IRAK1_HUMAN
ID IRAK1_HUMAN Reviewed; 712 AA.
AC P51617; D3DWW3; D3DWW4; Q7Z5V4; Q96C06; Q96RL2;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 03-AUG-2022, entry version 220.
DE RecName: Full=Interleukin-1 receptor-associated kinase 1 {ECO:0000303|PubMed:16024789};
DE Short=IRAK-1 {ECO:0000303|PubMed:16024789};
DE EC=2.7.11.1;
GN Name=IRAK1 {ECO:0000312|HGNC:HGNC:6112}; Synonyms=IRAK;
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] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, AND
RP VARIANTS SER-196 AND LEU-532.
RX PubMed=8599092; DOI=10.1126/science.271.5252.1128;
RA Cao Z., Henzel W.J., Gao X.;
RT "IRAK: a kinase associated with the interleukin-1 receptor.";
RL Science 271:1128-1131(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=10723722; DOI=10.1007/s003350010035;
RA Reichwald K., Thiesen J., Wiehe T., Weitzel J., Poustka W.A., Rosenthal A.,
RA Platzer M., Stratling W.H., Kioschis P.;
RT "Comparative sequence analysis of the MECP2-locus in human and mouse
RT reveals new transcribed regions.";
RL Mamm. Genome 11:182-190(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, AND
RP PHOSPHORYLATION.
RX PubMed=11397809; DOI=10.1074/jbc.m103815200;
RA Jensen L.E., Whitehead A.S.;
RT "IRAK1b, a novel alternative splice variant of interleukin-1 receptor-
RT associated kinase (IRAK), mediates interleukin-1 signaling and has
RT prolonged stability.";
RL J. Biol. Chem. 276:29037-29044(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RX PubMed=16024789; DOI=10.1128/mcb.25.15.6521-6532.2005;
RA Rao N., Nguyen S., Ngo K., Fung-Leung W.P.;
RT "A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase
RT 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory
RT signaling.";
RL Mol. Cell. Biol. 25:6521-6532(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
RC TISSUE=Placenta;
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 [8]
RP INTERACTION WITH MYD88.
RX PubMed=9430229; DOI=10.1016/s1074-7613(00)80402-1;
RA Wesche H., Henzel W.J., Shillinglaw W., Li S., Cao Z.;
RT "MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.";
RL Immunity 7:837-847(1997).
RN [9]
RP INTERACTION WITH TOLLIP.
RX PubMed=10854325; DOI=10.1038/35014038;
RA Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C., Maschera B.,
RA Lewis A., Ray K., Tschopp J., Volpe F.;
RT "Tollip, a new component of the IL-1R1 pathway, links IRAK to the IL-1
RT receptor.";
RL Nat. Cell Biol. 2:346-351(2000).
RN [10]
RP INTERACTION WITH IRAK4.
RX PubMed=11960013; DOI=10.1073/pnas.082100399;
RA Li S., Strelow A., Fontana E.J., Wesche H.;
RT "IRAK4: a novel member of the IRAK family with the properties of an IRAK-
RT kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:5567-5572(2002).
RN [11]
RP INTERACTION WITH PELI1 AND TRAF6.
RX PubMed=12496252; DOI=10.1074/jbc.m212112200;
RA Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X.;
RT "Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through
RT its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-
RT tumor necrosis factor receptor-associated factor 6 (TRAF6) complex.";
RL J. Biol. Chem. 278:10952-10956(2003).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF PELI2.
RX PubMed=12860405; DOI=10.1016/s0014-5793(03)00697-5;
RA Strelow A., Kollewe C., Wesche H.;
RT "Characterization of Pellino2, a substrate of IRAK1 and IRAK4.";
RL FEBS Lett. 547:157-161(2003).
RN [13]
RP PHOSPHORYLATION BY IRAK4.
RX PubMed=12538665; DOI=10.1084/jem.20021790;
RA Burns K., Janssens S., Brissoni B., Olivos N., Beyaert R., Tschopp J.;
RT "Inhibition of interleukin 1 receptor/Toll-like receptor signaling through
RT the alternatively spliced, short form of MyD88 is due to its failure to
RT recruit IRAK-4.";
RL J. Exp. Med. 197:263-268(2003).
RN [14]
RP INTERACTION WITH PELI3.
RX PubMed=12874243; DOI=10.4049/jimmunol.171.3.1500;
RA Jensen L.E., Whitehead A.S.;
RT "Pellino3, a novel member of the Pellino protein family, promotes
RT activation of c-Jun and Elk-1 and may act as a scaffolding protein.";
RL J. Immunol. 171:1500-1506(2003).
RN [15]
RP FUNCTION, AND PHOSPHORYLATION AT THR-66.
RX PubMed=14684752; DOI=10.1074/jbc.c300431200;
RA Mamidipudi V., Lin C., Seibenhener M.L., Wooten M.W.;
RT "Regulation of interleukin receptor-associated kinase (IRAK)
RT phosphorylation and signaling by iota protein kinase C.";
RL J. Biol. Chem. 279:4161-4165(2004).
RN [16]
RP PHOSPHORYLATION AT THR-209 AND THR-387, DOMAIN, AND MUTAGENESIS OF THR-209
RP AND THR-387.
RX PubMed=14625308; DOI=10.1074/jbc.m309251200;
RA Kollewe C., Mackensen A.C., Neumann D., Knop J., Cao P., Li S., Wesche H.,
RA Martin M.U.;
RT "Sequential autophosphorylation steps in the interleukin-1 receptor-
RT associated kinase-1 regulate its availability as an adapter in interleukin-
RT 1 signaling.";
RL J. Biol. Chem. 279:5227-5236(2004).
RN [17]
RP FUNCTION, AND MUTAGENESIS OF LYS-239.
RX PubMed=15084582; DOI=10.1074/jbc.m400785200;
RA Qin J., Jiang Z., Qian Y., Casanova J.-L., Li X.;
RT "IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-
RT associated kinase phosphorylation and IL-1 responsiveness.";
RL J. Biol. Chem. 279:26748-26753(2004).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF STAT3.
RX PubMed=15465816; DOI=10.1074/jbc.m410369200;
RA Huang Y., Li T., Sane D.C., Li L.;
RT "IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced
RT interleukin-10 gene expression.";
RL J. Biol. Chem. 279:51697-51703(2004).
RN [19]
RP INTERACTION WITH IL1RL1.
RX PubMed=16286016; DOI=10.1016/j.immuni.2005.09.015;
RA Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K.,
RA Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F.,
RA Kastelein R.A.;
RT "IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-
RT related protein ST 2 and induces T helper type 2-associated cytokines.";
RL Immunity 23:479-490(2005).
RN [20]
RP FUNCTION IN PHOSPHORYLATION OF IRF7.
RX PubMed=15767370; DOI=10.1084/jem.20042372;
RA Uematsu S., Sato S., Yamamoto M., Hirotani T., Kato H., Takeshita F.,
RA Matsuda M., Coban C., Ishii K.J., Kawai T., Takeuchi O., Akira S.;
RT "Interleukin-1 receptor-associated kinase-1 plays an essential role for
RT Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha}
RT induction.";
RL J. Exp. Med. 201:915-923(2005).
RN [21]
RP IDENTIFICATION IN COMPLEX WITH IRAK4; MYD88; PELI1 AND TRAF6.
RX PubMed=16951688; DOI=10.1038/ni1383;
RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S.,
RA Kim I.H., Kim S.J., Park S.H.;
RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor
RT signaling through direct interaction with the adapter Pellino-1.";
RL Nat. Immunol. 7:1057-1065(2006).
RN [22]
RP SUMOYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=16690127; DOI=10.1016/j.molimm.2006.03.021;
RA Su J., Richter K., Zhang C., Gu Q., Li L.;
RT "Differential regulation of interleukin-1 receptor associated kinase 1
RT (IRAK1) splice variants.";
RL Mol. Immunol. 44:900-905(2007).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF PELI1.
RX PubMed=17997719; DOI=10.1042/bj20071365;
RA Ordureau A., Smith H., Windheim M., Peggie M., Carrick E., Morrice N.,
RA Cohen P.;
RT "The IRAK-catalysed activation of the E3 ligase function of Pellino
RT isoforms induces the Lys63-linked polyubiquitination of IRAK1.";
RL Biochem. J. 409:43-52(2008).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [25]
RP UBIQUITINATION AT LYS-134 AND LYS-180 BY TRAF6, AND INTERACTION WITH
RP IKBKG/NEMO.
RX PubMed=18347055; DOI=10.1128/mcb.02098-07;
RA Conze D.B., Wu C.J., Thomas J.A., Landstrom A., Ashwell J.D.;
RT "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1
RT receptor- and toll-like receptor-mediated NF-kappaB activation.";
RL Mol. Cell. Biol. 28:3538-3547(2008).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [27]
RP UBIQUITINATION.
RX PubMed=19675569; DOI=10.1038/nature08247;
RA Xia Z.-P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W.,
RA Chen Z.J.;
RT "Direct activation of protein kinases by unanchored polyubiquitin chains.";
RL Nature 461:114-119(2009).
RN [28]
RP FUNCTION IN PHOSPHORYLATION OF TIRAP.
RX PubMed=20400509; DOI=10.1074/jbc.m109.098137;
RA Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H.,
RA Morrice N., O'Neill L.A.;
RT "IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation
RT of MyD88 adaptor-like (Mal).";
RL J. Biol. Chem. 285:18276-18282(2010).
RN [29]
RP REVIEW ON FUNCTION.
RX PubMed=17890055; DOI=10.1016/j.cellsig.2007.08.009;
RA Gottipati S., Rao N.L., Fung-Leung W.P.;
RT "IRAK1: a critical signaling mediator of innate immunity.";
RL Cell. Signal. 20:269-276(2008).
RN [30]
RP INTERACTION WITH NFATC4, AND MUTAGENESIS OF ASP-340.
RX PubMed=18691762; DOI=10.1016/j.molimm.2008.06.023;
RA Wang D., Fasciano S., Li L.;
RT "The interleukin-1 receptor associated kinase 1 contributes to the
RT regulation of NFAT.";
RL Mol. Immunol. 45:3902-3908(2008).
RN [31]
RP REVIEW ON FUNCTION.
RX PubMed=19022706; DOI=10.1016/j.it.2008.10.001;
RA Moynagh P.N.;
RT "The Pellino family: IRAK E3 ligases with emerging roles in innate immune
RT signalling.";
RL Trends Immunol. 30:33-42(2009).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-371; SER-375 AND SER-556, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [34]
RP INTERACTION WITH INAVA.
RX PubMed=28436939; DOI=10.1172/jci86282;
RA Yan J., Hedl M., Abraham C.;
RT "An inflammatory bowel disease-risk variant in INAVA decreases pattern
RT recognition receptor-induced outcomes.";
RL J. Clin. Invest. 127:2192-2205(2017).
RN [35]
RP INTERACTION WITH MUMPS VIRUS PROTEIN SH.
RX PubMed=28659487; DOI=10.1128/jvi.01037-17;
RA Franz S., Rennert P., Woznik M., Gruetzke J., Luedde A., Arriero Pais E.M.,
RA Finsterbusch T., Geyer H., Mankertz A., Friedrich N.;
RT "Mumps virus SH protein inhibits NF-kappaB activation by interacting with
RT tumor necrosis factor receptor 1, interleukin-1 receptor 1, and Toll-like
RT receptor 3 complexes.";
RL J. Virol. 91:0-0(2017).
RN [36]
RP INTERACTION WITH PELI1.
RX PubMed=29883609; DOI=10.1016/j.molcel.2018.05.016;
RA Choi S.W., Park H.H., Kim S., Chung J.M., Noh H.J., Kim S.K., Song H.K.,
RA Lee C.W., Morgan M.J., Kang H.C., Kim Y.S.;
RT "PELI1 selectively targets kinase-active RIP3 for ubiquitylation-dependent
RT proteasomal degradation.";
RL Mol. Cell 70:920-935(2018).
RN [37]
RP INTERACTION WITH ALPHAVIRUS CAPSID PROTEINS (MICROBIAL INFECTION).
RX PubMed=33673546; DOI=10.3390/v13030377;
RA Landers V.D., Wilkey D.W., Merchant M.L., Mitchell T.C., Sokoloski K.J.;
RT "The Alphaviral Capsid Protein Inhibits IRAK1-Dependent TLR Signaling.";
RL Viruses 13:0-0(2021).
RN [38]
RP VARIANTS [LARGE SCALE ANALYSIS] MET-398; MET-412; HIS-421; LEU-532;
RP SER-619; MET-625; TRP-638 AND GLY-690.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that plays a critical role in
CC initiating innate immune response against foreign pathogens. Involved
CC in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly
CC recruited by MYD88 to the receptor-signaling complex upon TLR
CC activation. Association with MYD88 leads to IRAK1 phosphorylation by
CC IRAK4 and subsequent autophosphorylation and kinase activation.
CC Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and
CC PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then,
CC the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated
CC IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the
CC NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA
CC and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and
CC activation. Alternatively, phosphorylates TIRAP to promote its
CC ubiquitination and subsequent degradation. Phosphorylates the
CC interferon regulatory factor 7 (IRF7) to induce its activation and
CC translocation to the nucleus, resulting in transcriptional activation
CC of type I IFN genes, which drive the cell in an antiviral state. When
CC sumoylated, translocates to the nucleus and phosphorylates STAT3.
CC {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405,
CC ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582,
CC ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370,
CC ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- SUBUNIT: Homodimer (By similarity). Forms a complex with TRAF6, PELI1,
CC IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1
CC prevents complex formation and hence negatively regulates IL1R-TLR
CC signaling and eventually NF-kappa-B-mediated gene expression
CC (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits
CC MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation
CC (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the
CC stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP;
CC this interaction occurs in the cytosol prior to receptor activation
CC (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts
CC with PELI1 and TRAF6 (PubMed:12496252). Interacts (when
CC polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with
CC RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity).
CC Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this
CC interaction increases the interaction between ZC3H12A and IKBKB/IKKB
CC (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with
CC PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes
CC place upon PRR stimulation (PubMed:28436939). Interacts (via C-
CC terminus) with NFATC4 (via N-terminus) (PubMed:18691762).
CC {ECO:0000250|UniProtKB:Q62406, ECO:0000269|PubMed:10854325,
CC ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12496252,
CC ECO:0000269|PubMed:12874243, ECO:0000269|PubMed:16286016,
CC ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:18347055,
CC ECO:0000269|PubMed:18691762, ECO:0000269|PubMed:28436939,
CC ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:9430229}.
CC -!- SUBUNIT: (Microbial infection) Interacts with mumps virus protein SH;
CC this interaction inhibits downstream NF-kappa-B pathway activation.
CC {ECO:0000269|PubMed:28659487}.
CC -!- SUBUNIT: (Microbial infection) Interacts with alphaviruses SINV, CHIKV,
CC RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition
CC of IRAK1-dependent signaling. {ECO:0000269|PubMed:33673546}.
CC -!- INTERACTION:
CC P51617; Q15306: IRF4; NbExp=2; IntAct=EBI-358664, EBI-751345;
CC P51617; Q92985: IRF7; NbExp=2; IntAct=EBI-358664, EBI-968267;
CC P51617; Q99836: MYD88; NbExp=2; IntAct=EBI-358664, EBI-447677;
CC P51617; Q96FA3: PELI1; NbExp=4; IntAct=EBI-358664, EBI-448369;
CC P51617; Q9HAT8: PELI2; NbExp=4; IntAct=EBI-358664, EBI-448407;
CC P51617; Q8N2H9-2: PELI3; NbExp=2; IntAct=EBI-358664, EBI-448472;
CC P51617; Q13526: PIN1; NbExp=10; IntAct=EBI-358664, EBI-714158;
CC P51617; Q86WV6: STING1; NbExp=2; IntAct=EBI-358664, EBI-2800345;
CC P51617; P58753: TIRAP; NbExp=2; IntAct=EBI-358664, EBI-528644;
CC P51617; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-358664, EBI-359276;
CC P51617; Q8VCW4: Unc93b1; Xeno; NbExp=2; IntAct=EBI-358664, EBI-6116986;
CC P51617; Q5D1E7: Zc3h12a; Xeno; NbExp=3; IntAct=EBI-358664, EBI-5326026;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16690127}. Nucleus
CC {ECO:0000269|PubMed:16690127}. Lipid droplet {ECO:0000250}.
CC Note=Translocates to the nucleus when sumoylated. RSAD2/viperin
CC recruits it to the lipid droplet (By similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=a;
CC IsoId=P51617-1; Sequence=Displayed;
CC Name=2; Synonyms=b;
CC IsoId=P51617-2; Sequence=VSP_011851;
CC Name=3;
CC IsoId=P51617-3; Sequence=VSP_011849, VSP_011850, VSP_011851;
CC Name=4;
CC IsoId=P51617-4; Sequence=VSP_041950;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 are ubiquitously expressed
CC in all tissues examined, with isoform 1 being more strongly expressed
CC than isoform 2. {ECO:0000269|PubMed:11397809}.
CC -!- DOMAIN: The ProST region is composed of many proline and serine
CC residues (more than 20 of each) and some threonines. This region is the
CC site of IRAK-1 hyperphosphorylation. {ECO:0000269|PubMed:14625308}.
CC -!- PTM: Following recruitment on the activated receptor complex,
CC phosphorylated on Thr-209, probably by IRAK4, resulting in a
CC conformational change of the kinase domain, allowing further
CC phosphorylations to take place. Thr-387 phosphorylation in the
CC activation loop is required to achieve full enzymatic activity.
CC {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12538665,
CC ECO:0000269|PubMed:14625308, ECO:0000269|PubMed:14684752}.
CC -!- PTM: Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta
CC by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin
CC chains linked through 'Lys-63'. Ubiquitination promotes interaction
CC with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation.
CC {ECO:0000269|PubMed:16690127, ECO:0000269|PubMed:18347055,
CC ECO:0000269|PubMed:19675569}.
CC -!- MISCELLANEOUS: [Isoform 2]: Inactive. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily. {ECO:0000305}.
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DR EMBL; L76191; AAC41949.1; -; mRNA.
DR EMBL; AF030876; AAC08756.1; -; Genomic_DNA.
DR EMBL; AF346607; AAK62888.1; -; mRNA.
DR EMBL; DQ054788; AAY88246.1; -; mRNA.
DR EMBL; U52112; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471172; EAW72762.1; -; Genomic_DNA.
DR EMBL; CH471172; EAW72763.1; -; Genomic_DNA.
DR EMBL; CH471172; EAW72764.1; -; Genomic_DNA.
DR EMBL; CH471172; EAW72765.1; -; Genomic_DNA.
DR EMBL; BC054000; AAH54000.1; -; mRNA.
DR EMBL; BC014963; AAH14963.1; -; mRNA.
DR CCDS; CCDS14740.1; -. [P51617-1]
DR CCDS; CCDS35443.1; -. [P51617-4]
DR CCDS; CCDS35444.1; -. [P51617-2]
DR PIR; G02512; G02512.
DR RefSeq; NP_001020413.1; NM_001025242.1. [P51617-2]
DR RefSeq; NP_001020414.1; NM_001025243.1. [P51617-4]
DR RefSeq; NP_001560.2; NM_001569.3. [P51617-1]
DR PDB; 6BFN; X-ray; 2.26 A; A/B=194-530.
DR PDBsum; 6BFN; -.
DR AlphaFoldDB; P51617; -.
DR SMR; P51617; -.
DR BioGRID; 109863; 245.
DR CORUM; P51617; -.
DR DIP; DIP-397N; -.
DR ELM; P51617; -.
DR IntAct; P51617; 188.
DR MINT; P51617; -.
DR STRING; 9606.ENSP00000358997; -.
DR BindingDB; P51617; -.
DR ChEMBL; CHEMBL3357; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; P51617; -.
DR GuidetoPHARMACOLOGY; 2042; -.
DR GlyGen; P51617; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P51617; -.
DR PhosphoSitePlus; P51617; -.
DR BioMuta; IRAK1; -.
DR DMDM; 8928535; -.
DR EPD; P51617; -.
DR jPOST; P51617; -.
DR MassIVE; P51617; -.
DR MaxQB; P51617; -.
DR PaxDb; P51617; -.
DR PeptideAtlas; P51617; -.
DR PRIDE; P51617; -.
DR ProteomicsDB; 56349; -. [P51617-1]
DR ProteomicsDB; 56350; -. [P51617-2]
DR ProteomicsDB; 56351; -. [P51617-3]
DR ProteomicsDB; 56352; -. [P51617-4]
DR Antibodypedia; 3845; 1053 antibodies from 47 providers.
DR DNASU; 3654; -.
DR Ensembl; ENST00000369974.6; ENSP00000358991.2; ENSG00000184216.14. [P51617-4]
DR Ensembl; ENST00000369980.8; ENSP00000358997.3; ENSG00000184216.14. [P51617-1]
DR Ensembl; ENST00000393687.6; ENSP00000377291.2; ENSG00000184216.14. [P51617-2]
DR GeneID; 3654; -.
DR KEGG; hsa:3654; -.
DR MANE-Select; ENST00000369980.8; ENSP00000358997.3; NM_001569.4; NP_001560.2.
DR UCSC; uc004fjr.2; human. [P51617-1]
DR CTD; 3654; -.
DR DisGeNET; 3654; -.
DR GeneCards; IRAK1; -.
DR HGNC; HGNC:6112; IRAK1.
DR HPA; ENSG00000184216; Low tissue specificity.
DR MalaCards; IRAK1; -.
DR MIM; 300283; gene.
DR neXtProt; NX_P51617; -.
DR OpenTargets; ENSG00000184216; -.
DR Orphanet; 93552; Pediatric systemic lupus erythematosus.
DR Orphanet; 536; Systemic lupus erythematosus.
DR PharmGKB; PA29912; -.
DR VEuPathDB; HostDB:ENSG00000184216; -.
DR eggNOG; KOG1187; Eukaryota.
DR GeneTree; ENSGT00940000160502; -.
DR HOGENOM; CLU_000288_173_1_1; -.
DR InParanoid; P51617; -.
DR OMA; HFQTQAC; -.
DR OrthoDB; 684563at2759; -.
DR PhylomeDB; P51617; -.
DR TreeFam; TF328924; -.
DR BRENDA; 2.7.10.2; 2681.
DR PathwayCommons; P51617; -.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes.
DR Reactome; R-HSA-209560; NF-kB is activated and signals survival.
DR Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR Reactome; R-HSA-450302; activated TAK1 mediates p38 MAPK activation.
DR Reactome; R-HSA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-8986944; Transcriptional Regulation by MECP2.
DR Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR Reactome; R-HSA-937039; IRAK1 recruits IKK complex.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR Reactome; R-HSA-975110; TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
DR Reactome; R-HSA-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
DR Reactome; R-HSA-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-HSA-975155; MyD88 dependent cascade initiated on endosome.
DR Reactome; R-HSA-975871; MyD88 cascade initiated on plasma membrane.
DR SignaLink; P51617; -.
DR SIGNOR; P51617; -.
DR BioGRID-ORCS; 3654; 20 hits in 741 CRISPR screens.
DR ChiTaRS; IRAK1; human.
DR GeneWiki; IRAK1; -.
DR GenomeRNAi; 3654; -.
DR Pharos; P51617; Tchem.
DR PRO; PR:P51617; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; P51617; protein.
DR Bgee; ENSG00000184216; Expressed in parotid gland and 201 other tissues.
DR ExpressionAtlas; P51617; baseline and differential.
DR Genevisible; P51617; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0031072; F:heat shock protein binding; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0016301; F:kinase activity; IDA:MGI.
DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; TAS:ProtInc.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0034605; P:cellular response to heat; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IBA:GO_Central.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:MGI.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IMP:ARUK-UCL.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IBA:GO_Central.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IMP:ARUK-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IMP:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
DR GO; GO:0001959; P:regulation of cytokine-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0070555; P:response to interleukin-1; IMP:BHF-UCL.
DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:BHF-UCL.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IMP:BHF-UCL.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IBA:GO_Central.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0002224; P:toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060337; P:type I interferon signaling pathway; IMP:BHF-UCL.
DR CDD; cd08794; Death_IRAK1; 1.
DR DisProt; DP02467; -.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR035533; Death_IRAK1.
DR InterPro; IPR035536; IRAK1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24419:SF1; PTHR24419:SF1; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasm;
KW Direct protein sequencing; Host-virus interaction; Immunity;
KW Innate immunity; Isopeptide bond; Kinase; Lipid droplet; Magnesium;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..712
FT /note="Interleukin-1 receptor-associated kinase 1"
FT /id="PRO_0000086030"
FT DOMAIN 27..106
FT /note="Death"
FT DOMAIN 212..521
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 105..187
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 110..211
FT /note="ProST region"
FT REGION 532..591
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 613..660
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 690..712
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 134..151
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 163..179
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 538..556
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 572..590
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 646..660
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 340
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 218..226
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 239
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 342..345
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 358
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 66
FT /note="Phosphothreonine; by PKC/PRKCI"
FT /evidence="ECO:0000269|PubMed:14684752"
FT MOD_RES 131
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 209
FT /note="Phosphothreonine; by IRAK4"
FT /evidence="ECO:0000305|PubMed:14625308"
FT MOD_RES 371
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 375
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 387
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:14625308"
FT MOD_RES 556
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 134
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:18347055"
FT CROSSLNK 180
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:18347055"
FT VAR_SEQ 45
FT /note="F -> FGGWRRAAGGREARGLLAPTPDAPRPA (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_011849"
FT VAR_SEQ 435..513
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16024789"
FT /id="VSP_041950"
FT VAR_SEQ 478..492
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_011850"
FT VAR_SEQ 513..542
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:11397809,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_011851"
FT VARIANT 194
FT /note="R -> H (in dbSNP:rs11465830)"
FT /id="VAR_051629"
FT VARIANT 196
FT /note="F -> S (in dbSNP:rs1059702)"
FT /evidence="ECO:0000269|PubMed:8599092"
FT /id="VAR_051630"
FT VARIANT 203
FT /note="C -> S (in dbSNP:rs10127175)"
FT /id="VAR_051631"
FT VARIANT 398
FT /note="T -> M (in dbSNP:rs56340948)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040573"
FT VARIANT 412
FT /note="V -> M (in a glioblastoma multiforme sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040574"
FT VARIANT 421
FT /note="Q -> H (in a breast pleomorphic lobular carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040575"
FT VARIANT 532
FT /note="S -> L (in dbSNP:rs1059703)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:8599092"
FT /id="VAR_040576"
FT VARIANT 619
FT /note="G -> S (in dbSNP:rs34112487)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040577"
FT VARIANT 625
FT /note="T -> M (in dbSNP:rs35638718)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040578"
FT VARIANT 638
FT /note="R -> W (in dbSNP:rs56082801)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040579"
FT VARIANT 690
FT /note="S -> G (in a lung adenocarcinoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040580"
FT MUTAGEN 209
FT /note="T->A: Completely abolishes auto-phosphorylation in
FT the kinase domain."
FT /evidence="ECO:0000269|PubMed:14625308"
FT MUTAGEN 239
FT /note="K->S: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:15084582"
FT MUTAGEN 340
FT /note="D->N: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:18691762"
FT MUTAGEN 387
FT /note="T->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:14625308"
FT STRAND 195..197
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 202..209
FT /evidence="ECO:0007829|PDB:6BFN"
FT TURN 210..212
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 217..220
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 222..231
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 234..241
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 249..265
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 274..280
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 283..289
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 296..301
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 304..307
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 312..331
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 332..334
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 345..348
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 354..356
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 359..361
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 388..390
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 393..397
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 403..419
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 423..427
FT /evidence="ECO:0007829|PDB:6BFN"
FT STRAND 430..433
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 434..436
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 437..445
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 464..466
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 467..476
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 487..500
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 505..507
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 511..521
FT /evidence="ECO:0007829|PDB:6BFN"
FT HELIX 522..524
FT /evidence="ECO:0007829|PDB:6BFN"
SQ SEQUENCE 712 AA; 76537 MW; A7ADED75D3A3981D CRC64;
MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE
RSGQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT AWHPPAPLPS PGTTAPRPSS
IPAPAEAEAW SPRKLPSSAS TFLSPAFPGS QTHSGPELGL VPSPASLWPP PPSPAPSSTK
PGPESSVSLL QGARPFPFCW PLCEISRGTH NFSEELKIGE GGFGCVYRAV MRNTVYAVKR
LKENADLEWT AVKQSFLTEV EQLSRFRHPN IVDFAGYCAQ NGFYCLVYGF LPNGSLEDRL
HCQTQACPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE RLTPKLGDFG
LARFSRFAGS SPSQSSMVAR TQTVRGTLAY LPEEYIKTGR LAVDTDTFSF GVVVLETLAG
QRAVKTHGAR TKYLKDLVEE EAEEAGVALR STQSTLQAGL AADAWAAPIA MQIYKKHLDP
RPGPCPPELG LGLGQLACCC LHRRAKRRPP MTQVYERLEK LQAVVAGVPG HSEAASCIPP
SPQENSYVSS TGRAHSGAAP WQPLAAPSGA SAQAAEQLQR GPNQPVESDE SLGGLSAALR
SWHLTPSCPL DPAPLREAGC PQGDTAGESS WGSGPGSRPT AVEGLALGSS ASSSSEPPQI
IINPARQKMV QKLALYEDGA LDSLQLLSSS SLPGLGLEQD RQGPEESDEF QS
