IRS1_HUMAN
ID IRS1_HUMAN Reviewed; 1242 AA.
AC P35568;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 03-AUG-2022, entry version 228.
DE RecName: Full=Insulin receptor substrate 1;
DE Short=IRS-1;
GN Name=IRS1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=8513971; DOI=10.2337/diab.42.7.1041;
RA Araki E., Sun X.J., Haag B.L. III, Chuang L.M., Zhang Y., Yang-Feng T.L.,
RA White M.F., Kahn C.R.;
RT "Human skeletal muscle insulin receptor substrate-1. Characterization of
RT the cDNA, gene, and chromosomal localization.";
RL Diabetes 42:1041-1054(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1311924; DOI=10.1016/0006-291x(92)91640-c;
RA Nishiyama M., Wands J.R.;
RT "Cloning and increased expression of an insulin receptor substrate-1-like
RT gene in human hepatocellular carcinoma.";
RL Biochem. Biophys. Res. Commun. 183:280-285(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP TURNOVER.
RX PubMed=8240352; DOI=10.1006/bbrc.1993.2315;
RA Smith L.K., Bradshaw M., Croall D.E., Garner C.W.;
RT "The insulin receptor substrate (IRS-1) is a PEST protein that is
RT susceptible to calpain degradation in vitro.";
RL Biochem. Biophys. Res. Commun. 196:767-772(1993).
RN [5]
RP INTERACTION WITH IGF1R.
RX PubMed=7541045; DOI=10.1074/jbc.270.26.15639;
RA Craparo A., O'Neill T.J., Gustafson T.A.;
RT "Non-SH2 domains within insulin receptor substrate-1 and SHC mediate their
RT phosphotyrosine-dependent interaction with the NPEY motif of the insulin-
RT like growth factor I receptor.";
RL J. Biol. Chem. 270:15639-15643(1995).
RN [6]
RP INTERACTION WITH INSR.
RX PubMed=7559478; DOI=10.1074/jbc.270.40.23258;
RA He W., O'Neill T.J., Gustafson T.A.;
RT "Distinct modes of interaction of SHC and insulin receptor substrate-1 with
RT the insulin receptor NPEY region via non-SH2 domains.";
RL J. Biol. Chem. 270:23258-23262(1995).
RN [7]
RP INTERACTION WITH INSR.
RX PubMed=7537849; DOI=10.1128/mcb.15.5.2500;
RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor
RT substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2
RT domain.";
RL Mol. Cell. Biol. 15:2500-2508(1995).
RN [8]
RP MUTAGENESIS OF SER-794, AND PHOSPHORYLATION AT SER-794.
RX PubMed=12624099; DOI=10.1074/jbc.m211770200;
RA Horike N., Takemori H., Katoh Y., Doi J., Min L., Asano T., Sun X.J.,
RA Yamamoto H., Kasayama S., Muraoka M., Nonaka Y., Okamoto M.;
RT "Adipose-specific expression, phosphorylation of Ser794 in insulin receptor
RT substrate-1, and activation in diabetic animals of salt-inducible kinase-
RT 2.";
RL J. Biol. Chem. 278:18440-18447(2003).
RN [9]
RP PHOSPHORYLATION AT SER-1101.
RX PubMed=15364919; DOI=10.1074/jbc.c400186200;
RA Li Y., Soos T.J., Li X., Wu J., Degennaro M., Sun X., Littman D.R.,
RA Birnbaum M.J., Polakiewicz R.D.;
RT "Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1
RT at Ser(1101).";
RL J. Biol. Chem. 279:45304-45307(2004).
RN [10]
RP PHOSPHORYLATION BY ALK, AND INTERACTION WITH ALK.
RX PubMed=15226403; DOI=10.1242/jcs.01183;
RA Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.;
RT "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth.";
RL J. Cell Sci. 117:3319-3329(2004).
RN [11]
RP INTERACTION WITH SOCS7.
RX PubMed=16127460; DOI=10.1172/jci23853;
RA Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D.,
RA Rothman P.B.;
RT "Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of
RT Langerhans.";
RL J. Clin. Invest. 115:2462-2471(2005).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-662, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629 AND SER-636, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [14]
RP INTERACTION WITH ALK, AND FUNCTION.
RX PubMed=16878150; DOI=10.1038/sj.onc.1209840;
RA Kuo A.H., Stoica G.E., Riegel A.T., Wellstein A.;
RT "Recruitment of insulin receptor substrate-1 and activation of NF-kappaB
RT essential for midkine growth signaling through anaplastic lymphoma
RT kinase.";
RL Oncogene 26:859-869(2007).
RN [15]
RP PHOSPHORYLATION AT SER-270; SER-307; SER-636 AND SER-1101.
RX PubMed=18952604; DOI=10.1074/jbc.m806480200;
RA Zhang J., Gao Z., Yin J., Quon M.J., Ye J.;
RT "S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance
RT in response to TNF-(alpha) signaling through IKK2.";
RL J. Biol. Chem. 283:35375-35382(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [17]
RP UBIQUITINATION, PHOSPHORYLATION AT SER-307; SER-312; SER-527 AND SER-636,
RP AND MUTAGENESIS OF SER-307; SER-312; SER-527; SER-636 AND SER-639.
RX PubMed=18498745; DOI=10.1016/j.molcel.2008.03.009;
RA Xu X., Sarikas A., Dias-Santagata D.C., Dolios G., Lafontant P.J.,
RA Tsai S.C., Zhu W., Nakajima H., Nakajima H.O., Field L.J., Wang R.,
RA Pan Z.Q.;
RT "The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for
RT ubiquitin-dependent degradation.";
RL Mol. Cell 30:403-414(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP PHOSPHORYLATION AT SER-312 AND TYR-941.
RX PubMed=20685959; DOI=10.1091/mbc.e10-06-0481;
RA Yang X., Nath A., Opperman M.J., Chan C.;
RT "The double-stranded RNA-dependent protein kinase differentially regulates
RT insulin receptor substrates 1 and 2 in HepG2 cells.";
RL Mol. Biol. Cell 21:3449-3458(2010).
RN [21]
RP PHOSPHORYLATION AT TYR-612; TYR-632 AND TYR-896, AND MUTAGENESIS OF TYR-612
RP AND TYR-632.
RX PubMed=23401856; DOI=10.1128/mcb.01447-12;
RA Koh A., Lee M.N., Yang Y.R., Jeong H., Ghim J., Noh J., Kim J., Ryu D.,
RA Park S., Song P., Koo S.H., Leslie N.R., Berggren P.O., Choi J.H.,
RA Suh P.G., Ryu S.H.;
RT "C1-Ten is a protein tyrosine phosphatase of insulin receptor substrate 1
RT (IRS-1), regulating IRS-1 stability and muscle atrophy.";
RL Mol. Cell. Biol. 33:1608-1620(2013).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-323; THR-453; SER-527 AND
RP SER-629, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [23]
RP STRUCTURE BY NMR OF 157-267.
RX PubMed=8599766; DOI=10.1038/nsb0496-388;
RA Zhou M.-M., Huang B., Olejniczak E.T., Meadows R.P., Shuker S.B.,
RA Miyazaki M., Trueb T., Shoelson S.E., Fesik S.W.;
RT "Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1
RT PTB domain.";
RL Nat. Struct. Biol. 3:388-393(1996).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 4-267.
RX PubMed=10411883; DOI=10.1073/pnas.96.15.8378;
RA Dhe-Paganon S., Ottinger E.A., Nolte R.T., Eck M.J., Shoelson S.E.;
RT "Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-
RT PTB) targeting region of insulin receptor substrate 1.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:8378-8383(1999).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 889-902 IN COMPLEX WITH IGF1R.
RX PubMed=11694888; DOI=10.1038/nsb721;
RA Favelyukis S., Till J.H., Hubbard S.R., Miller W.T.;
RT "Structure and autoregulation of the insulin-like growth factor 1 receptor
RT kinase.";
RL Nat. Struct. Biol. 8:1058-1063(2001).
RN [26]
RP VARIANTS PRO-512 AND ARG-971.
RX PubMed=8104271; DOI=10.1016/0140-6736(93)92694-o;
RA Almind K., Bjoerbaek C., Vestergaard H., Hansen T., Echwald S.,
RA Pedersen O.;
RT "Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-
RT dependent diabetes mellitus.";
RL Lancet 342:828-832(1993).
RN [27]
RP VARIANT NIDDM GLY-723 DEL.
RX PubMed=8723689;
RX DOI=10.1002/(sici)1098-1004(1996)7:4<364::aid-humu13>3.0.co;2-0;
RA Esposito D.L., Mammarella S., Ranieri A., della Loggia F., Capani F.,
RA Consoli A., Mariani-Costantini R., Caramia F.G., Cama A., Battista P.;
RT "Deletion of Gly723 in the insulin receptor substrate-1 of a patient with
RT noninsulin-dependent diabetes mellitus.";
RL Hum. Mutat. 7:364-366(1996).
RN [28]
RP VARIANTS NIDDM TYR-1043 AND TYR-1095.
RX PubMed=10206679;
RX DOI=10.1002/(sici)1098-1004(1998)11:5<411::aid-humu12>3.0.co;2-#;
RA Mammarella S., Creati B., Esposito D.L., Arcuri P., della Loggia F.,
RA Capani F., Mariani-Costantini R., Caramia F.G., Battista P., Cama A.;
RT "Novel allele of the insulin receptor substrate-1 bearing two non-
RT conservative amino acid substitutions in a patient with noninsulin-
RT dependent diabetes mellitus.";
RL Hum. Mutat. 11:411-411(1998).
RN [29]
RP CHARACTERIZATION OF VARIANT ARG-971.
RX PubMed=10843189; DOI=10.1210/jcem.85.5.6608;
RA Hribal M.L., Federici M., Porzio O., Lauro D., Borboni P., Accili D.,
RA Lauro R., Sesti G.;
RT "The Gly-->Arg(972) amino acid polymorphism in insulin receptor substrate-1
RT affects glucose metabolism in skeletal muscle cells.";
RL J. Clin. Endocrinol. Metab. 85:2004-2013(2000).
RN [30]
RP ASSOCIATION OF VARIANT ARG-971 WITH NIDDM.
RX PubMed=12843189; DOI=10.1210/jc.2002-021716;
RA Marini M.A., Frontoni S., Mineo D., Bracaglia D., Cardellini M.,
RA De Nicolais P., Baroni A., D'Alfonso R., Perna M., Lauro D., Federici M.,
RA Gambardella S., Lauro R., Sesti G.;
RT "The Arg(972) variant in insulin receptor substrate-1 is associated with an
RT atherogenic profile in offspring of type 2 diabetic patients.";
RL J. Clin. Endocrinol. Metab. 88:3368-3371(2003).
RN [31]
RP VARIANT ARG-971.
RX PubMed=14671192; DOI=10.1210/jc.2003-030453;
RA Abate N., Carulli L., Cabo-Chan A. Jr., Chandalia M., Snell P.G.,
RA Grundy S.M.;
RT "Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin
RT resistance.";
RL J. Clin. Endocrinol. Metab. 88:5927-5934(2003).
RN [32]
RP VARIANT ARG-608, AND CHARACTERIZATION OF VARIANT ARG-608.
RX PubMed=12679424; DOI=10.1210/jc.2002-020933;
RA Esposito D.L., Li Y., Vanni C., Mammarella S., Veschi S., Della Loggia F.,
RA Mariani-Costantini R., Battista P., Quon M.J., Cama A.;
RT "A novel T608R missense mutation in insulin receptor substrate-1 identified
RT in a subject with type 2 diabetes impairs metabolic insulin signaling.";
RL J. Clin. Endocrinol. Metab. 88:1468-1475(2003).
RN [33]
RP VARIANT ARG-971, ASSOCIATION WITH ENDOTHELIAL DYSFUNCTION, AND
RP CARDIOVASCULAR DISEASE.
RX PubMed=14707024; DOI=10.1161/01.cir.0000109498.77895.6f;
RA Federici M., Pandolfi A., De Filippis E.A., Pellegrini G., Menghini R.,
RA Lauro D., Cardellini M., Romano M., Sesti G., Lauro R., Consoli A.;
RT "G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide
RT synthase in cultured human endothelial cells.";
RL Circulation 109:399-405(2004).
RN [34]
RP VARIANT ARG-971, AND MOLECULAR MECHANISM OF LINKAGE TO NIDDM.
RX PubMed=15590636; DOI=10.1074/jbc.m412300200;
RA McGettrick A.J., Feener E.P., Kahn C.R.;
RT "Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1
RT to associate with the insulin receptor and inhibit receptor
RT autophosphorylation.";
RL J. Biol. Chem. 280:6441-6446(2005).
CC -!- FUNCTION: May mediate the control of various cellular processes by
CC insulin. When phosphorylated by the insulin receptor binds specifically
CC to various cellular proteins containing SH2 domains such as
CC phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates
CC phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit
CC (By similarity). {ECO:0000250, ECO:0000269|PubMed:16878150}.
CC -!- SUBUNIT: Interacts with UBTF and PIK3CA (By similarity). Interacts (via
CC phosphorylated YXXM motifs) with PIK3R1 (By similarity). Interacts with
CC ROCK1 and FER (By similarity). Interacts (via PH domain) with PHIP (By
CC similarity). Interacts with GRB2 (By similarity). Interacts with SOCS7
CC (PubMed:16127460). Interacts (via IRS-type PTB domain) with IGF1R and
CC INSR (via the tyrosine-phosphorylated NPXY motif) (PubMed:7541045,
CC PubMed:7559478, PubMed:7537849). Interacts with ALK (PubMed:15226403,
CC PubMed:16878150). Interacts with EIF2AK2/PKR (By similarity). Interacts
CC with GKAP1 (By similarity). Interacts with DGKZ in the absence of
CC insulin; insulin stimulation decreases this interaction (By
CC similarity). Found in a ternary complex with DGKZ and PIP5K1A in the
CC absence of insulin stimulation (By similarity).
CC {ECO:0000250|UniProtKB:P35569, ECO:0000250|UniProtKB:P35570,
CC ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:16127460,
CC ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:7537849,
CC ECO:0000269|PubMed:7541045, ECO:0000269|PubMed:7559478}.
CC -!- INTERACTION:
CC P35568; O75815: BCAR3; NbExp=3; IntAct=EBI-517592, EBI-702336;
CC P35568; P04626: ERBB2; NbExp=2; IntAct=EBI-517592, EBI-641062;
CC P35568; P06213: INSR; NbExp=3; IntAct=EBI-517592, EBI-475899;
CC P35568; P11940: PABPC1; NbExp=2; IntAct=EBI-517592, EBI-81531;
CC P35568; P42336: PIK3CA; NbExp=20; IntAct=EBI-517592, EBI-2116585;
CC P35568; P27986: PIK3R1; NbExp=12; IntAct=EBI-517592, EBI-79464;
CC P35568; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-517592, EBI-9090282;
CC P35568; Q92569: PIK3R3; NbExp=4; IntAct=EBI-517592, EBI-79893;
CC P35568; Q06124: PTPN11; NbExp=3; IntAct=EBI-517592, EBI-297779;
CC P35568; P03495: NS; Xeno; NbExp=2; IntAct=EBI-517592, EBI-2548993;
CC P35568; P03070; Xeno; NbExp=2; IntAct=EBI-517592, EBI-617698;
CC -!- PTM: Serine phosphorylation of IRS1 is a mechanism for insulin
CC resistance. Ser-312 phosphorylation inhibits insulin action through
CC disruption of IRS1 interaction with the insulin receptor (By
CC similarity). Phosphorylation of Tyr-896 is required for GRB2-binding
CC (By similarity). Phosphorylated by ALK. Phosphorylated at Ser-270, Ser-
CC 307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces
CC accelerated degradation of IRS1 (PubMed:18952604). Phosphorylated on
CC tyrosine residues in response to insulin (PubMed:23401856). In skeletal
CC muscles, dephosphorylated on Tyr-612 by TNS2 under anabolic conditions;
CC dephosphorylation results in the proteasomal degradation of IRS1
CC (PubMed:23401856). {ECO:0000250|UniProtKB:P35569,
CC ECO:0000250|UniProtKB:P35570, ECO:0000269|PubMed:15364919,
CC ECO:0000269|PubMed:18498745, ECO:0000269|PubMed:18952604,
CC ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:23401856}.
CC -!- PTM: Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent
CC manner, leading to its degradation: the Cul7-RING(FBXW8) complex
CC recognizes and binds IRS1 previously phosphorylated by S6 kinase
CC (RPS6KB1 or RPS6KB2). {ECO:0000269|PubMed:18498745}.
CC -!- POLYMORPHISM: The Arg-971 polymorphism impairs the ability of insulin
CC to stimulate glucose transport, glucose transporter translocation, and
CC glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway.
CC The polymorphism at Arg-971 may contribute to the in vivo insulin
CC resistance observed in carriers of this variant. Arg-971 could
CC contribute to the risk for atherosclerotic cardiovascular diseases
CC associated with non-insulin-dependent diabetes mellitus (NIDDM) by
CC producing a cluster of insulin resistance-related metabolic
CC abnormalities. In insulin-stimulated human endothelial cells from
CC carriers of the Arg-971 polymorphism, genetic impairment of the
CC IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired
CC insulin-stimulated nitric oxide (NO) release and suggested that this
CC may be a mechanism through which the Arg-971 polymorphism contributes
CC to the genetic predisposition to develop endothelial dysfunction and
CC cardiovascular disease. The Arg-971 polymorphism not only reduces
CC phosphorylation of the substrate but allows IRS1 to act as an inhibitor
CC of PI3K, producing global insulin resistance.
CC -!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]:
CC A multifactorial disorder of glucose homeostasis caused by a lack of
CC sensitivity to the body's own insulin. Affected individuals usually
CC have an obese body habitus and manifestations of a metabolic syndrome
CC characterized by diabetes, insulin resistance, hypertension and
CC hypertriglyceridemia. The disease results in long-term complications
CC that affect the eyes, kidneys, nerves, and blood vessels.
CC {ECO:0000269|PubMed:10206679, ECO:0000269|PubMed:12843189,
CC ECO:0000269|PubMed:8723689}. Note=The gene represented in this entry
CC may be involved in disease pathogenesis.
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DR EMBL; S85963; AAB21608.1; -; Genomic_DNA.
DR EMBL; S62539; AAB27175.1; -; mRNA.
DR EMBL; BC053895; AAH53895.1; -; mRNA.
DR CCDS; CCDS2463.1; -.
DR PIR; I53160; JS0670.
DR RefSeq; NP_005535.1; NM_005544.2.
DR PDB; 1IRS; NMR; -; A=157-267.
DR PDB; 1K3A; X-ray; 2.10 A; B=891-902.
DR PDB; 1QQG; X-ray; 2.30 A; A/B=4-267.
DR PDB; 2Z8C; X-ray; 3.25 A; B=731-736.
DR PDB; 5U1M; X-ray; 1.80 A; A=161-265.
DR PDB; 6BNT; X-ray; 3.20 A; B=607-620.
DR PDBsum; 1IRS; -.
DR PDBsum; 1K3A; -.
DR PDBsum; 1QQG; -.
DR PDBsum; 2Z8C; -.
DR PDBsum; 5U1M; -.
DR PDBsum; 6BNT; -.
DR AlphaFoldDB; P35568; -.
DR BMRB; P35568; -.
DR SMR; P35568; -.
DR BioGRID; 109874; 101.
DR CORUM; P35568; -.
DR DIP; DIP-523N; -.
DR ELM; P35568; -.
DR IntAct; P35568; 34.
DR MINT; P35568; -.
DR STRING; 9606.ENSP00000304895; -.
DR ChEMBL; CHEMBL4523219; -.
DR DrugBank; DB08513; [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID.
DR GlyGen; P35568; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P35568; -.
DR PhosphoSitePlus; P35568; -.
DR BioMuta; IRS1; -.
DR DMDM; 547738; -.
DR EPD; P35568; -.
DR jPOST; P35568; -.
DR MassIVE; P35568; -.
DR MaxQB; P35568; -.
DR PaxDb; P35568; -.
DR PeptideAtlas; P35568; -.
DR PRIDE; P35568; -.
DR ProteomicsDB; 55088; -.
DR Antibodypedia; 3935; 2594 antibodies from 48 providers.
DR DNASU; 3667; -.
DR Ensembl; ENST00000305123.6; ENSP00000304895.4; ENSG00000169047.6.
DR GeneID; 3667; -.
DR KEGG; hsa:3667; -.
DR MANE-Select; ENST00000305123.6; ENSP00000304895.4; NM_005544.3; NP_005535.1.
DR UCSC; uc002voh.5; human.
DR CTD; 3667; -.
DR DisGeNET; 3667; -.
DR GeneCards; IRS1; -.
DR HGNC; HGNC:6125; IRS1.
DR HPA; ENSG00000169047; Low tissue specificity.
DR MalaCards; IRS1; -.
DR MIM; 125853; phenotype.
DR MIM; 147545; gene.
DR neXtProt; NX_P35568; -.
DR OpenTargets; ENSG00000169047; -.
DR PharmGKB; PA203; -.
DR VEuPathDB; HostDB:ENSG00000169047; -.
DR eggNOG; ENOG502QUNU; Eukaryota.
DR GeneTree; ENSGT00940000161579; -.
DR HOGENOM; CLU_004902_2_0_1; -.
DR InParanoid; P35568; -.
DR OMA; MTMQMGC; -.
DR OrthoDB; 298675at2759; -.
DR PhylomeDB; P35568; -.
DR TreeFam; TF325994; -.
DR PathwayCommons; P35568; -.
DR Reactome; R-HSA-109704; PI3K Cascade.
DR Reactome; R-HSA-112399; IRS-mediated signalling.
DR Reactome; R-HSA-112412; SOS-mediated signalling.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-1266695; Interleukin-7 signaling.
DR Reactome; R-HSA-198203; PI3K/AKT activation.
DR Reactome; R-HSA-201556; Signaling by ALK.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-2428928; IRS-related events triggered by IGF1R.
DR Reactome; R-HSA-2586552; Signaling by Leptin.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-74713; IRS activation.
DR Reactome; R-HSA-74749; Signal attenuation.
DR Reactome; R-HSA-9603381; Activated NTRK3 signals through PI3K.
DR Reactome; R-HSA-9725370; Signaling by ALK fusions and activated point mutants.
DR Reactome; R-HSA-982772; Growth hormone receptor signaling.
DR SignaLink; P35568; -.
DR SIGNOR; P35568; -.
DR BioGRID-ORCS; 3667; 37 hits in 1081 CRISPR screens.
DR ChiTaRS; IRS1; human.
DR EvolutionaryTrace; P35568; -.
DR GeneWiki; IRS1; -.
DR GenomeRNAi; 3667; -.
DR Pharos; P35568; Tchem.
DR PRO; PR:P35568; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P35568; protein.
DR Bgee; ENSG00000169047; Expressed in endometrium epithelium and 205 other tissues.
DR Genevisible; P35568; HS.
DR GO; GO:0005901; C:caveola; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005899; C:insulin receptor complex; ISS:BHF-UCL.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005158; F:insulin receptor binding; IPI:UniProtKB.
DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IPI:UniProtKB.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IPI:UniProtKB.
DR GO; GO:0001784; F:phosphotyrosine residue binding; IPI:CAFA.
DR GO; GO:0005080; F:protein kinase C binding; ISS:BHF-UCL.
DR GO; GO:0042169; F:SH2 domain binding; ISS:UniProtKB.
DR GO; GO:0030159; F:signaling receptor complex adaptor activity; IDA:BHF-UCL.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; ISS:BHF-UCL.
DR GO; GO:0071398; P:cellular response to fatty acid; ISS:ARUK-UCL.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
DR GO; GO:0042593; P:glucose homeostasis; TAS:BHF-UCL.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IPI:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IDA:BHF-UCL.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase signaling; IDA:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; NAS:BHF-UCL.
DR GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; IMP:BHF-UCL.
DR GO; GO:0046326; P:positive regulation of glucose import; IDA:BHF-UCL.
DR GO; GO:0010907; P:positive regulation of glucose metabolic process; IMP:BHF-UCL.
DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:BHF-UCL.
DR GO; GO:0032868; P:response to insulin; IDA:BHF-UCL.
DR GO; GO:0043434; P:response to peptide hormone; ISS:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR CDD; cd01204; PTB_IRS; 1.
DR Gene3D; 2.30.29.30; -; 2.
DR IDEAL; IID00657; -.
DR InterPro; IPR039011; IRS.
DR InterPro; IPR002404; IRS_PTB.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR PANTHER; PTHR10614; PTHR10614; 1.
DR Pfam; PF02174; IRS; 1.
DR Pfam; PF00169; PH; 1.
DR PRINTS; PR00628; INSULINRSI.
DR SMART; SM00233; PH; 1.
DR SMART; SM00310; PTBI; 1.
DR PROSITE; PS51064; IRS_PTB; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Diabetes mellitus; Disease variant; Phosphoprotein;
KW Reference proteome; Repeat; Transducer; Ubl conjugation.
FT CHAIN 1..1242
FT /note="Insulin receptor substrate 1"
FT /id="PRO_0000084236"
FT DOMAIN 12..115
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 160..264
FT /note="IRS-type PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00389"
FT REGION 3..137
FT /note="Mediates interaction with PHIP"
FT /evidence="ECO:0000250"
FT REGION 262..430
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 592..616
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 668..693
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 771..900
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 896..898
FT /note="GRB2-binding"
FT /evidence="ECO:0000250"
FT REGION 918..937
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1057..1146
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1190..1242
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 465..468
FT /note="YXXM motif 1"
FT MOTIF 551..554
FT /note="YXXM motif 2"
FT MOTIF 612..615
FT /note="YXXM motif 3"
FT MOTIF 632..635
FT /note="YXXM motif 4"
FT MOTIF 662..665
FT /note="YXXM motif 5"
FT MOTIF 732..735
FT /note="YXXM motif 6"
FT MOTIF 941..944
FT /note="YXXM motif 7"
FT MOTIF 989..992
FT /note="YXXM motif 8"
FT MOTIF 1012..1015
FT /note="YXXM motif 9"
FT COMPBIAS 266..281
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 293..316
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 376..430
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 592..606
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 675..693
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 774..788
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 789..817
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1071..1087
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1099..1114
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1195..1211
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1212..1236
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 3
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT MOD_RES 99
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT MOD_RES 270
FT /note="Phosphoserine; by RPS6KB1"
FT /evidence="ECO:0000269|PubMed:18952604"
FT MOD_RES 307
FT /note="Phosphoserine; by RPS6KB1"
FT /evidence="ECO:0000269|PubMed:18498745,
FT ECO:0000269|PubMed:18952604"
FT MOD_RES 312
FT /note="Phosphoserine; by IKKB, MAPK8 and RPS6KB1"
FT /evidence="ECO:0000269|PubMed:18498745,
FT ECO:0000269|PubMed:20685959"
FT MOD_RES 323
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 330
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35569"
FT MOD_RES 345
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35569"
FT MOD_RES 348
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 419
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35569"
FT MOD_RES 446
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT MOD_RES 453
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 465
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT MOD_RES 527
FT /note="Phosphoserine; by RPS6KB1"
FT /evidence="ECO:0000269|PubMed:18498745,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 612
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000269|PubMed:23401856"
FT MOD_RES 629
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 632
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000269|PubMed:23401856"
FT MOD_RES 636
FT /note="Phosphoserine; by RPS6KB1"
FT /evidence="ECO:0000269|PubMed:18498745,
FT ECO:0000269|PubMed:18952604, ECO:0007744|PubMed:17081983"
FT MOD_RES 662
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15592455"
FT MOD_RES 794
FT /note="Phosphoserine; by AMPK and SIK2"
FT /evidence="ECO:0000269|PubMed:12624099"
FT MOD_RES 892
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35569"
FT MOD_RES 896
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000269|PubMed:23401856"
FT MOD_RES 941
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000269|PubMed:20685959"
FT MOD_RES 989
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT MOD_RES 1100
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35569"
FT MOD_RES 1101
FT /note="Phosphoserine; by RPS6KB1 and PKC/PRKCQ"
FT /evidence="ECO:0000269|PubMed:15364919,
FT ECO:0000269|PubMed:18952604"
FT MOD_RES 1179
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT MOD_RES 1229
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000250|UniProtKB:P35570"
FT VARIANT 158
FT /note="P -> R (in dbSNP:rs1801108)"
FT /id="VAR_014853"
FT VARIANT 209
FT /note="M -> T (in dbSNP:rs1801118)"
FT /id="VAR_014854"
FT VARIANT 512
FT /note="A -> P (in dbSNP:rs1801276)"
FT /evidence="ECO:0000269|PubMed:8104271"
FT /id="VAR_005299"
FT VARIANT 608
FT /note="T -> R (may contribute to insulin resistance by
FT impairing metabolic signaling through PI3K-dependent
FT pathways; dbSNP:rs104893642)"
FT /evidence="ECO:0000269|PubMed:12679424"
FT /id="VAR_025320"
FT VARIANT 723
FT /note="Missing (in NIDDM; dbSNP:rs1259467443)"
FT /evidence="ECO:0000269|PubMed:8723689"
FT /id="VAR_005301"
FT VARIANT 809
FT /note="S -> F (in dbSNP:rs1801120)"
FT /id="VAR_014855"
FT VARIANT 892
FT /note="S -> G (in dbSNP:rs1801277)"
FT /id="VAR_014856"
FT VARIANT 971
FT /note="G -> R (in dbSNP:rs1801278)"
FT /evidence="ECO:0000269|PubMed:10843189,
FT ECO:0000269|PubMed:14671192, ECO:0000269|PubMed:14707024,
FT ECO:0000269|PubMed:15590636, ECO:0000269|PubMed:8104271"
FT /id="VAR_005300"
FT VARIANT 1043
FT /note="S -> Y (in NIDDM)"
FT /evidence="ECO:0000269|PubMed:10206679"
FT /id="VAR_005302"
FT VARIANT 1095
FT /note="C -> Y (in NIDDM)"
FT /evidence="ECO:0000269|PubMed:10206679"
FT /id="VAR_005303"
FT VARIANT 1137
FT /note="D -> N (in dbSNP:rs3731594)"
FT /id="VAR_021837"
FT MUTAGEN 307
FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8)
FT complex; when associated with A-312; A-527; A-636 and A-
FT 639."
FT /evidence="ECO:0000269|PubMed:18498745"
FT MUTAGEN 312
FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8)
FT complex; when associated with A-307; A-527; A-636 and A-
FT 639."
FT /evidence="ECO:0000269|PubMed:18498745"
FT MUTAGEN 527
FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8)
FT complex; when associated with A-307; A-312; A-636 and A-
FT 639."
FT /evidence="ECO:0000269|PubMed:18498745"
FT MUTAGEN 612
FT /note="Y->F: Induces IRS1 degradation."
FT /evidence="ECO:0000269|PubMed:23401856"
FT MUTAGEN 632
FT /note="Y->F: Does not affect IRS1 stability."
FT /evidence="ECO:0000269|PubMed:23401856"
FT MUTAGEN 636
FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8)
FT complex; when associated with A-307; A-312; A-527 and A-
FT 639."
FT /evidence="ECO:0000269|PubMed:18498745"
FT MUTAGEN 639
FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8)
FT complex; when associated with A-307; A-312; A-527 and A-
FT 636."
FT /evidence="ECO:0000269|PubMed:18498745"
FT MUTAGEN 794
FT /note="S->A: Loss of phosphorylation by SIK2."
FT /evidence="ECO:0000269|PubMed:12624099"
FT CONFLICT 134
FT /note="G -> GG (in Ref. 2; AAB21608)"
FT /evidence="ECO:0000305"
FT CONFLICT 362
FT /note="S -> R (in Ref. 2; AAB21608)"
FT /evidence="ECO:0000305"
FT CONFLICT 384
FT /note="P -> R (in Ref. 2; AAB21608)"
FT /evidence="ECO:0000305"
FT STRAND 13..20
FT /evidence="ECO:0007829|PDB:1QQG"
FT TURN 22..24
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 27..33
FT /evidence="ECO:0007829|PDB:1QQG"
FT TURN 37..39
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 40..49
FT /evidence="ECO:0007829|PDB:1QQG"
FT HELIX 50..54
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 61..65
FT /evidence="ECO:0007829|PDB:1QQG"
FT HELIX 66..68
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 69..75
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 81..90
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 92..96
FT /evidence="ECO:0007829|PDB:1QQG"
FT HELIX 100..113
FT /evidence="ECO:0007829|PDB:1QQG"
FT STRAND 162..172
FT /evidence="ECO:0007829|PDB:5U1M"
FT HELIX 173..176
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 181..187
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 189..196
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 203..207
FT /evidence="ECO:0007829|PDB:5U1M"
FT HELIX 208..210
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 211..217
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 220..225
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 233..239
FT /evidence="ECO:0007829|PDB:5U1M"
FT HELIX 243..262
FT /evidence="ECO:0007829|PDB:5U1M"
FT STRAND 897..901
FT /evidence="ECO:0007829|PDB:1K3A"
SQ SEQUENCE 1242 AA; 131591 MW; 3C0EFD9E32B3E64A CRC64;
MASPPESDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE KKWRHKSSAP
KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE AEQDSWYQAL LQLHNRAKGH
HDGAAALGAG GGGGSCSGSS GLGEAGEDLS YGDVPPGPAF KEVWQVILKP KGLGQTKNLI
GIYRLCLTSK TISFVKLNSE AAAVVLQLMN IRRCGHSENF FFIEVGRSAV TGPGEFWMQV
DDSVVAQNMH ETILEAMRAM SDEFRPRSKS QSSSNCSNPI SVPLRRHHLN NPPPSQVGLT
RRSRTESITA TSPASMVGGK PGSFRVRASS DGEGTMSRPA SVDGSPVSPS TNRTHAHRHR
GSARLHPPLN HSRSIPMPAS RCSPSATSPV SLSSSSTSGH GSTSDCLFPR RSSASVSGSP
SDGGFISSDE YGSSPCDFRS SFRSVTPDSL GHTPPARGEE ELSNYICMGG KGPSTLTAPN
GHYILSRGGN GHRCTPGTGL GTSPALAGDE AASAADLDNR FRKRTHSAGT SPTITHQKTP
SQSSVASIEE YTEMMPAYPP GGGSGGRLPG HRHSAFVPTR SYPEEGLEMH PLERRGGHHR
PDSSTLHTDD GYMPMSPGVA PVPSGRKGSG DYMPMSPKSV SAPQQIINPI RRHPQRVDPN
GYMMMSPSGG CSPDIGGGPS SSSSSSNAVP SGTSYGKLWT NGVGGHHSHV LPHPKPPVES
SGGKLLPCTG DYMNMSPVGD SNTSSPSDCY YGPEDPQHKP VLSYYSLPRS FKHTQRPGEP
EEGARHQHLR LSTSSGRLLY AATADDSSSS TSSDSLGGGY CGARLEPSLP HPHHQVLQPH
LPRKVDTAAQ TNSRLARPTR LSLGDPKAST LPRAREQQQQ QQPLLHPPEP KSPGEYVNIE
FGSDQSGYLS GPVAFHSSPS VRCPSQLQPA PREEETGTEE YMKMDLGPGR RAAWQESTGV
EMGRLGPAPP GAASICRPTR AVPSSRGDYM TMQMSCPRQS YVDTSPAAPV SYADMRTGIA
AEEVSLPRAT MAAASSSSAA SASPTGPQGA AELAAHSSLL GGPQGPGGMS AFTRVNLSPN
RNQSAKVIRA DPQGCRRRHS SETFSSTPSA TRVGNTVPFG AGAAVGGGGG SSSSSEDVKR
HSSASFENVW LRPGELGGAP KEPAKLCGAA GGLENGLNYI DLDLVKDFKQ CPQECTPEPQ
PPPPPPPHQP LGSGESSSTR RSSEDLSAYA SISFQKQPED RQ
