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MGP001646

UniProt Annotations

Entry Information
Gene Nameinterleukin-1 receptor-associated kinase 1
Protein EntryIRAK1_HUMAN
UniProt IDP51617
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=4; Name=1; Synonyms=a; IsoId=P51617-1; Sequence=Displayed; Name=2; Synonyms=b; IsoId=P51617-2; Sequence=VSP_011851; Note=Inactive.; Name=3; IsoId=P51617-3; Sequence=VSP_011849, VSP_011850, VSP_011851; Note=No experimental confirmation available.; Name=4; IsoId=P51617-4; Sequence=VSP_041950;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
CofactorName=Mg(2+); Xref=ChEBI:CHEBI:18420;
DomainThe ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation. {ECO:0000269|PubMed:14625308}.
FunctionSerine/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. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. 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 the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}.
InteractionQ15306:IRF4; NbExp=2; IntAct=EBI-358664, EBI-751345; Q92985:IRF7; NbExp=2; IntAct=EBI-358664, EBI-968267; Q99836:MYD88; NbExp=2; IntAct=EBI-358664, EBI-447677; Q96FA3:PELI1; NbExp=3; IntAct=EBI-358664, EBI-448369; Q9HAT8:PELI2; NbExp=3; IntAct=EBI-358664, EBI-448407; Q13526:PIN1; NbExp=10; IntAct=EBI-358664, EBI-714158; P58753:TIRAP; NbExp=2; IntAct=EBI-358664, EBI-528644; Q86WV6:TMEM173; NbExp=2; IntAct=EBI-358664, EBI-2800345; Q9Y4K3:TRAF6; NbExp=2; IntAct=EBI-358664, EBI-359276; Q8VCW4:Unc93b1 (xeno); NbExp=2; IntAct=EBI-358664, EBI-6116986; Q5D1E7:Zc3h12a (xeno); NbExp=3; IntAct=EBI-358664, EBI-5326026;
PtmFollowing recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity. {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:14625308, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:18691976}.
PtmPolyubiquitinated by TRAF6 after cell stimulation with IL-1- beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation. {ECO:0000269|PubMed:16690127, ECO:0000269|PubMed:18347055, ECO:0000269|PubMed:19675569}.
SimilarityBelongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. {ECO:0000305}.
SimilarityContains 1 death domain. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm {ECO:0000269|PubMed:16690127}. Nucleus {ECO:0000269|PubMed:16690127}. Lipid droplet {ECO:0000250}. Note=Translocates to the nucleus when sumoylated. RSAD2/viperin recruits it to the lipid droplet (By similarity). {ECO:0000250}.
SubunitHomodimer (By similarity). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation. Interacts with IL1RL1. Forms a complex with TRAF6, PELI1, IRAK4 and MYD88. Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex. The TRAF6-PELI1-IRAK1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Interacts with IRAK1BP1 (By similarity). Interacts (when polyubiquitinated) with IKBKG/NEMO. Interacts with RSAD2/viperin (By similarity). {ECO:0000250}.
Tissue SpecificityIsoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2. {ECO:0000269|PubMed:11397809}.
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