ID:IRAK1_HUMAN DESCRIPTION: RecName: Full=Interleukin-1 receptor-associated kinase 1; Short=IRAK-1; EC=2.7.11.1; 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. 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. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Magnesium. SUBUNIT: Homodimer (By similarity). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation. Interacts with MYD88; this interaction recruits IRAK1 to the stimulated receptor complex. Interacts with IL1RL1. Interacts with IRAK1BP1 (By similarity). Associates with TRAF6, PELI1 and IRAK4; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF- kappa-B activation. Interacts (when polyubiquitinated) with IKBKG/NEMO. Interacts with RSAD2/viperin (By similarity). INTERACTION: O43187:IRAK2; NbExp=3; IntAct=EBI-358664, EBI-447733; Q9Y616:IRAK3; NbExp=3; IntAct=EBI-358664, EBI-447690; Q15306:IRF4; NbExp=2; IntAct=EBI-358664, EBI-751345; Q92985:IRF7; NbExp=2; IntAct=EBI-358664, EBI-968267; Q9HAT8:PELI2; NbExp=2; 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=3; 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; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Lipid droplet (By similarity). Note=Translocates to the nucleus when sumoylated. RSAD2/viperin recruits it to the lipid droplet (By similarity). TISSUE SPECIFICITY: Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2. DOMAIN: The 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. PTM: Following 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. PTM: Polyubiquitinated 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. 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.
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.
Pfam Domains: PF00069 - Protein kinase domain PF00531 - Death domain PF07714 - Protein tyrosine and serine/threonine kinase
SCOP Domains: 47986 - DEATH domain 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on P51617
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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.
LF211533 - JP 2014500723-A/19036: Polycomb-Associated Non-Coding RNAs. BC014963 - Homo sapiens interleukin-1 receptor-associated kinase 1, mRNA (cDNA clone MGC:23051 IMAGE:4906853), complete cds. JB406685 - Sequence 11 from Patent WO2012072685. BC054000 - Homo sapiens interleukin-1 receptor-associated kinase 1, mRNA (cDNA clone MGC:61493 IMAGE:6164719), complete cds. L76191 - Homo sapiens interleukin-1 receptor-associated kinase (IRAK) mRNA, complete cds. JD384268 - Sequence 365292 from Patent EP1572962. JD186126 - Sequence 167150 from Patent EP1572962. JD561249 - Sequence 542273 from Patent EP1572962. JD304250 - Sequence 285274 from Patent EP1572962. JD191664 - Sequence 172688 from Patent EP1572962. JD436895 - Sequence 417919 from Patent EP1572962. LF380818 - JP 2014500723-A/188321: Polycomb-Associated Non-Coding RNAs. JD457254 - Sequence 438278 from Patent EP1572962. JD459918 - Sequence 440942 from Patent EP1572962. JD141695 - Sequence 122719 from Patent EP1572962. JD310713 - Sequence 291737 from Patent EP1572962. JD024176 - Sequence 5200 from Patent EP1572962. JD030334 - Sequence 11358 from Patent EP1572962. JD306556 - Sequence 287580 from Patent EP1572962. JD437993 - Sequence 419017 from Patent EP1572962. JD268481 - Sequence 249505 from Patent EP1572962. JD088874 - Sequence 69898 from Patent EP1572962. JD377782 - Sequence 358806 from Patent EP1572962. JD445139 - Sequence 426163 from Patent EP1572962. JD201767 - Sequence 182791 from Patent EP1572962. JD273708 - Sequence 254732 from Patent EP1572962. JD354876 - Sequence 335900 from Patent EP1572962. JD553210 - Sequence 534234 from Patent EP1572962. JD296453 - Sequence 277477 from Patent EP1572962. JD093580 - Sequence 74604 from Patent EP1572962. JD472274 - Sequence 453298 from Patent EP1572962. JD278829 - Sequence 259853 from Patent EP1572962. JD466524 - Sequence 447548 from Patent EP1572962. JD424215 - Sequence 405239 from Patent EP1572962. JD100583 - Sequence 81607 from Patent EP1572962. JD452300 - Sequence 433324 from Patent EP1572962. JD502493 - Sequence 483517 from Patent EP1572962. JD319170 - Sequence 300194 from Patent EP1572962. JD384132 - Sequence 365156 from Patent EP1572962. JD511446 - Sequence 492470 from Patent EP1572962. JD491636 - Sequence 472660 from Patent EP1572962. JD286586 - Sequence 267610 from Patent EP1572962. JD511445 - Sequence 492469 from Patent EP1572962. JD540575 - Sequence 521599 from Patent EP1572962. JD523678 - Sequence 504702 from Patent EP1572962. JD361908 - Sequence 342932 from Patent EP1572962. JD188822 - Sequence 169846 from Patent EP1572962. JD127221 - Sequence 108245 from Patent EP1572962. JD187605 - Sequence 168629 from Patent EP1572962. JD104366 - Sequence 85390 from Patent EP1572962. JD388657 - Sequence 369681 from Patent EP1572962. JD442292 - Sequence 423316 from Patent EP1572962. JD465617 - Sequence 446641 from Patent EP1572962. JD474444 - Sequence 455468 from Patent EP1572962. JD475055 - Sequence 456079 from Patent EP1572962. LF380819 - JP 2014500723-A/188322: Polycomb-Associated Non-Coding RNAs. JD195862 - Sequence 176886 from Patent EP1572962. FW573285 - JP 2010529847-A/6: Oligonucleotides for modulation of target RNA activity. JD287695 - Sequence 268719 from Patent EP1572962. AF346607 - Homo sapiens interleukin-1 receptor associated kinase 1b (IRAK) mRNA, complete cds, alternatively spliced. DQ054788 - Homo sapiens interleukin-1 receptor associated-kinase 1 splice variant c (IRAK1) mRNA, complete cds, alternatively spliced. EU831427 - Synthetic construct Homo sapiens clone HAIB:100066456; DKFZo008C0217 interleukin-1 receptor-associated kinase 1 protein (IRAK1) gene, encodes complete protein. EU831520 - Synthetic construct Homo sapiens clone HAIB:100066549; DKFZo004C0218 interleukin-1 receptor-associated kinase 1 protein (IRAK1) gene, encodes complete protein. AM392624 - Synthetic construct Homo sapiens clone IMAGE:100002476 for hypothetical protein (IRAK1 gene). AM393211 - Synthetic construct Homo sapiens clone IMAGE:100002478 for hypothetical protein (IRAK1 gene). AB463802 - Synthetic construct DNA, clone: pF1KB8352, Homo sapiens IRAK1 gene for interleukin-1 receptor-associated kinase 1, without stop codon, in Flexi system. LF380820 - JP 2014500723-A/188323: Polycomb-Associated Non-Coding RNAs. LF380821 - JP 2014500723-A/188324: Polycomb-Associated Non-Coding RNAs. LF380822 - JP 2014500723-A/188325: Polycomb-Associated Non-Coding RNAs. LF380823 - JP 2014500723-A/188326: Polycomb-Associated Non-Coding RNAs. LF380824 - JP 2014500723-A/188327: Polycomb-Associated Non-Coding RNAs. LF380826 - JP 2014500723-A/188329: Polycomb-Associated Non-Coding RNAs. LF380830 - JP 2014500723-A/188333: Polycomb-Associated Non-Coding RNAs. MA447110 - JP 2018138019-A/19036: Polycomb-Associated Non-Coding RNAs. MA616395 - JP 2018138019-A/188321: Polycomb-Associated Non-Coding RNAs. MA616396 - JP 2018138019-A/188322: Polycomb-Associated Non-Coding RNAs. MA616397 - JP 2018138019-A/188323: Polycomb-Associated Non-Coding RNAs. MA616398 - JP 2018138019-A/188324: Polycomb-Associated Non-Coding RNAs. MA616399 - JP 2018138019-A/188325: Polycomb-Associated Non-Coding RNAs. MA616400 - JP 2018138019-A/188326: Polycomb-Associated Non-Coding RNAs. MA616401 - JP 2018138019-A/188327: Polycomb-Associated Non-Coding RNAs. MA616403 - JP 2018138019-A/188329: Polycomb-Associated Non-Coding RNAs. MA616407 - JP 2018138019-A/188333: Polycomb-Associated Non-Coding RNAs.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_il1rPathway - Signal transduction through IL1R
Reactome (by CSHL, EBI, and GO)
Protein P51617 (Reactome details) participates in the following event(s):
R-HSA-209543 p75NTR recruits signalling complexes R-HSA-193639 p75NTR signals via NF-kB R-HSA-193704 p75 NTR receptor-mediated signalling R-HSA-73887 Death Receptor Signalling R-HSA-162582 Signal Transduction R-HSA-446692 IRAK1 binds to MYD88 within the IL1R complex R-HSA-451561 NEMO binds polyubiquitinated IRAK1 R-HSA-166286 Multiple IRAK1 autophosphorylation steps R-HSA-166284 Second phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal R-HSA-975853 Multiple IRAK1 autophosphorylation within the complex p-IRAK4:oligo MyD88:activated TLR R-HSA-975874 Second phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR complex R-HSA-193686 p75NTR interacts with IRAK:MYD88 R-HSA-446694 IRAK4 phosphorylates IRAK1 R-HSA-166091 IRAK1 or IRAK2 binds to the activated IRAK4 :activated TLR:MyD88:Mal complex R-HSA-975115 IRAK1/or IRAK2 binds to the activated IRAK4 :MyD88:activated TLR 7/8 or 9. R-HSA-975852 IRAK1/or IRAK2 binds to the activated IRAK4 :oligo MyD88:activated TLR5 or 10 complex R-HSA-446862 Hyperphosphorylated IRAK1 associates with TRAF6 R-HSA-446701 IRAK4-activated IRAK1 autophosphorylates R-HSA-450173 IRAK1 induces oligomerisation of TRAF6 R-HSA-446894 TRAF6 binding leads to IRAK1:TRAF6 release R-HSA-450690 hp-IRAK1,hp-IRAK4 bind Pellino1,2,3 R-HSA-937032 NEMO subunit of IKK complex binds to activated IRAK1 R-HSA-937050 Pellino ubiquitinates hp-IRAK1 R-HSA-166363 TRAF6 binds to hp- IRAK1 R-HSA-937044 Pellino binds hp-IRAK1:TRAF6 R-HSA-166362 Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex R-HSA-166119 First phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal R-HSA-975878 First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR R-HSA-975119 NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of TLR7/8 or 9. R-HSA-975122 Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation
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-975142 Pellino binds hp-IRAK1:TRAF6 upon TLR7/8 or 9 activation R-HSA-193703 IKKbeta is activated R-HSA-193694 p62 is recruited and forms a complex with TRAF6 R-HSA-193665 MYD88 dissociates R-HSA-193695 IRAK interacts with TRAF6 R-HSA-193647 IRAK is activated R-HSA-8948015 hp-IRAK1:3xTRAF6 binds UBE2N:UBE2V1:K63-polyUb R-HSA-446877 TRAF6 is K63 poly-ubiquitinated R-HSA-446870 Polyubiquitinated TRAF6 binds the TAK1 complex R-HSA-451418 Pellino ubiquitinates IRAK1 R-HSA-937034 IRAK1 phosphorylates Pellino 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-975857 TRAF6 binds to hp- IRAK1 or p-IRAK2 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-975139 IRAK1 phosphorylates Pellino upon TLR7/8 or 9 activation 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-975111 TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9 R-HSA-193705 IKKbeta phosphorylates IkB causing NF-kB to dissociate R-HSA-193641 IKK-beta is recruited R-HSA-193684 p62 recruits an atypical PKC R-HSA-975118 TRAF6 ubiquitinqtes IRF7 in a K63-dependent manner following TLR7/8 or 9 stimulation R-HSA-168184 Activated TAK1 mediates phosphorylation of the IKK Complex R-HSA-450337 Activated TAK1 phosphorylates MKK4/MKK7 R-HSA-450346 activated human TAK1 phosphorylates MKK3/MKK6 R-HSA-9020702 Interleukin-1 signaling R-HSA-166058 MyD88:Mal cascade initiated on plasma membrane R-HSA-975871 MyD88 cascade initiated on plasma membrane R-HSA-209543 p75NTR recruits signalling complexes R-HSA-975155 MyD88 dependent cascade initiated on endosome R-HSA-446652 Interleukin-1 family signaling R-HSA-937039 IRAK1 recruits IKK complex R-HSA-975144 IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation R-HSA-209560 NF-kB is activated and signals survival 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-168142 Toll Like Receptor 10 (TLR10) Cascade R-HSA-168176 Toll Like Receptor 5 (TLR5) Cascade R-HSA-193639 p75NTR signals via NF-kB R-HSA-168138 Toll Like Receptor 9 (TLR9) Cascade R-HSA-168181 Toll Like Receptor 7/8 (TLR7/8) Cascade R-HSA-449147 Signaling by Interleukins R-HSA-975138 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation R-HSA-975110 TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling R-HSA-168898 Toll-Like Receptors Cascades R-HSA-181438 Toll Like Receptor 2 (TLR2) Cascade R-HSA-193704 p75 NTR receptor-mediated signalling R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-168249 Innate Immune System R-HSA-73887 Death Receptor Signalling R-HSA-168256 Immune System R-HSA-162582 Signal Transduction R-HSA-168638 NOD1/2 Signaling Pathway R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex R-HSA-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 R-HSA-450302 activated TAK1 mediates p38 MAPK activation R-HSA-168643 Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways R-HSA-168164 Toll Like Receptor 3 (TLR3) Cascade R-HSA-937061 TRIF(TICAM1)-mediated TLR4 signaling R-HSA-450294 MAP kinase activation R-HSA-166166 MyD88-independent TLR4 cascade R-HSA-448424 Interleukin-17 signaling
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
