IRAK4_MOUSE
ID IRAK4_MOUSE Reviewed; 459 AA.
AC Q8R4K2; Q80WW1;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Interleukin-1 receptor-associated kinase 4;
DE Short=IRAK-4;
DE EC=2.7.11.1;
GN Name=Irak4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ;
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 [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Skin;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP DISRUPTION PHENOTYPE.
RX PubMed=11923871; DOI=10.1038/nature736;
RA Suzuki N., Suzuki S., Duncan G.S., Millar D.G., Wada T., Mirtsos C.,
RA Takada H., Wakeham A., Itie A., Li S., Penninger J.M., Wesche H.,
RA Ohashi P.S., Mak T.W., Yeh W.C.;
RT "Severe impairment of interleukin-1 and Toll-like receptor signalling in
RT mice lacking IRAK-4.";
RL Nature 416:750-756(2002).
RN [5]
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=21396111; DOI=10.1186/1478-811x-9-6;
RA Dufner A., Schamel W.W.;
RT "B cell antigen receptor-induced activation of an IRAK4-dependent signaling
RT pathway revealed by a MALT1-IRAK4 double knockout mouse model.";
RL Cell Commun. Signal. 9:6-6(2011).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 1-113.
RX PubMed=16177054; DOI=10.4049/jimmunol.175.7.4175;
RA Lasker M.V., Gajjar M.M., Nair S.K.;
RT "Molecular structure of the IL-1R-associated kinase-4 death domain and its
RT implications for TLR signaling.";
RL J. Immunol. 175:4175-4179(2005).
RN [9]
RP STRUCTURE BY NMR OF 1-114.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the death domain of interleukin-1 receptor-
RT associated kinase 4 (IRAK4) from Mus musculus.";
RL Submitted (NOV-2004) to the PDB data bank.
CC -!- FUNCTION: Serine/threonine-protein kinase that plays a critical role in
CC initiating innate immune response against foreign pathogens. Involved
CC in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly
CC recruited by MYD88 to the receptor-signaling complex upon TLR
CC activation to form the Myddosome together with IRAK2. Phosphorylates
CC initially IRAK1, thus stimulating the kinase activity and intensive
CC autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases
CC Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated
CC polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of
CC IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the
CC IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In
CC turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to
CC NF-kappa-B nuclear translocation and activation. Alternatively,
CC phosphorylates TIRAP to promote its ubiquitination and subsequent
CC degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation
CC after LPS stimulation suggesting a similar mechanism during microbial
CC infections (By similarity). {ECO:0000250}.
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; Evidence={ECO:0000250};
CC -!- SUBUNIT: Associates with MYD88 and IRAK2 to form a ternary complex
CC called the Myddosome (PubMed:16951688). Once phosphorylated, IRAK4
CC dissociates from the receptor complex and then associates with the TNF
CC receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this
CC intermediate complex is required for subsequent NF-kappa-B activation
CC (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex
CC formation and hence negatively regulates IL1R-TLR signaling and
CC eventually NF-kappa-B-mediated gene expression (By similarity).
CC Interacts with IL1RL1 (By similarity). Interacts (when phosphorylated)
CC with IRAK1 (By similarity). May interact (when phosphorylated) with
CC IRAK3 (By similarity). {ECO:0000250|UniProtKB:Q9NWZ3,
CC ECO:0000269|PubMed:16951688}.
CC -!- INTERACTION:
CC Q8R4K2; Q8K4B2: Irak3; NbExp=7; IntAct=EBI-3842721, EBI-646179;
CC Q8R4K2; P22366: Myd88; NbExp=8; IntAct=EBI-3842721, EBI-525108;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- PTM: Phosphorylated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mice are strongly altered in their responses to
CC viral and bacterial challenges due to a severe impairment of
CC interleukin-1 and Toll-like receptor signaling pathways. Malt1 and
CC Irak4 double knockout suggests an additional role of Irak4 in B-cell
CC antigen receptor (BCR) mediated signaling pathway, since the double
CC mutant inhibits B-cell proliferation. {ECO:0000269|PubMed:11923871,
CC ECO:0000269|PubMed:21396111}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily. {ECO:0000305}.
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DR EMBL; AF445803; AAM15773.1; -; mRNA.
DR EMBL; AK028837; BAC26146.1; -; mRNA.
DR EMBL; BC051676; AAH51676.1; -; mRNA.
DR CCDS; CCDS27772.1; -.
DR RefSeq; NP_084202.2; NM_029926.5.
DR PDB; 1WH4; NMR; -; A=1-114.
DR PDB; 2A9I; X-ray; 1.70 A; A=1-113.
DR PDBsum; 1WH4; -.
DR PDBsum; 2A9I; -.
DR AlphaFoldDB; Q8R4K2; -.
DR BMRB; Q8R4K2; -.
DR SMR; Q8R4K2; -.
DR BioGRID; 234465; 6.
DR DIP; DIP-48996N; -.
DR IntAct; Q8R4K2; 9.
DR MINT; Q8R4K2; -.
DR STRING; 10090.ENSMUSP00000074471; -.
DR BindingDB; Q8R4K2; -.
DR ChEMBL; CHEMBL4630844; -.
DR iPTMnet; Q8R4K2; -.
DR PhosphoSitePlus; Q8R4K2; -.
DR EPD; Q8R4K2; -.
DR MaxQB; Q8R4K2; -.
DR PaxDb; Q8R4K2; -.
DR PRIDE; Q8R4K2; -.
DR ProteomicsDB; 269095; -.
DR Antibodypedia; 696; 790 antibodies from 43 providers.
DR DNASU; 266632; -.
DR Ensembl; ENSMUST00000074936; ENSMUSP00000074471; ENSMUSG00000059883.
DR GeneID; 266632; -.
DR KEGG; mmu:266632; -.
DR UCSC; uc007xjj.2; mouse.
DR CTD; 51135; -.
DR MGI; MGI:2182474; Irak4.
DR VEuPathDB; HostDB:ENSMUSG00000059883; -.
DR eggNOG; KOG1187; Eukaryota.
DR GeneTree; ENSGT00940000158792; -.
DR HOGENOM; CLU_000288_21_15_1; -.
DR InParanoid; Q8R4K2; -.
DR OMA; WHQRCLI; -.
DR OrthoDB; 684563at2759; -.
DR PhylomeDB; Q8R4K2; -.
DR TreeFam; TF351380; -.
DR Reactome; R-MMU-1257604; PIP3 activates AKT signaling.
DR Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-MMU-9020702; Interleukin-1 signaling.
DR BioGRID-ORCS; 266632; 0 hits in 75 CRISPR screens.
DR ChiTaRS; Irak4; mouse.
DR EvolutionaryTrace; Q8R4K2; -.
DR PRO; PR:Q8R4K2; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q8R4K2; protein.
DR Bgee; ENSMUSG00000059883; Expressed in granulocyte and 135 other tissues.
DR ExpressionAtlas; Q8R4K2; baseline and differential.
DR Genevisible; Q8R4K2; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
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; IPI:MGI.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:MGI.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:MGI.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0007254; P:JNK cascade; ISO:MGI.
DR GO; GO:0002446; P:neutrophil mediated immunity; ISS:UniProtKB.
DR GO; GO:1990266; P:neutrophil migration; ISS:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
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 Pfam; PF00069; Pkinase; 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; ATP-binding; Cytoplasm; Immunity;
KW Innate immunity; Kinase; Magnesium; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..459
FT /note="Interleukin-1 receptor-associated kinase 4"
FT /id="PRO_0000086036"
FT DOMAIN 20..104
FT /note="Death"
FT DOMAIN 186..454
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 115..161
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
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 /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 313..316
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 329
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWZ3"
FT MOD_RES 34
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWZ3"
FT MOD_RES 342
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWZ3"
FT MOD_RES 345
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWZ3"
FT MOD_RES 346
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NWZ3"
FT CONFLICT 321
FT /note="K -> R (in Ref. 3; AAH51676)"
FT /evidence="ECO:0000305"
FT HELIX 11..13
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 16..26
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 28..30
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 31..38
FT /evidence="ECO:0007829|PDB:2A9I"
FT STRAND 44..48
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 50..58
FT /evidence="ECO:0007829|PDB:2A9I"
FT TURN 59..63
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 66..74
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 75..77
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 81..90
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 94..100
FT /evidence="ECO:0007829|PDB:2A9I"
FT HELIX 102..104
FT /evidence="ECO:0007829|PDB:2A9I"
SQ SEQUENCE 459 AA; 50872 MW; FC11AD06983B7AEB CRC64;
MNKPLTPSTY IRNLNVGILR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ FHIRRFEALL
QTGKSPTCEL LFDWGTTNCT VGDLVDLLVQ IELFAPATLL LPDAVPQTVK SLPPREAATV
AQTHGPCQEK DRTSVMPMPK LEHSCEPPDS SSPDNRSVES SDTRFHSFSF HELKSITNNF
DEQPASAGGN RMGEGGFGVV YKGCVNNTIV AVKKLGAMVE ISTEELKQQF DQEIKVMATC
QHENLVELLG FSSDSDNLCL VYAYMPNGSL LDRLSCLDGT PPLSWHTRCK VAQGTANGIR
FLHENHHIHR DIKSANILLD KDFTAKISDF GLARASARLA QTVMTSRIVG TTAYMAPEAL
RGEITPKSDI YSFGVVLLEL ITGLAAVDEN REPQLLLDIK EEIEDEEKTI EDYTDEKMSD
ADPASVEAMY SAASQCLHEK KNRRPDIAKV QQLLQEMSA
