ID:IRAK4_HUMAN DESCRIPTION: RecName: Full=Interleukin-1 receptor-associated kinase 4; Short=IRAK-4; EC=2.7.11.1; AltName: Full=Renal carcinoma antigen NY-REN-64; FUNCTION: Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor- signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Magnesium. BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=650 uM for ATP (at pH 7.5); KM=1100 uM for substrate (at pH 7.5); SUBUNIT: Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor- associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Interacts with IL1RL1. INTERACTION: Q9HAT8:PELI2; NbExp=3; IntAct=EBI-448378, EBI-448407; P58753:TIRAP; NbExp=2; IntAct=EBI-448378, EBI-528644; SUBCELLULAR LOCATION: Cytoplasm. PTM: Phosphorylated (By similarity). DISEASE: Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. DISEASE: Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:607676]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. SIMILARITY: Contains 1 death domain. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=IRAK4base; Note=IRAK4 mutation db; URL="http://bioinf.uta.fi/IRAK4base/"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/irak4/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9NWZ3
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
AK304583 - Homo sapiens cDNA FLJ50376 complete cds, highly similar to Interleukin-1 receptor-associated kinase 4 (EC 2.7.11.1). JB406689 - Sequence 15 from Patent WO2012072685. AK299944 - Homo sapiens cDNA FLJ50856 complete cds, highly similar to Interleukin-1 receptor-associated kinase 4 (EC 2.7.11.1). AK027301 - Homo sapiens cDNA FLJ14395 fis, clone HEMBA1003250. AK314288 - Homo sapiens cDNA, FLJ95044, highly similar to Homo sapiens interleukin-1 receptor-associated kinase 4 (IRAK4), mRNA. BC013316 - Homo sapiens interleukin-1 receptor-associated kinase 4, mRNA (cDNA clone MGC:13330 IMAGE:4287014), complete cds. AY340962 - Homo sapiens interleukin-1 receptor-associated kinase 4 (IRAK4) mRNA, complete cds; alternatively spliced. AY340963 - Homo sapiens interleukin-1 receptor-associated kinase 4 variant (IRAK4) mRNA, complete cds; alternatively spliced. AY340964 - Homo sapiens interleukin-1 receptor-associated kinase 4 short form variant 1 (IRAK4) mRNA, complete cds; alternatively spliced. AY340965 - Homo sapiens interleukin-1 receptor-associated kinase 4 short form variant 2 (IRAK4) mRNA, complete cds; alternatively spliced. AY340966 - Homo sapiens interleukin-1 receptor-associated kinase 4 short form variant 3 (IRAK4) mRNA, complete cds; alternatively spliced. AY340967 - Homo sapiens interleukin-1 receptor-associated kinase 4 short form variant 4 (IRAK4) mRNA, complete cds; alternatively spliced. AF155118 - Homo sapiens putative protein kinase NY-REN-64 antigen mRNA, complete cds. AK000528 - Homo sapiens cDNA FLJ20521 fis, clone KAT10395. CU680562 - Synthetic construct Homo sapiens gateway clone IMAGE:100018314 5' read IRAK4 mRNA. KU178631 - Homo sapiens interleukin-1 receptor-associated kinase 4 isoform 1 (IRAK4) mRNA, partial cds. KU178632 - Homo sapiens interleukin-1 receptor-associated kinase 4 isoform 2 (IRAK4) mRNA, complete cds. DQ896134 - Synthetic construct Homo sapiens clone IMAGE:100010594; FLH190644.01L; RZPDo839C0766D interleukin-1 receptor-associated kinase 4 (IRAK4) gene, encodes complete protein. DQ892885 - Synthetic construct clone IMAGE:100005515; FLH190648.01X; RZPDo839C0776D interleukin-1 receptor-associated kinase 4 (IRAK4) gene, encodes complete protein. KJ898836 - Synthetic construct Homo sapiens clone ccsbBroadEn_08230 IRAK4 gene, encodes complete protein. KJ905467 - Synthetic construct Homo sapiens clone ccsbBroadEn_15060 IRAK4 gene, encodes complete protein. AF445802 - Homo sapiens interleukin-1 receptor associated kinase 4 (IRAK4) mRNA, complete cds. AY283670 - Homo sapiens interleukin-1 receptor associated kinase 4 mutant form 1 (IRAK4) mRNA, complete cds. AY283671 - Homo sapiens interleukin-1 receptor associated kinase 4 mutant form 2 (IRAK4) mRNA, complete cds. AY730682 - Homo sapiens interleukin-1 receptor associated kinase-4 (IRAK4) mRNA, complete cds. JD297783 - Sequence 278807 from Patent EP1572962. JD305740 - Sequence 286764 from Patent EP1572962. JD506150 - Sequence 487174 from Patent EP1572962. JD242263 - Sequence 223287 from Patent EP1572962. JD113913 - Sequence 94937 from Patent EP1572962. JD486629 - Sequence 467653 from Patent EP1572962. JD263339 - Sequence 244363 from Patent EP1572962. JD047065 - Sequence 28089 from Patent EP1572962. JD491032 - Sequence 472056 from Patent EP1572962. JD132470 - Sequence 113494 from Patent EP1572962. JD188489 - Sequence 169513 from Patent EP1572962. JD226243 - Sequence 207267 from Patent EP1572962. JD550036 - Sequence 531060 from Patent EP1572962. JD503821 - Sequence 484845 from Patent EP1572962. JD158408 - Sequence 139432 from Patent EP1572962. JD283374 - Sequence 264398 from Patent EP1572962. JD231924 - Sequence 212948 from Patent EP1572962. JD279094 - Sequence 260118 from Patent EP1572962. JD543086 - Sequence 524110 from Patent EP1572962. JD478427 - Sequence 459451 from Patent EP1572962. JD463652 - Sequence 444676 from Patent EP1572962. JD147987 - Sequence 129011 from Patent EP1572962. JD516211 - Sequence 497235 from Patent EP1572962. JD516212 - Sequence 497236 from Patent EP1572962. JD110243 - Sequence 91267 from Patent EP1572962. JD421848 - Sequence 402872 from Patent EP1572962. JD533646 - Sequence 514670 from Patent EP1572962. JD286850 - Sequence 267874 from Patent EP1572962. JD286851 - Sequence 267875 from Patent EP1572962. JD144735 - Sequence 125759 from Patent EP1572962. JD294148 - Sequence 275172 from Patent EP1572962. JD441846 - Sequence 422870 from Patent EP1572962. JD441847 - Sequence 422871 from Patent EP1572962. JD424703 - Sequence 405727 from Patent EP1572962. JD203299 - Sequence 184323 from Patent EP1572962. JD169054 - Sequence 150078 from Patent EP1572962. JD169055 - Sequence 150079 from Patent EP1572962. JD040972 - Sequence 21996 from Patent EP1572962. JD319962 - Sequence 300986 from Patent EP1572962. JD384092 - Sequence 365116 from Patent EP1572962. JD384093 - Sequence 365117 from Patent EP1572962. JD384094 - Sequence 365118 from Patent EP1572962. JD408218 - Sequence 389242 from Patent EP1572962. JD395496 - Sequence 376520 from Patent EP1572962. JD408219 - Sequence 389243 from Patent EP1572962. JD425137 - Sequence 406161 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein Q9NWZ3 (Reactome details) participates in the following event(s):
R-HSA-166082 IRAK4 binds to the activated TLR receptor:Mal:MyD88 complex R-HSA-446648 IL1R1:IL1:IL1RAP:MYD88 homodimer binds IRAK4 R-HSA-975156 IRAK4 binds to the activated TLR7/8 or 9 receptor:MyD88 complex R-HSA-975873 IRAK4 binds to MyD88 bound to the activated TLR5 or 10 receptor R-HSA-446894 TRAF6 binding leads to IRAK1:TRAF6 release R-HSA-446868 The Interleukin 1 receptor complex binds Tollip R-HSA-450690 hp-IRAK1,hp-IRAK4 bind Pellino1,2,3 R-HSA-446692 IRAK1 binds to MYD88 within the IL1R complex R-HSA-446634 IRAK4 is activated by autophosphorylation R-HSA-166091 IRAK1 or IRAK2 binds to the activated IRAK4 :activated TLR:MyD88:Mal complex R-HSA-166362 Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-937022 IRAK4 autophosphorylation in the complex with activated TLR:MyD88:Mal R-HSA-2262775 Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-975852 IRAK1/or IRAK2 binds to the activated IRAK4 :oligo MyD88:activated TLR5 or 10 complex R-HSA-975865 IRAK4 autophosphorylation within the complex activated TLR:MyD88 R-HSA-975879 Dissociation of hp-IRAK1:TRAF6 or IRAK2:TRAF6-oligomer from the activated TLR5 or 10:oligo-Myd88:p-IRAK4 complex R-HSA-975115 IRAK1/or IRAK2 binds to the activated IRAK4 :MyD88:activated TLR 7/8 or 9. R-HSA-975100 Dissociation of hp-IRAK1/or IRAK2:TRAF6-oligomer from the p-IRAK4 :oligo-Myd88:activated TLR7/8 or 9 complex R-HSA-975170 IRAK4 autophosphorylation in the complex with MyD88:activated TLR 7/8 or 9 R-HSA-446701 IRAK4-activated IRAK1 autophosphorylates R-HSA-446694 IRAK4 phosphorylates IRAK1 R-HSA-446862 Hyperphosphorylated IRAK1 associates with TRAF6 R-HSA-166284 Second phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal R-HSA-166119 First phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal R-HSA-166363 TRAF6 binds to hp- IRAK1 R-HSA-166286 Multiple IRAK1 autophosphorylation steps R-HSA-937059 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:Mal:activated TLR complex R-HSA-2262777 TRAF6 binds to p-IRAK2 R-HSA-975861 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomerl:activated TLR5 or 10 complex R-HSA-975878 First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR R-HSA-975874 Second phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR complex R-HSA-975853 Multiple IRAK1 autophosphorylation within the complex p-IRAK4:oligo MyD88:activated TLR R-HSA-975857 TRAF6 binds to hp- IRAK1 or p-IRAK2 R-HSA-975125 Multiple IRAK1 autophosphorylation steps within the complex pIRAK4:MyD88:activated TLR7/8 or 9 R-HSA-975134 Second phosphorylation of IRAK1 by IRAK4 bound to MyD88: activated TLR 7/8 or 9 R-HSA-975180 First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR 7/8 or 9 R-HSA-975160 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:activated TLR 7/8 or 9 R-HSA-975111 TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9 R-HSA-975188 TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation R-HSA-975106 Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation R-HSA-975118 TRAF6 ubiquitinqtes IRF7 in a K63-dependent manner following TLR7/8 or 9 stimulation R-HSA-166058 MyD88:Mal cascade initiated on plasma membrane R-HSA-9020702 Interleukin-1 signaling R-HSA-975155 MyD88 dependent cascade initiated on endosome R-HSA-975871 MyD88 cascade initiated on plasma membrane R-HSA-5603037 IRAK4 deficiency (TLR5) R-HSA-5603041 IRAK4 deficiency (TLR2/4) R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade R-HSA-168179 Toll Like Receptor TLR1:TLR2 Cascade R-HSA-168188 Toll Like Receptor TLR6:TLR2 Cascade R-HSA-446652 Interleukin-1 family signaling R-HSA-168138 Toll Like Receptor 9 (TLR9) Cascade R-HSA-168181 Toll Like Receptor 7/8 (TLR7/8) Cascade R-HSA-168142 Toll Like Receptor 10 (TLR10) Cascade R-HSA-168176 Toll Like Receptor 5 (TLR5) Cascade R-HSA-975138 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation R-HSA-5602358 Diseases associated with the TLR signaling cascade R-HSA-168898 Toll-Like Receptors Cascades R-HSA-181438 Toll Like Receptor 2 (TLR2) Cascade R-HSA-449147 Signaling by Interleukins R-HSA-5260271 Diseases of Immune System R-HSA-168249 Innate Immune System R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-975110 TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling R-HSA-1643685 Disease R-HSA-168256 Immune System
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
