IRAK3_HUMAN
ID IRAK3_HUMAN Reviewed; 596 AA.
AC Q9Y616; B4DQ57;
DT 09-NOV-2004, integrated into UniProtKB/Swiss-Prot.
DT 08-FEB-2011, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Interleukin-1 receptor-associated kinase 3;
DE Short=IRAK-3;
DE AltName: Full=IL-1 receptor-associated kinase M;
DE Short=IRAK-M;
DE AltName: Full=Inactive IL-1 receptor-associated kinase 3 {ECO:0000305};
GN Name=IRAK3 {ECO:0000312|EMBL:AAH57800.1};
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] {ECO:0000305, ECO:0000312|EMBL:AAD40879.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND
RP VARIANT VAL-147.
RC TISSUE=Peripheral blood lymphocyte;
RX PubMed=10383454; DOI=10.1074/jbc.274.27.19403;
RA Wesche H., Gao X., Li X., Kirschning C.J., Stark G.R., Cao Z.;
RT "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated
RT kinase (IRAK) family.";
RL J. Biol. Chem. 274:19403-19410(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT VAL-147.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [4] {ECO:0000312|EMBL:AAH57800.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-147.
RC TISSUE=Placenta {ECO:0000312|EMBL:AAH57800.1};
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 [5]
RP INVOLVEMENT IN ASRT5, AND VARIANTS LEU-22; ALA-111; MET-134; VAL-400 AND
RP GLN-429.
RX PubMed=17503328; DOI=10.1086/518259;
RA Balaci L., Spada M.C., Olla N., Sole G., Loddo L., Anedda F., Naitza S.,
RA Zuncheddu M.A., Maschio A., Altea D., Uda M., Pilia S., Sanna S.,
RA Masala M., Crisponi L., Fattori M., Devoto M., Doratiotto S., Rassu S.,
RA Mereu S., Giua E., Cadeddu N.G., Atzeni R., Pelosi U., Corrias A.,
RA Perra R., Torrazza P.L., Pirina P., Ginesu F., Marcias S., Schintu M.G.,
RA Del Giacco G.S., Manconi P.E., Malerba G., Bisognin A., Trabetti E.,
RA Boner A., Pescollderungg L., Pignatti P.F., Schlessinger D., Cao A.,
RA Pilia G.;
RT "IRAK-M is involved in the pathogenesis of early-onset persistent asthma.";
RL Am. J. Hum. Genet. 80:1103-1114(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-467, AND IDENTIFICATION BY
RP 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 [7] {ECO:0007744|PDB:5UKE}
RP STRUCTURE BY NMR OF 1-119 OF MUTANTS ASP-56 AND GLU-61, FUNCTION,
RP INTERACTION WITH PIN1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP PHOSPHORYLATION AT SER-110, ISOMERIZATION AT 110-SER-PRO-111, MUTAGENESIS
RP OF SER-110 AND SER-467, AND VARIANT ALA-111.
RX PubMed=29686383; DOI=10.1038/s41467-018-03886-6;
RA Nechama M., Kwon J., Wei S., Kyi A.T., Welner R.S., Ben-Dov I.Z.,
RA Arredouani M.S., Asara J.M., Chen C.H., Tsai C.Y., Nelson K.F.,
RA Kobayashi K.S., Israel E., Zhou X.Z., Nicholson L.K., Lu K.P.;
RT "The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-
RT induced allergic airway inflammation.";
RL Nat. Commun. 9:1603-1603(2018).
RN [8] {ECO:0007744|PDB:6ZIW}
RP X-RAY CRYSTALLOGRAPHY (2.18 ANGSTROMS) OF 141-455 IN COMPLEX WITH ATP
RP ANALOG.
RA Mathea S., Chatterjee D., Preuss F., Kraemer A., Knapp S.;
RT "The IRAK3 Pseudokinase Domain Bound To ATPgammaS.";
RL Submitted (JUN-2020) to the PDB data bank.
RN [9] {ECO:0007744|PDB:6RUU}
RP X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) OF 145-454, SUBUNIT, INTERACTION
RP WITH IRAK4, ATP-BINDING, DISULFIDE BONDS, AND MUTAGENESIS OF LEU-210 AND
RP GLU-214.
RX PubMed=33238146; DOI=10.1016/j.str.2020.11.004;
RA Lange S.M., Nelen M.I., Cohen P., Kulathu Y.;
RT "Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric
RT Mechanism for Negative Regulation.";
RL Structure 29:238-251.e4(2021).
RN [10]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-57; SER-84; VAL-147; VAL-171; LEU-288;
RP GLN-384; THR-391 AND ASN-482.
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: Putative inactive protein kinase which regulates signaling
CC downstream of immune receptors including IL1R and Toll-like receptors
CC (PubMed:10383454, PubMed:29686383). Inhibits dissociation of IRAK1 and
CC IRAK4 from the Toll-like receptor signaling complex by either
CC inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the
CC receptor complex (By similarity). Upon IL33-induced lung inflammation,
CC positively regulates expression of IL6, CSF3, CXCL2 and CCL5 mRNAs in
CC dendritic cells (PubMed:29686383). {ECO:0000250|UniProtKB:Q8K4B2,
CC ECO:0000269|PubMed:10383454, ECO:0000269|PubMed:29686383}.
CC -!- SUBUNIT: Monomer (PubMed:33238146). Homodimer; disulfide-linked
CC (PubMed:33238146). May interact with IRAK4 (when phosphorylated)
CC (PubMed:33238146). Interacts (when phosphorylated at Ser-110) with PIN1
CC (via WW domain) in response to IL33-mediated (but not TLR4 ligand LPS)
CC dendritic cell stimulation (PubMed:29686383).
CC {ECO:0000269|PubMed:29686383, ECO:0000269|PubMed:33238146}.
CC -!- INTERACTION:
CC Q9Y616; Q9Y4K3: TRAF6; NbExp=3; IntAct=EBI-447690, EBI-359276;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:29686383}. Nucleus
CC {ECO:0000269|PubMed:29686383}. Note=In dendritic cells, translocates
CC into the nucleus upon IL33 stimulation. {ECO:0000250|UniProtKB:Q8K4B2}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y616-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y616-2; Sequence=VSP_041020;
CC -!- TISSUE SPECIFICITY: Expressed in eosinophils, dendritic cells and/or
CC monocytes (at protein level) (PubMed:29686383). Expressed predominantly
CC in peripheral blood lymphocytes (PubMed:10383454).
CC {ECO:0000269|PubMed:10383454, ECO:0000269|PubMed:29686383}.
CC -!- DOMAIN: The nucleotide binding domain binds ATP with low affinity.
CC {ECO:0000269|PubMed:33238146}.
CC -!- DISEASE: Asthma-related traits 5 (ASRT5) [MIM:611064]: Asthma-related
CC traits include clinical symptoms of asthma, such as coughing, wheezing,
CC dyspnea, bronchial hyperresponsiveness as assessed by methacholine
CC challenge test, serum IgE levels, atopy and atopic dermatitis.
CC {ECO:0000269|PubMed:17503328}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily. {ECO:0000305}.
CC -!- CAUTION: Ser-293 is present instead of the conserved Asp which is
CC expected to be an active site residue. Low level autophosphorylation
CC activity has been reported in PubMed:10383454, while other authors
CC describe this as an inactive kinase. {ECO:0000305}.
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DR EMBL; AF113136; AAD40879.1; -; mRNA.
DR EMBL; AK298645; BAG60819.1; -; mRNA.
DR EMBL; AC078889; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC078927; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC057800; AAH57800.1; -; mRNA.
DR EMBL; BC069388; AAH69388.1; -; mRNA.
DR CCDS; CCDS44937.1; -. [Q9Y616-2]
DR CCDS; CCDS8975.1; -. [Q9Y616-1]
DR RefSeq; NP_001135995.1; NM_001142523.1. [Q9Y616-2]
DR RefSeq; NP_009130.2; NM_007199.2. [Q9Y616-1]
DR PDB; 5UKE; NMR; -; A=1-119.
DR PDB; 6RUU; X-ray; 2.95 A; A/B/C=145-454.
DR PDB; 6ZIW; X-ray; 2.18 A; I=141-455.
DR PDBsum; 5UKE; -.
DR PDBsum; 6RUU; -.
DR PDBsum; 6ZIW; -.
DR AlphaFoldDB; Q9Y616; -.
DR SMR; Q9Y616; -.
DR BioGRID; 116382; 28.
DR CORUM; Q9Y616; -.
DR IntAct; Q9Y616; 21.
DR MINT; Q9Y616; -.
DR STRING; 9606.ENSP00000261233; -.
DR BindingDB; Q9Y616; -.
DR ChEMBL; CHEMBL5081; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9Y616; -.
DR GuidetoPHARMACOLOGY; 2044; -.
DR iPTMnet; Q9Y616; -.
DR PhosphoSitePlus; Q9Y616; -.
DR BioMuta; IRAK3; -.
DR DMDM; 322510038; -.
DR EPD; Q9Y616; -.
DR jPOST; Q9Y616; -.
DR MassIVE; Q9Y616; -.
DR PaxDb; Q9Y616; -.
DR PeptideAtlas; Q9Y616; -.
DR PRIDE; Q9Y616; -.
DR ProteomicsDB; 86578; -. [Q9Y616-1]
DR ProteomicsDB; 86579; -. [Q9Y616-2]
DR Antibodypedia; 16652; 579 antibodies from 45 providers.
DR DNASU; 11213; -.
DR Ensembl; ENST00000261233.9; ENSP00000261233.4; ENSG00000090376.11. [Q9Y616-1]
DR Ensembl; ENST00000457197.2; ENSP00000409852.2; ENSG00000090376.11. [Q9Y616-2]
DR GeneID; 11213; -.
DR KEGG; hsa:11213; -.
DR MANE-Select; ENST00000261233.9; ENSP00000261233.4; NM_007199.3; NP_009130.2.
DR UCSC; uc001sth.4; human. [Q9Y616-1]
DR CTD; 11213; -.
DR DisGeNET; 11213; -.
DR GeneCards; IRAK3; -.
DR HGNC; HGNC:17020; IRAK3.
DR HPA; ENSG00000090376; Tissue enhanced (bone).
DR MalaCards; IRAK3; -.
DR MIM; 604459; gene.
DR MIM; 611064; phenotype.
DR neXtProt; NX_Q9Y616; -.
DR OpenTargets; ENSG00000090376; -.
DR PharmGKB; PA38431; -.
DR VEuPathDB; HostDB:ENSG00000090376; -.
DR eggNOG; KOG1187; Eukaryota.
DR GeneTree; ENSGT00940000161222; -.
DR HOGENOM; CLU_029530_0_0_1; -.
DR InParanoid; Q9Y616; -.
DR OMA; QKIPFEC; -.
DR OrthoDB; 684563at2759; -.
DR PhylomeDB; Q9Y616; -.
DR TreeFam; TF328924; -.
DR PathwayCommons; Q9Y616; -.
DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR SignaLink; Q9Y616; -.
DR SIGNOR; Q9Y616; -.
DR BioGRID-ORCS; 11213; 15 hits in 1109 CRISPR screens.
DR ChiTaRS; IRAK3; human.
DR GeneWiki; IRAK3; -.
DR GenomeRNAi; 11213; -.
DR Pharos; Q9Y616; Tchem.
DR PRO; PR:Q9Y616; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9Y616; protein.
DR Bgee; ENSG00000090376; Expressed in monocyte and 159 other tissues.
DR ExpressionAtlas; Q9Y616; baseline and differential.
DR Genevisible; Q9Y616; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISS:UniProtKB.
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:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:BHF-UCL.
DR GO; GO:0001960; P:negative regulation of cytokine-mediated signaling pathway; IC:BHF-UCL.
DR GO; GO:0045824; P:negative regulation of innate immune response; ISS:BHF-UCL.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IMP:BHF-UCL.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IMP:BHF-UCL.
DR GO; GO:0010936; P:negative regulation of macrophage cytokine production; ISS:BHF-UCL.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IMP:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL.
DR GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; IMP:BHF-UCL.
DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:BHF-UCL.
DR GO; GO:0001819; P:positive regulation of cytokine production; IEA:Ensembl.
DR GO; GO:0010933; P:positive regulation of macrophage tolerance induction; ISS:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0043244; P:regulation of protein-containing complex disassembly; ISS:UniProtKB.
DR GO; GO:0043330; P:response to exogenous dsRNA; ISS:BHF-UCL.
DR GO; GO:0070555; P:response to interleukin-1; IMP:BHF-UCL.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:BHF-UCL.
DR GO; GO:0032494; P:response to peptidoglycan; ISS:BHF-UCL.
DR GO; GO:0009615; P:response to virus; IC:BHF-UCL.
DR CDD; cd08796; Death_IRAK-M; 1.
DR CDD; cd14160; PK_IRAK3; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR033610; IRAK3.
DR InterPro; IPR042747; IRAK3_death.
DR InterPro; IPR042698; IRAK3_PK.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR PANTHER; PTHR24419:SF7; PTHR24419:SF7; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00005; DEATH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Asthma; ATP-binding; Cytoplasm;
KW Disulfide bond; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..596
FT /note="Interleukin-1 receptor-associated kinase 3"
FT /id="PRO_0000086033"
FT DOMAIN 41..106
FT /note="Death"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064"
FT DOMAIN 165..452
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 560..596
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 171..179
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|Ref.8, ECO:0007744|PDB:6ZIW"
FT BINDING 192
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|Ref.8, ECO:0007744|PDB:6ZIW"
FT BINDING 295..298
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 311
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 110..111
FT /note="Cis/trans isomerization of proline peptide bond; by
FT PIN1; dependent on Ser-110 phosphorylation"
FT /evidence="ECO:0000269|PubMed:29686383"
FT MOD_RES 110
FT /note="Phosphoserine; by IRAK1"
FT /evidence="ECO:0000269|PubMed:29686383"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT DISULFID 202
FT /note="Interchain (with C-287); in linked form"
FT /evidence="ECO:0000269|PubMed:33238146"
FT DISULFID 287
FT /note="Interchain (with C-202); in linked form"
FT /evidence="ECO:0000269|PubMed:33238146"
FT VAR_SEQ 45..105
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_041020"
FT VARIANT 22
FT /note="P -> L (may be associated with ASRT5;
FT dbSNP:rs536546109)"
FT /evidence="ECO:0000269|PubMed:17503328"
FT /id="VAR_035212"
FT VARIANT 57
FT /note="H -> R (in dbSNP:rs35239505)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040581"
FT VARIANT 84
FT /note="G -> S (in dbSNP:rs34443407)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040582"
FT VARIANT 111
FT /note="P -> A (may be associated with ASRT5; abolishes
FT phosphorylation of Ser-110; abolishes interaction with
FT PIN1; no effect on cytoplasmic localization; reduces
FT protein stability; dbSNP:rs373806603)"
FT /evidence="ECO:0000269|PubMed:17503328,
FT ECO:0000269|PubMed:29686383"
FT /id="VAR_035213"
FT VARIANT 134
FT /note="V -> M (may be associated with ASRT5;
FT dbSNP:rs138559915)"
FT /evidence="ECO:0000269|PubMed:17503328"
FT /id="VAR_035214"
FT VARIANT 147
FT /note="I -> V (in dbSNP:rs1152888)"
FT /evidence="ECO:0000269|PubMed:10383454,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_019812"
FT VARIANT 171
FT /note="I -> V (in dbSNP:rs34682166)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040583"
FT VARIANT 269
FT /note="G -> S (in dbSNP:rs35823766)"
FT /id="VAR_033901"
FT VARIANT 270
FT /note="I -> V (in dbSNP:rs11465972)"
FT /id="VAR_031077"
FT VARIANT 288
FT /note="S -> L (in dbSNP:rs35574245)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040584"
FT VARIANT 384
FT /note="R -> Q (in dbSNP:rs34272472)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040585"
FT VARIANT 391
FT /note="M -> T (in dbSNP:rs35737689)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040586"
FT VARIANT 400
FT /note="L -> V (may be associated with ASRT5;
FT dbSNP:rs146120640)"
FT /evidence="ECO:0000269|PubMed:17503328"
FT /id="VAR_035215"
FT VARIANT 429
FT /note="R -> Q (may be associated with ASRT5;
FT dbSNP:rs140671957)"
FT /evidence="ECO:0000269|PubMed:17503328"
FT /id="VAR_035216"
FT VARIANT 482
FT /note="D -> N (in dbSNP:rs35756811)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040587"
FT MUTAGEN 110
FT /note="S->A: Abolishes phosphorylation. Abolishes
FT interaction with PIN1. Reduces protein stability."
FT /evidence="ECO:0000269|PubMed:29686383"
FT MUTAGEN 110
FT /note="S->E: Phosphomimic. Slight decrease in the
FT interaction with PIN1. Weak interaction with PIN1 in
FT absence of IL33-mediated dendritic cell stimulation.
FT Increases resistant to degradation. Localizes to the
FT nucleus in absence of stimulus. Does not affect
FT isomerization of Pro-111 peptide bond."
FT /evidence="ECO:0000269|PubMed:29686383"
FT MUTAGEN 210
FT /note="L->E: Abolishes dimerization."
FT /evidence="ECO:0000269|PubMed:33238146"
FT MUTAGEN 214
FT /note="E->L: Enhances dimerization."
FT /evidence="ECO:0000269|PubMed:33238146"
FT MUTAGEN 467
FT /note="S->A: No effect on the interaction with PIN1."
FT /evidence="ECO:0000269|PubMed:29686383"
FT CONFLICT 560
FT /note="N -> D (in Ref. 2; BAG60819)"
FT /evidence="ECO:0000305"
FT STRAND 17..19
FT /evidence="ECO:0007829|PDB:5UKE"
FT TURN 22..24
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 25..31
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 32..34
FT /evidence="ECO:0007829|PDB:5UKE"
FT STRAND 36..39
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 43..48
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 54..61
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 62..64
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 68..74
FT /evidence="ECO:0007829|PDB:5UKE"
FT STRAND 76..78
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 83..93
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 96..102
FT /evidence="ECO:0007829|PDB:5UKE"
FT STRAND 107..109
FT /evidence="ECO:0007829|PDB:5UKE"
FT HELIX 155..161
FT /evidence="ECO:0007829|PDB:6ZIW"
FT TURN 162..165
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 170..173
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 175..184
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 187..194
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 203..218
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 233..235
FT /evidence="ECO:0007829|PDB:6RUU"
FT STRAND 238..242
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 249..253
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 256..258
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 264..281
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 285..287
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 295..301
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 307..309
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 316..318
FT /evidence="ECO:0007829|PDB:6RUU"
FT HELIX 343..348
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 353..369
FT /evidence="ECO:0007829|PDB:6ZIW"
FT STRAND 376..379
FT /evidence="ECO:0007829|PDB:6RUU"
FT HELIX 383..394
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 396..402
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 412..425
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 430..432
FT /evidence="ECO:0007829|PDB:6ZIW"
FT HELIX 436..449
FT /evidence="ECO:0007829|PDB:6ZIW"
SQ SEQUENCE 596 AA; 67767 MW; D050150B7BDA5B9A CRC64;
MAGNCGARGA LSAHTLLFDL PPALLGELCA VLDSCDGALG WRGLAERLSS SWLDVRHIEK
YVDQGKSGTR ELLWSWAQKN KTIGDLLQVL QEMGHRRAIH LITNYGAVLS PSEKSYQEGG
FPNILFKETA NVTVDNVLIP EHNEKGILLK SSISFQNIIE GTRNFHKDFL IGEGEIFEVY
RVEIQNLTYA VKLFKQEKKM QCKKHWKRFL SELEVLLLFH HPNILELAAY FTETEKFCLI
YPYMRNGTLF DRLQCVGDTA PLPWHIRIGI LIGISKAIHY LHNVQPCSVI CGSISSANIL
LDDQFQPKLT DFAMAHFRSH LEHQSCTINM TSSSSKHLWY MPEEYIRQGK LSIKTDVYSF
GIVIMEVLTG CRVVLDDPKH IQLRDLLREL MEKRGLDSCL SFLDKKVPPC PRNFSAKLFC
LAGRCAATRA KLRPSMDEVL NTLESTQASL YFAEDPPTSL KSFRCPSPLF LENVPSIPVE
DDESQNNNLL PSDEGLRIDR MTQKTPFECS QSEVMFLSLD KKPESKRNEE ACNMPSSSCE
ESWFPKYIVP SQDLRPYKVN IDPSSEAPGH SCRSRPVESS CSSKFSWDEY EQYKKE
