttt gtg
caa cct gga gat cta gtc 432Met Gln Thr Lys Pro Asn Ala Asn Phe Val
Gln Pro Gly Asp Leu Val 130 135 140cta
agc cac aca cct ggg cag cca ctt cat ata aag gtt act cca gac 480Leu
Ser His Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro Asp145
150 155 160cat gta caa aac aca gcc
act ctt gaa atc aca agt cca acc aca gag 528His Val Gln Asn Thr Ala
Thr Leu Glu Ile Thr Ser Pro Thr Thr Glu 165
170 175agt cct cac tct tac acg agt act gca gtg ata ccg
aac tgt ggc acg 576Ser Pro His Ser Tyr Thr Ser Thr Ala Val Ile Pro
Asn Cys Gly Thr 180 185 190cca
aag caa agg ata acc atc ctc caa aac gcc tcc ata aca cca gta 624Pro
Lys Gln Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val 195
200 205aag tcc aaa acc tct acc gaa gac ctc
atg aat tta gaa caa ggc atg 672Lys Ser Lys Thr Ser Thr Glu Asp Leu
Met Asn Leu Glu Gln Gly Met 210 215
220tcc cca att acc atg gca acc ttt gcc aga gca cag acc cca gag tct
720Ser Pro Ile Thr Met Ala Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser225
230 235 240tgt ggt tct cta
act cca gaa agg aca atg tcc cct att cag gtt ttg 768Cys Gly Ser Leu
Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu 245
250 255gct gtg act ggt tca gct agc tct cct gag
cag gga cgc tcc cca gaa 816Ala Val Thr Gly Ser Ala Ser Ser Pro Glu
Gln Gly Arg Ser Pro Glu 260 265
270cca aca gaa atc agt gcc aag cat gcg ata ttc aga gtc tcc cca gac
864Pro Thr Glu Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp
275 280 285cgg cag tca tca tgg cag ttt
cag cgt tca aac agc aat agc tca agt 912Arg Gln Ser Ser Trp Gln Phe
Gln Arg Ser Asn Ser Asn Ser Ser Ser 290 295
300gtg ata act act gag gat aat aaa atc cac att cac tta gga agt cct
960Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu Gly Ser Pro305
310 315 320tac atg caa gct
gta gcc agc cct gtg aga cct gcc agc cct tca gca 1008Tyr Met Gln Ala
Val Ala Ser Pro Val Arg Pro Ala Ser Pro Ser Ala 325
330 335cca ctg cag gat aac cga act caa ggc tta
att aac ggg gca cta aac 1056Pro Leu Gln Asp Asn Arg Thr Gln Gly Leu
Ile Asn Gly Ala Leu Asn 340 345
350aaa aca acc aat aaa gtc acc agc agt att act atc aca cca aca gcc
1104Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile Thr Pro Thr Ala
355 360 365aca cct ctt cct cga caa tca
caa att aca gta agt aat ata tat aac 1152Thr Pro Leu Pro Arg Gln Ser
Gln Ile Thr Val Ser Asn Ile Tyr Asn 370 375
38038384PRTHomo sapiens 38Leu Asn Gln Gln Glu Asn Arg Asn Arg Asp
Leu Gly Arg Glu Ile Glu1 5 10
15Asn Leu Thr Lys Glu Leu Glu Arg Tyr Arg His Phe Ser Lys Ser Leu
20 25 30Arg Pro Ser Leu Asn Gly
Arg Arg Ile Ser Asp Pro Gln Val Phe Ser 35 40
45Lys Glu Val Gln Thr Glu Ala Val Asp Asn Glu Pro Pro Asp
Tyr Lys 50 55 60Ser Leu Ile Pro Leu
Glu Arg Ala Val Ile Asn Gly Gln Leu Tyr Glu65 70
75 80Glu Ser Glu Asn Gln Asp Glu Asp Pro Asn
Asp Glu Gly Ser Val Leu 85 90
95Ser Phe Lys Cys Ser Gln Ser Thr Pro Cys Pro Val Asn Arg Lys Leu
100 105 110Trp Ile Pro Trp Met
Lys Ser Lys Glu Gly His Leu Gln Asn Gly Lys 115
120 125Met Gln Thr Lys Pro Asn Ala Asn Phe Val Gln Pro
Gly Asp Leu Val 130 135 140Leu Ser His
Thr Pro Gly Gln Pro Leu His Ile Lys Val Thr Pro Asp145
150 155 160His Val Gln Asn Thr Ala Thr
Leu Glu Ile Thr Ser Pro Thr Thr Glu 165
170 175Ser Pro His Ser Tyr Thr Ser Thr Ala Val Ile Pro
Asn Cys Gly Thr 180 185 190Pro
Lys Gln Arg Ile Thr Ile Leu Gln Asn Ala Ser Ile Thr Pro Val 195
200 205Lys Ser Lys Thr Ser Thr Glu Asp Leu
Met Asn Leu Glu Gln Gly Met 210 215
220Ser Pro Ile Thr Met Ala Thr Phe Ala Arg Ala Gln Thr Pro Glu Ser225
230 235 240Cys Gly Ser Leu
Thr Pro Glu Arg Thr Met Ser Pro Ile Gln Val Leu 245
250 255Ala Val Thr Gly Ser Ala Ser Ser Pro Glu
Gln Gly Arg Ser Pro Glu 260 265
270Pro Thr Glu Ile Ser Ala Lys His Ala Ile Phe Arg Val Ser Pro Asp
275 280 285Arg Gln Ser Ser Trp Gln Phe
Gln Arg Ser Asn Ser Asn Ser Ser Ser 290 295
300Val Ile Thr Thr Glu Asp Asn Lys Ile His Ile His Leu Gly Ser
Pro305 310 315 320Tyr Met
Gln Ala Val Ala Ser Pro Val Arg Pro Ala Ser Pro Ser Ala
325 330 335Pro Leu Gln Asp Asn Arg Thr
Gln Gly Leu Ile Asn Gly Ala Leu Asn 340 345
350Lys Thr Thr Asn Lys Val Thr Ser Ser Ile Thr Ile Thr Pro
Thr Ala 355 360 365Thr Pro Leu Pro
Arg Gln Ser Gln Ile Thr Val Ser Asn Ile Tyr Asn 370
375 380
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