ID IRAK4_HUMAN Reviewed; 460 AA. AC Q9NWZ3; Q69FE1; Q8TDF7; Q9Y589; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 27-MAR-2024, entry version 211. DE RecName: Full=Interleukin-1 receptor-associated kinase 4; DE Short=IRAK-4; DE EC=2.7.11.1; DE AltName: Full=Renal carcinoma antigen NY-REN-64; GN Name=IRAK4; 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), FUNCTION, AND INTERACTION WITH RP IRAK1 AND TRAF6. 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 [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND IDENTIFICATION AS A RENAL RP CANCER ANTIGEN. RX PubMed=10508479; RX DOI=10.1002/(sici)1097-0215(19991112)83:4<456::aid-ijc4>3.0.co;2-5; RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H., RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T., RA Old L.J.; RT "Antigens recognized by autologous antibody in patients with renal-cell RT carcinoma."; RL Int. J. Cancer 83:456-464(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Spleen; RA Chuang T.H., Ulevitch R.J.; RT "Human interleukin-1 receptor associated kinase 4 cDNA sequences."; RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). 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 [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-98; ARG-390 AND RP THR-428. RG SeattleSNPs variation discovery resource; RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases. RN [6] 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; 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 IRAK1; 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 [9] RP FUNCTION IN PHOSPHORYLATION OF IRAK1. 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 [10] RP INVOLVEMENT IN IMD67. RX PubMed=12925671; DOI=10.1084/jem.20030701; RA Medvedev A.E., Lentschat A., Kuhns D.B., Blanco J.C.G., Salkowski C., RA Zhang S., Arditi M., Gallin J.I., Vogel S.N.; RT "Distinct mutations in IRAK-4 confer hyporesponsiveness to RT lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial RT infections."; RL J. Exp. Med. 198:521-531(2003). RN [11] RP FUNCTION, AND MUTAGENESIS OF LYS-213. 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 [12] RP INVOLVEMENT IN IMD67. RX PubMed=12637671; DOI=10.1126/science.1081902; RA Picard C., Puel A., Bonnet M., Ku C.-L., Bustamante J., Yang K., RA Soudais C., Dupuis S., Feinberg J., Fieschi C., Elbim C., Hitchcock R., RA Lammas D., Davies G., Al-Ghonaium A., Al-Rayes H., Al-Jumaah S., RA Al-Hajjar S., Al-Mohsen I.Z., Frayha H.H., Rucker R., Hawn T.R., Aderem A., RA Tufenkeji H., Haraguchi S., Day N.K., Good R.A., Gougerot-Pocidalo M.-A., RA Ozinsky A., Casanova J.-L.; RT "Pyogenic bacterial infections in humans with IRAK-4 deficiency."; RL Science 299:2076-2079(2003). RN [13] 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 [14] RP IDENTIFICATION IN COMPLEX WITH IRAK1; 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 [15] RP FUNCTION IN PHOSPHORYLATION OF NCF1. RX PubMed=17217339; DOI=10.1042/bj20061184; RA Pacquelet S., Johnson J.L., Ellis B.A., Brzezinska A.A., Lane W.S., RA Munafo D.B., Catz S.D.; RT "Cross-talk between IRAK-4 and the NADPH oxidase."; RL Biochem. J. 403:451-461(2007). RN [16] RP FUNCTION IN TLR7 SIGNALING PATHWAY. RX PubMed=17337443; DOI=10.1074/jbc.m700548200; RA Koziczak-Holbro M., Joyce C., Gluck A., Kinzel B., Muller M., Tschopp C., RA Mathison J.C., Davis C.N., Gram H.; RT "IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and RT toll-like receptor 7-mediated signaling and gene expression."; RL J. Biol. Chem. 282:13552-13560(2007). RN [17] RP INVOLVEMENT IN IMD67. RX PubMed=16950813; DOI=10.1136/jmg.2006.044446; RA Ku C.-L., Picard C., Erdos M., Jeurissen A., Bustamante J., Puel A., RA von Bernuth H., Filipe-Santos O., Chang H.-H., Lawrence T., Raes M., RA Marodi L., Bossuyt X., Casanova J.-L.; RT "IRAK4 and NEMO mutations in otherwise healthy children with recurrent RT invasive pneumococcal disease."; RL J. Med. Genet. 44:16-23(2007). RN [18] 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 [19] RP IDENTIFICATION BY 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 [20] 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 [21] RP IDENTIFICATION BY 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 [22] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-34, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [23] 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 [24] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [25] 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 [26] RP SUBCELLULAR LOCATION. RX PubMed=21325272; DOI=10.1074/jbc.m110.199653; RA Nagpal K., Plantinga T.S., Sirois C.M., Monks B.G., Latz E., Netea M.G., RA Golenbock D.T.; RT "Natural loss-of-function mutation of myeloid differentiation protein 88 RT disrupts its ability to form Myddosomes."; RL J. Biol. Chem. 286:11875-11882(2011). RN [27] RP REVIEW ON MYDDOSOME. RX PubMed=21269878; DOI=10.1016/j.it.2010.12.005; RA Gay N.J., Gangloff M., O'Neill L.A.; RT "What the Myddosome structure tells us about the initiation of innate RT immunity."; RL Trends Immunol. 32:104-109(2011). RN [28] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [29] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=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 [30] RP INTERACTION WITH IRAK1 AND IRAK3. 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 [31] RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 154-460 IN COMPLEX WITH RP INHIBITORS, AND PHOSPHORYLATION AT THR-345 AND SER-346. RX PubMed=17161373; DOI=10.1016/j.str.2006.11.001; RA Wang Z., Liu J., Sudom A., Ayres M., Li S., Wesche H., Powers J.P., RA Walker N.P.C.; RT "Crystal structures of IRAK-4 kinase in complex with inhibitors: a RT serine/threonine kinase with tyrosine as a gatekeeper."; RL Structure 14:1835-1844(2006). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 163-460, AND PHOSPHORYLATION AT RP THR-342 AND THR-345. RA Mol C.D., Arduini R.M., Baker D.P., Chien E.Y., Dougan D.R., Friedman J., RA Gibaja V., Hession C.A., Horne A.; RT "Crystal structures of the apo and inhibited IRAK4 kinase domain."; RL Submitted (DEC-2006) to the PDB data bank. RN [33] RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 160-460 IN COMPLEX WITH ATP RP ANALOGS, PHOSPHORYLATION AT THR-342; THR-345 AND SER-346, AND RP BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=17312103; DOI=10.4049/jimmunol.178.5.2641; RA Kuglstatter A., Villasenor A.G., Shaw D., Lee S.W., Tsing S., Niu L., RA Song K.W., Barnett J.W., Browner M.F.; RT "Cutting Edge: IL-1 receptor-associated kinase 4 structures reveal novel RT features and multiple conformations."; RL J. Immunol. 178:2641-2645(2007). RN [34] RP X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) OF 4-106. RX PubMed=20485341; DOI=10.1038/nature09121; RA Lin S.-C., Lo Y.-C., Wu H.; RT "Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R RT signalling."; RL Nature 465:885-890(2010). RN [35] RP VARIANT IMD67 CYS-12, CHARACTERIZATION OF VARIANT IMD67 CYS-12, VARIANT RP HIS-391, AND FUNCTION. RX PubMed=17878374; DOI=10.4049/jimmunol.179.7.4754; RA Hoarau C., Gerard B., Lescanne E., Henry D., Francois S., Lacapere J.J., RA El Benna J., Dang P.M., Grandchamp B., Lebranchu Y., RA Gougerot-Pocidalo M.A., Elbim C.; RT "TLR9 activation induces normal neutrophil responses in a child with IRAK-4 RT deficiency: involvement of the direct PI3K pathway."; RL J. Immunol. 179:4754-4765(2007). RN [36] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-5; VAL-355; HIS-391 AND THR-428. 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). RN [37] RP VARIANT IMD67 ASP-298, AND CHARACTERIZATION OF VARIANT IMD67 ASP-298. RX PubMed=19663824; DOI=10.1111/j.1365-2141.2009.07838.x; RA Bouma G., Doffinger R., Patel S.Y., Peskett E., Sinclair J.C., RA Barcenas-Morales G., Cerron-Gutierrez L., Kumararatne D.S., Davies E.G., RA Thrasher A.J., Burns S.O.; RT "Impaired neutrophil migration and phagocytosis in IRAK-4 deficiency."; RL Br. J. Haematol. 147:153-156(2009). RN [38] RP INVOLVEMENT IN IMD67, AND VARIANT IMD67 ASP-298. RX PubMed=21057262; DOI=10.1097/md.0b013e3181fd8ec3; RA Picard C., von Bernuth H., Ghandil P., Chrabieh M., Levy O., RA Arkwright P.D., McDonald D., Geha R.S., Takada H., Krause J.C., RA Creech C.B., Ku C.L., Ehl S., Marodi L., Al-Muhsen S., Al-Hajjar S., RA Al-Ghonaium A., Day-Good N.K., Holland S.M., Gallin J.I., Chapel H., RA Speert D.P., Rodriguez-Gallego C., Colino E., Garty B.Z., Roifman C., RA Hara T., Yoshikawa H., Nonoyama S., Domachowske J., Issekutz A.C., Tang M., RA Smart J., Zitnik S.E., Hoarau C., Kumararatne D.S., Thrasher A.J., RA Davies E.G., Bethune C., Sirvent N., de Ricaud D., Camcioglu Y., RA Vasconcelos J., Guedes M., Vitor A.B., Rodrigo C., Almazan F., Mendez M., RA Arostegui J.I., Alsina L., Fortuny C., Reichenbach J., Verbsky J.W., RA Bossuyt X., Doffinger R., Abel L., Puel A., Casanova J.L.; RT "Clinical features and outcome of patients with IRAK-4 and MyD88 RT deficiency."; RL Medicine (Baltimore) 89:403-425(2010). RN [39] RP CHARACTERIZATION OF VARIANTS VAL-5; TRP-20; THR-26; VAL-39 AND ARG-98, RP CHARACTERIZATION OF VARIANTS IMD67 CYS-12 AND ASP-298, FUNCTION, AND RP INTERACTION WITH MYD88. RX PubMed=24316379; DOI=10.1016/j.molimm.2013.11.008; RA Yamamoto T., Tsutsumi N., Tochio H., Ohnishi H., Kubota K., Kato Z., RA Shirakawa M., Kondo N.; RT "Functional assessment of the mutational effects of human IRAK4 and MyD88 RT genes."; RL Mol. Immunol. 58:66-76(2014). 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 CC (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor- CC signaling complex upon TLR activation to form the Myddosome together CC with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase CC activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 CC ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote CC pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin- CC binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing CC together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB CC complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) CC leading to NF-kappa-B nuclear translocation and activation. CC Alternatively, phosphorylates TIRAP to promote its ubiquitination and CC subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase CC activation after LPS stimulation suggesting a similar mechanism during CC microbial infections. {ECO:0000269|PubMed:11960013, CC ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:15084582, CC ECO:0000269|PubMed:17217339, ECO:0000269|PubMed:17337443, CC ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:17997719, CC ECO:0000269|PubMed:20400509, ECO:0000269|PubMed:24316379}. 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 -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=650 uM for ATP (at pH 7.5) {ECO:0000269|PubMed:17312103}; CC KM=1100 uM for substrate (at pH 7.5) {ECO:0000269|PubMed:17312103}; CC -!- SUBUNIT: Associates with MYD88 and IRAK2 to form a ternary complex CC called the Myddosome (PubMed:16951688, PubMed:24316379). Once CC phosphorylated, IRAK4 dissociates from the receptor complex and then CC associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, CC and PELI1; this intermediate complex is required for subsequent NF- CC kappa-B activation (PubMed:11960013, PubMed:12496252, PubMed:16951688). CC Direct binding of SMAD6 to PELI1 prevents complex formation and hence CC negatively regulates IL1R-TLR signaling and eventually NF-kappa-B- CC mediated gene expression (PubMed:16951688). Interacts with IL1RL1 CC (PubMed:16286016). Interacts (when phosphorylated) with IRAK1 CC (PubMed:33238146). May interact (when phosphorylated) with IRAK3 CC (PubMed:33238146). {ECO:0000269|PubMed:11960013, CC ECO:0000269|PubMed:12496252, ECO:0000269|PubMed:16286016, CC ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:24316379, CC ECO:0000269|PubMed:33238146}. CC -!- INTERACTION: CC Q9NWZ3; Q9UBH0: IL36RN; NbExp=3; IntAct=EBI-448378, EBI-465156; CC Q9NWZ3; O43187: IRAK2; NbExp=6; IntAct=EBI-448378, EBI-447733; CC Q9NWZ3; Q99836: MYD88; NbExp=15; IntAct=EBI-448378, EBI-447677; CC Q9NWZ3; Q99836-1: MYD88; NbExp=9; IntAct=EBI-448378, EBI-15855480; CC Q9NWZ3; Q96FA3: PELI1; NbExp=6; IntAct=EBI-448378, EBI-448369; CC Q9NWZ3; Q9HAT8: PELI2; NbExp=3; IntAct=EBI-448378, EBI-448407; CC Q9NWZ3; P58753: TIRAP; NbExp=2; IntAct=EBI-448378, EBI-528644; CC Q9NWZ3; Q9C029: TRIM7; NbExp=3; IntAct=EBI-448378, EBI-2813981; CC Q9NWZ3; Q96LX8: ZNF597; NbExp=3; IntAct=EBI-448378, EBI-9091553; CC Q9NWZ3; Q8K4B2: Irak3; Xeno; NbExp=4; IntAct=EBI-448378, EBI-646179; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21325272}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NWZ3-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NWZ3-2; Sequence=VSP_041556; CC -!- PTM: Phosphorylated. {ECO:0000250}. CC -!- DISEASE: Immunodeficiency 67 (IMD67) [MIM:607676]: An autosomal CC recessive primary immunodeficiency characterized by recurrent, life- CC threatening systemic and invasive bacterial infections beginning in CC infancy or early childhood. {ECO:0000269|PubMed:12637671, CC ECO:0000269|PubMed:12925671, ECO:0000269|PubMed:16950813, CC ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:19663824, CC ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. Pelle subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=IRAK4base; Note=IRAK4 mutation db; CC URL="http://structure.bmc.lu.se/idbase/IRAK4base/"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/irak4/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF445802; AAM15772.1; -; mRNA. DR EMBL; AF155118; AAD42884.1; -; mRNA. DR EMBL; AY340964; AAR02360.1; -; mRNA. DR EMBL; AY340965; AAR02361.1; -; mRNA. DR EMBL; AY340966; AAR02362.1; -; mRNA. DR EMBL; AY340967; AAR02363.1; -; mRNA. DR EMBL; AK000528; BAA91232.1; -; mRNA. DR EMBL; AK299944; BAG61774.1; -; mRNA. DR EMBL; AY186092; AAN75440.1; -; Genomic_DNA. DR EMBL; AC093012; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC013316; AAH13316.1; -; mRNA. DR CCDS; CCDS44862.1; -. [Q9NWZ3-2] DR CCDS; CCDS8744.1; -. [Q9NWZ3-1] DR RefSeq; NP_001107654.1; NM_001114182.2. [Q9NWZ3-1] DR RefSeq; NP_001138728.1; NM_001145256.1. [Q9NWZ3-2] DR RefSeq; NP_001138729.1; NM_001145257.1. [Q9NWZ3-2] DR RefSeq; NP_001138730.1; NM_001145258.1. [Q9NWZ3-2] DR RefSeq; NP_057207.2; NM_016123.3. [Q9NWZ3-1] DR RefSeq; XP_005269000.1; XM_005268943.3. [Q9NWZ3-1] DR RefSeq; XP_005269001.1; XM_005268944.4. [Q9NWZ3-1] DR RefSeq; XP_005269002.1; XM_005268945.4. [Q9NWZ3-1] DR RefSeq; XP_005269004.1; XM_005268947.4. DR RefSeq; XP_005269005.1; XM_005268948.2. DR RefSeq; XP_005269006.1; XM_005268949.2. DR RefSeq; XP_006719501.1; XM_006719438.3. [Q9NWZ3-1] DR RefSeq; XP_006719502.1; XM_006719439.2. DR RefSeq; XP_011536733.1; XM_011538431.2. [Q9NWZ3-1] DR RefSeq; XP_011536734.1; XM_011538432.1. DR RefSeq; XP_011536735.1; XM_011538433.2. DR RefSeq; XP_016874879.1; XM_017019390.1. [Q9NWZ3-1] DR RefSeq; XP_016874880.1; XM_017019391.1. DR PDB; 2NRU; X-ray; 2.00 A; A/B/C/D=154-460. DR PDB; 2NRY; X-ray; 2.15 A; A/B/C/D=154-460. DR PDB; 2O8Y; X-ray; 2.40 A; A/B=163-460. DR PDB; 2OIB; X-ray; 2.00 A; A/B/C/D=160-460. DR PDB; 2OIC; X-ray; 2.40 A; A/B/C/D=160-460. DR PDB; 2OID; X-ray; 2.30 A; A/B/C/D=160-460. DR PDB; 3MOP; X-ray; 3.40 A; G/H/I/J=4-106. DR PDB; 4RMZ; X-ray; 2.20 A; A/B=154-460. DR PDB; 4U97; X-ray; 2.65 A; A/B=154-460. DR PDB; 4U9A; X-ray; 2.80 A; A/B=154-460. DR PDB; 4XS2; X-ray; 2.73 A; A/B/C/D=160-460. DR PDB; 4Y73; X-ray; 2.14 A; A/B/C/D=160-460. DR PDB; 4YO6; X-ray; 2.32 A; A/B/C/D=160-460. DR PDB; 4YP8; X-ray; 2.64 A; A/B/C/D=160-460. DR PDB; 4ZTL; X-ray; 2.39 A; A/B/C/D=160-460. DR PDB; 4ZTM; X-ray; 2.66 A; A/B/C/D=160-460. DR PDB; 4ZTN; X-ray; 2.23 A; A/B/C/D=160-460. DR PDB; 5K72; X-ray; 2.22 A; A/B/C/D=160-460. DR PDB; 5K75; X-ray; 2.03 A; A/B/C/D=160-460. DR PDB; 5K76; X-ray; 2.74 A; A/B=160-460. DR PDB; 5K7G; X-ray; 2.23 A; A/B/C/D=160-460. DR PDB; 5K7I; X-ray; 2.31 A; A/B=160-460. DR PDB; 5KX7; X-ray; 2.80 A; A/B=160-460. DR PDB; 5KX8; X-ray; 2.67 A; A/B/C/D=160-460. DR PDB; 5T1S; X-ray; 2.30 A; A/B/C/D=160-460. DR PDB; 5T1T; X-ray; 2.34 A; A/B/C/D=160-460. DR PDB; 5UIQ; X-ray; 2.64 A; A/B/C/D=154-460. DR PDB; 5UIR; X-ray; 2.64 A; A/B=154-460. DR PDB; 5UIS; X-ray; 2.50 A; A/B/C/D=154-460. DR PDB; 5UIT; X-ray; 1.84 A; A/B=154-460. DR PDB; 5UIU; X-ray; 2.02 A; A/B=154-460. DR PDB; 5W84; X-ray; 2.90 A; A/B=160-460. DR PDB; 5W85; X-ray; 2.25 A; A/B=160-460. DR PDB; 6EG9; X-ray; 2.41 A; A/B=154-460. DR PDB; 6EGA; X-ray; 2.51 A; A/B=154-460. DR PDB; 6EGD; X-ray; 2.10 A; A/D=164-460. DR PDB; 6EGE; X-ray; 1.40 A; A/D=164-460. DR PDB; 6EGF; X-ray; 2.61 A; B=164-460. DR PDB; 6F3D; X-ray; 2.38 A; A/B=164-458. DR PDB; 6F3E; X-ray; 2.67 A; A/B=164-458. DR PDB; 6F3G; X-ray; 2.37 A; A/B=164-458. DR PDB; 6F3I; X-ray; 2.14 A; A/B=154-460. DR PDB; 6LXY; X-ray; 2.19 A; A/B/D/E=160-460. DR PDB; 6MOM; X-ray; 2.10 A; A/B/C/D=160-460. DR PDB; 6N8G; X-ray; 2.00 A; A/B/C/D=164-460. DR PDB; 6O8U; X-ray; 1.80 A; A/B/C/D=160-460. DR PDB; 6O94; X-ray; 1.98 A; A/B/C/D=160-460. DR PDB; 6O95; X-ray; 1.77 A; A/B/C/D=160-460. DR PDB; 6O9D; X-ray; 2.51 A; A/B/C/D=160-460. DR PDB; 6RFI; X-ray; 2.31 A; A/B=154-460. DR PDB; 6RFJ; X-ray; 2.61 A; A/B=154-460. DR PDB; 6THW; X-ray; 2.44 A; A/B=154-460. DR PDB; 6THX; X-ray; 1.99 A; A/B=154-460. DR PDB; 6THZ; X-ray; 2.38 A; A/B=154-460. DR PDB; 6TI8; X-ray; 2.32 A; A/B/C/D=154-460. DR PDB; 6TIA; X-ray; 2.52 A; A/B=154-460. DR PDB; 6UYA; X-ray; 1.74 A; A/B/C/D=160-460. DR PDB; 6VQL; X-ray; 2.07 A; A/B/C/D=160-460. DR PDB; 7C2V; X-ray; 2.44 A; A/B/C/D=162-460. DR PDB; 7C2W; X-ray; 3.20 A; A/B/C/D=163-458. DR PDB; 7QG1; X-ray; 2.07 A; A/B=154-460. DR PDB; 7QG2; X-ray; 3.03 A; A/B/C/D=154-460. DR PDB; 7QG3; X-ray; 2.11 A; A/B=154-460. DR PDB; 7QG5; X-ray; 2.30 A; A/B=154-460. DR PDB; 8ATB; X-ray; 2.35 A; AAA/BBB=165-460. DR PDB; 8ATL; X-ray; 2.46 A; AAA/BBB=165-460. DR PDB; 8ATN; X-ray; 2.17 A; AAA/BBB=165-460. DR PDB; 8DKS; X-ray; 2.45 A; A/B=1-460. DR PDB; 8WTF; X-ray; 2.00 A; A=164-460. DR PDBsum; 2NRU; -. DR PDBsum; 2NRY; -. DR PDBsum; 2O8Y; -. DR PDBsum; 2OIB; -. DR PDBsum; 2OIC; -. DR PDBsum; 2OID; -. DR PDBsum; 3MOP; -. DR PDBsum; 4RMZ; -. DR PDBsum; 4U97; -. DR PDBsum; 4U9A; -. DR PDBsum; 4XS2; -. DR PDBsum; 4Y73; -. DR PDBsum; 4YO6; -. DR PDBsum; 4YP8; -. DR PDBsum; 4ZTL; -. DR PDBsum; 4ZTM; -. DR PDBsum; 4ZTN; -. DR PDBsum; 5K72; -. DR PDBsum; 5K75; -. DR PDBsum; 5K76; -. DR PDBsum; 5K7G; -. DR PDBsum; 5K7I; -. DR PDBsum; 5KX7; -. DR PDBsum; 5KX8; -. DR PDBsum; 5T1S; -. DR PDBsum; 5T1T; -. DR PDBsum; 5UIQ; -. DR PDBsum; 5UIR; -. DR PDBsum; 5UIS; -. DR PDBsum; 5UIT; -. DR PDBsum; 5UIU; -. DR PDBsum; 5W84; -. DR PDBsum; 5W85; -. DR PDBsum; 6EG9; -. DR PDBsum; 6EGA; -. DR PDBsum; 6EGD; -. DR PDBsum; 6EGE; -. DR PDBsum; 6EGF; -. DR PDBsum; 6F3D; -. DR PDBsum; 6F3E; -. DR PDBsum; 6F3G; -. DR PDBsum; 6F3I; -. DR PDBsum; 6LXY; -. DR PDBsum; 6MOM; -. DR PDBsum; 6N8G; -. DR PDBsum; 6O8U; -. DR PDBsum; 6O94; -. DR PDBsum; 6O95; -. DR PDBsum; 6O9D; -. DR PDBsum; 6RFI; -. DR PDBsum; 6RFJ; -. DR PDBsum; 6THW; -. DR PDBsum; 6THX; -. DR PDBsum; 6THZ; -. DR PDBsum; 6TI8; -. DR PDBsum; 6TIA; -. DR PDBsum; 6UYA; -. DR PDBsum; 6VQL; -. DR PDBsum; 7C2V; -. DR PDBsum; 7C2W; -. DR PDBsum; 7QG1; -. DR PDBsum; 7QG2; -. DR PDBsum; 7QG3; -. DR PDBsum; 7QG5; -. DR PDBsum; 8ATB; -. DR PDBsum; 8ATL; -. DR PDBsum; 8ATN; -. DR PDBsum; 8DKS; -. DR PDBsum; 8WTF; -. DR AlphaFoldDB; Q9NWZ3; -. DR SMR; Q9NWZ3; -. DR BioGRID; 119322; 43. DR CORUM; Q9NWZ3; -. DR DIP; DIP-31351N; -. DR IntAct; Q9NWZ3; 23. DR MINT; Q9NWZ3; -. DR STRING; 9606.ENSP00000479889; -. DR BindingDB; Q9NWZ3; -. DR ChEMBL; CHEMBL3778; -. DR DrugBank; DB08590; 1-(3-HYDROXYPROPYL)-2-[(3-NITROBENZOYL)AMINO]-1H-BENZIMIDAZOL-5-YL PIVALATE. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; Q9NWZ3; -. DR GuidetoPHARMACOLOGY; 2045; -. DR GlyGen; Q9NWZ3; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9NWZ3; -. DR PhosphoSitePlus; Q9NWZ3; -. DR BioMuta; IRAK4; -. DR DMDM; 50401181; -. DR CPTAC; CPTAC-2956; -. DR CPTAC; CPTAC-2957; -. DR EPD; Q9NWZ3; -. DR jPOST; Q9NWZ3; -. DR MassIVE; Q9NWZ3; -. DR MaxQB; Q9NWZ3; -. DR PaxDb; 9606-ENSP00000390651; -. DR PeptideAtlas; Q9NWZ3; -. DR ProteomicsDB; 83000; -. [Q9NWZ3-1] DR ProteomicsDB; 83001; -. [Q9NWZ3-2] DR Pumba; Q9NWZ3; -. DR Antibodypedia; 696; 860 antibodies from 43 providers. DR DNASU; 51135; -. DR Ensembl; ENST00000440781.6; ENSP00000408734.2; ENSG00000198001.16. [Q9NWZ3-2] DR Ensembl; ENST00000551736.5; ENSP00000446490.1; ENSG00000198001.16. [Q9NWZ3-1] DR Ensembl; ENST00000613694.5; ENSP00000479889.3; ENSG00000198001.16. [Q9NWZ3-1] DR GeneID; 51135; -. DR KEGG; hsa:51135; -. DR MANE-Select; ENST00000613694.5; ENSP00000479889.3; NM_016123.4; NP_057207.2. DR UCSC; uc001rnt.4; human. [Q9NWZ3-1] DR AGR; HGNC:17967; -. DR CTD; 51135; -. DR DisGeNET; 51135; -. DR GeneCards; IRAK4; -. DR HGNC; HGNC:17967; IRAK4. DR HPA; ENSG00000198001; Low tissue specificity. DR MalaCards; IRAK4; -. DR MIM; 606883; gene. DR MIM; 607676; phenotype. DR neXtProt; NX_Q9NWZ3; -. DR OpenTargets; ENSG00000198001; -. DR Orphanet; 70592; Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency. DR PharmGKB; PA134914577; -. DR VEuPathDB; HostDB:ENSG00000198001; -. DR eggNOG; KOG1187; Eukaryota. DR GeneTree; ENSGT00940000158792; -. DR HOGENOM; CLU_000288_21_4_1; -. DR InParanoid; Q9NWZ3; -. DR OMA; LTDTYMP; -. DR OrthoDB; 2999496at2759; -. DR PhylomeDB; Q9NWZ3; -. DR TreeFam; TF351380; -. DR PathwayCommons; Q9NWZ3; -. 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-5603037; IRAK4 deficiency (TLR5). DR Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4). DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. 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-975155; MyD88 dependent cascade initiated on endosome. DR Reactome; R-HSA-975871; MyD88 cascade initiated on plasma membrane. DR SABIO-RK; Q9NWZ3; -. DR SignaLink; Q9NWZ3; -. DR SIGNOR; Q9NWZ3; -. DR BioGRID-ORCS; 51135; 17 hits in 1152 CRISPR screens. DR ChiTaRS; IRAK4; human. DR EvolutionaryTrace; Q9NWZ3; -. DR GenomeRNAi; 51135; -. DR Pharos; Q9NWZ3; Tchem. DR PRO; PR:Q9NWZ3; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q9NWZ3; Protein. DR Bgee; ENSG00000198001; Expressed in monocyte and 151 other cell types or tissues. DR ExpressionAtlas; Q9NWZ3; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProt. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IEA:Ensembl. DR GO; GO:0019897; C:extrinsic component of plasma membrane; IC:UniProt. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005149; F:interleukin-1 receptor binding; IEA:Ensembl. DR GO; GO:0016301; F:kinase activity; IDA:UniProt. DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro. 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:UniProt. 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; TAS:UniProtKB. DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IDA:UniProt. DR GO; GO:0038172; P:interleukin-33-mediated signaling pathway; IDA:UniProt. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:UniProtKB. DR GO; GO:0002446; P:neutrophil mediated immunity; IMP:UniProtKB. DR GO; GO:1990266; P:neutrophil migration; IMP:UniProtKB. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IMP:MGI. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0008063; P:Toll signaling pathway; IBA:GO_Central. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IC:UniProt. DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome. DR GO; GO:0002224; P:toll-like receptor signaling pathway; TAS:UniProtKB. DR CDD; cd08793; Death_IRAK4; 1. DR CDD; cd14158; STKc_IRAK4; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR017428; IRAK4. DR InterPro; IPR037970; IRAK4_Death. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR PANTHER; PTHR47989; OS01G0750732 PROTEIN; 1. DR PANTHER; PTHR47989:SF59; PROTEIN KINASE DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR PIRSF; PIRSF038189; IRAK4; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; Q9NWZ3; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cytoplasm; KW Disease variant; Immunity; Innate immunity; Kinase; Magnesium; KW Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase. FT CHAIN 1..460 FT /note="Interleukin-1 receptor-associated kinase 4" FT /id="PRO_0000086035" FT DOMAIN 20..104 FT /note="Death" FT DOMAIN 186..454 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT ACT_SITE 311 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 192..200 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 213 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT BINDING 313..316 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT BINDING 329 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 34 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 342 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:17312103, ECO:0000269|Ref.32" FT MOD_RES 345 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:17161373, FT ECO:0000269|PubMed:17312103, ECO:0000269|Ref.32" FT MOD_RES 346 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:17161373, FT ECO:0000269|PubMed:17312103" FT VAR_SEQ 1..124 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.3" FT /id="VSP_041556" FT VARIANT 5 FT /note="I -> V (no effect on inhibition of NF-kappa-B FT activation; no effect on interaction with MYD88; FT dbSNP:rs56312115)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:24316379" FT /id="VAR_040588" FT VARIANT 12 FT /note="R -> C (in IMD67; no effect on inhibition of FT NF-kappa-B complex activation; loss of interaction with FT MYD88; decreases protein stability; dbSNP:rs377584435)" FT /evidence="ECO:0000269|PubMed:17878374, FT ECO:0000269|PubMed:24316379" FT /id="VAR_072888" FT VARIANT 20 FT /note="R -> W (increases inhibition of NF-kappa-B complex FT activation; decreases interaction with MYD88; decreases FT protein stability; dbSNP:rs143625818)" FT /evidence="ECO:0000269|PubMed:24316379" FT /id="VAR_072889" FT VARIANT 26 FT /note="I -> T (no effect on inhibition of NF-kappa-B FT activation; no effect on interaction with MYD88; FT dbSNP:rs138116867)" FT /evidence="ECO:0000269|PubMed:24316379" FT /id="VAR_072890" FT VARIANT 39 FT /note="I -> V (no effect on inhibition of NF-kappa-B FT activation; no effect on interaction with MYD88; FT dbSNP:rs113588409)" FT /evidence="ECO:0000269|PubMed:24316379" FT /id="VAR_072891" FT VARIANT 98 FT /note="S -> R (no effect on inhibition of NF-kappa-B FT activation; no effect on interaction with MYD88; FT dbSNP:rs4251469)" FT /evidence="ECO:0000269|PubMed:24316379, ECO:0000269|Ref.5" FT /id="VAR_019354" FT VARIANT 298 FT /note="G -> D (in IMD67; decreases inhibition of NF-kappa-B FT complex activation; impairs neutrophil migration and FT phagocytosis; dbSNP:rs568782766)" FT /evidence="ECO:0000269|PubMed:19663824, FT ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379" FT /id="VAR_072892" FT VARIANT 355 FT /note="M -> V (in dbSNP:rs142376871)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040589" FT VARIANT 390 FT /note="H -> R (in dbSNP:rs4251583)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_019355" FT VARIANT 391 FT /note="R -> H (in dbSNP:rs55944915)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:17878374" FT /id="VAR_040590" FT VARIANT 428 FT /note="A -> T (in dbSNP:rs4251545)" FT /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.5" FT /id="VAR_019356" FT MUTAGEN 213 FT /note="K->A: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:15084582" FT CONFLICT 81 FT /note="V -> A (in Ref. 1; AAM15772)" FT /evidence="ECO:0000305" FT CONFLICT 432 FT /note="V -> G (in Ref. 2; AAD42884)" FT /evidence="ECO:0000305" FT CONFLICT 437 FT /note="L -> R (in Ref. 2; AAD42884)" FT /evidence="ECO:0000305" FT CONFLICT 444 FT /note="R -> S (in Ref. 2; AAD42884)" FT /evidence="ECO:0000305" FT CONFLICT 451 FT /note="Q -> H (in Ref. 2; AAD42884)" FT /evidence="ECO:0000305" FT HELIX 11..13 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 16..26 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 31..38 FT /evidence="ECO:0007829|PDB:3MOP" FT STRAND 42..48 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 50..57 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 58..60 FT /evidence="ECO:0007829|PDB:3MOP" FT TURN 61..63 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 66..73 FT /evidence="ECO:0007829|PDB:3MOP" FT TURN 74..77 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 81..89 FT /evidence="ECO:0007829|PDB:3MOP" FT TURN 90..92 FT /evidence="ECO:0007829|PDB:3MOP" FT HELIX 94..100 FT /evidence="ECO:0007829|PDB:3MOP" FT STRAND 102..104 FT /evidence="ECO:0007829|PDB:3MOP" FT STRAND 165..167 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 170..176 FT /evidence="ECO:0007829|PDB:6EGE" FT TURN 177..180 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 185..187 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 191..194 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 196..205 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 208..215 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 218..220 FT /evidence="ECO:0007829|PDB:5UIU" FT HELIX 225..239 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 248..252 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 254..257 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 259..263 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 270..274 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 277..279 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 285..304 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 314..316 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 317..319 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 325..327 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 334..336 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 343..345 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 349..351 FT /evidence="ECO:0007829|PDB:4U97" FT HELIX 352..354 FT /evidence="ECO:0007829|PDB:6UYA" FT HELIX 357..360 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 367..382 FT /evidence="ECO:0007829|PDB:6EGE" FT STRAND 391..395 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 396..398 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 399..404 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 410..413 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 423..436 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 441..443 FT /evidence="ECO:0007829|PDB:6EGE" FT HELIX 447..456 FT /evidence="ECO:0007829|PDB:6EGE" SQ SEQUENCE 460 AA; 51530 MW; 6C8156ADF25FF81E CRC64; MNKPITPSTY VRCLNVGLIR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ FHIRRFEALL QTGKSPTSEL LFDWGTTNCT VGDLVDLLIQ NEFFAPASLL LPDAVPKTAN TLPSKEAITV QQKQMPFCDK DRTLMTPVQN LEQSYMPPDS SSPENKSLEV SDTRFHSFSF YELKNVTNNF DERPISVGGN KMGEGGFGVV YKGYVNNTTV AVKKLAAMVD ITTEELKQQF DQEIKVMAKC QHENLVELLG FSSDGDDLCL VYVYMPNGSL LDRLSCLDGT PPLSWHMRCK IAQGAANGIN FLHENHHIHR DIKSANILLD EAFTAKISDF GLARASEKFA QTVMTSRIVG TTAYMAPEAL RGEITPKSDI YSFGVVLLEI ITGLPAVDEH REPQLLLDIK EEIEDEEKTI EDYIDKKMND ADSTSVEAMY SVASQCLHEK KNKRPDIKKV QQLLQEMTAS //