IRAK4_HUMAN
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 03-AUG-2022, entry version 202.
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 ---------------------------------------------------------------------------
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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. [Q9NWZ3-2]
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. [Q9NWZ3-1]
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 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 AlphaFoldDB; Q9NWZ3; -.
DR SMR; Q9NWZ3; -.
DR BioGRID; 119322; 34.
DR CORUM; Q9NWZ3; -.
DR DIP; DIP-31351N; -.
DR IntAct; Q9NWZ3; 23.
DR MINT; Q9NWZ3; -.
DR STRING; 9606.ENSP00000390651; -.
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 iPTMnet; Q9NWZ3; -.
DR PhosphoSitePlus; Q9NWZ3; -.
DR BioMuta; IRAK4; -.
DR DMDM; 50401181; -.
DR EPD; Q9NWZ3; -.
DR jPOST; Q9NWZ3; -.
DR MassIVE; Q9NWZ3; -.
DR MaxQB; Q9NWZ3; -.
DR PaxDb; Q9NWZ3; -.
DR PeptideAtlas; Q9NWZ3; -.
DR PRIDE; Q9NWZ3; -.
DR ProteomicsDB; 83000; -. [Q9NWZ3-1]
DR ProteomicsDB; 83001; -. [Q9NWZ3-2]
DR Antibodypedia; 696; 790 antibodies from 43 providers.
DR DNASU; 51135; -.
DR Ensembl; ENST00000431837.5; ENSP00000390327.1; ENSG00000198001.15. [Q9NWZ3-2]
DR Ensembl; ENST00000440781.6; ENSP00000408734.2; ENSG00000198001.15. [Q9NWZ3-2]
DR Ensembl; ENST00000551736.5; ENSP00000446490.1; ENSG00000198001.15. [Q9NWZ3-1]
DR Ensembl; ENST00000613694.5; ENSP00000479889.3; ENSG00000198001.15. [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 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; WHQRCLI; -.
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 1075 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 150 other tissues.
DR ExpressionAtlas; Q9NWZ3; baseline and differential.
DR Genevisible; Q9NWZ3; HS.
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: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: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; EXP:Reactome.
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; TAS:Reactome.
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:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:MGI.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
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 Gene3D; 1.10.533.10; -; 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 Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF038189; IRAK4; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
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 NF-
FT kappa-B complex activation; loss of interaction with MYD88;
FT 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
