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P51617

- IRAK1_HUMAN

UniProt

P51617 - IRAK1_HUMAN

Protein

Interleukin-1 receptor-associated kinase 1

Gene

IRAK1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 154 (01 Oct 2014)
      Sequence version 2 (01 Dec 2000)
      Previous versions | rss
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    Functioni

    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 STAT3.8 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei239 – 2391ATP
    Active sitei340 – 3401Proton acceptorPROSITE-ProRule annotation
    Binding sitei358 – 3581ATPPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi218 – 2269ATPPROSITE-ProRule annotation
    Nucleotide bindingi342 – 3454ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. kinase activity Source: MGI
    3. NF-kappaB-inducing kinase activity Source: ProtInc
    4. protein binding Source: UniProtKB
    5. protein heterodimerization activity Source: BHF-UCL
    6. protein homodimerization activity Source: UniProtKB
    7. protein kinase activity Source: MGI
    8. protein serine/threonine kinase activity Source: UniProtKB
    9. ubiquitin-protein transferase activity Source: Reactome

    GO - Biological processi

    1. activation of MAPK activity Source: Reactome
    2. activation of NF-kappaB-inducing kinase activity Source: UniProtKB
    3. cellular response to hypoxia Source: Ensembl
    4. innate immune response Source: Reactome
    5. interleukin-1-mediated signaling pathway Source: BHF-UCL
    6. JNK cascade Source: Reactome
    7. lipopolysaccharide-mediated signaling pathway Source: BHF-UCL
    8. MyD88-dependent toll-like receptor signaling pathway Source: BHF-UCL
    9. MyD88-independent toll-like receptor signaling pathway Source: Reactome
    10. negative regulation of apoptotic process Source: Reactome
    11. negative regulation of NF-kappaB transcription factor activity Source: BHF-UCL
    12. neurotrophin TRK receptor signaling pathway Source: Reactome
    13. nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Source: Reactome
    14. nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
    15. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
    16. positive regulation of NF-kappaB transcription factor activity Source: BHF-UCL
    17. positive regulation of smooth muscle cell proliferation Source: Ensembl
    18. positive regulation of transcription, DNA-templated Source: UniProtKB
    19. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    20. protein autophosphorylation Source: UniProtKB
    21. protein oligomerization Source: UniProtKB
    22. protein phosphorylation Source: ProtInc
    23. protein ubiquitination Source: GOC
    24. regulation of cytokine-mediated signaling pathway Source: BHF-UCL
    25. response to interleukin-1 Source: BHF-UCL
    26. response to lipopolysaccharide Source: BHF-UCL
    27. response to peptidoglycan Source: Ensembl
    28. signal transduction Source: UniProtKB
    29. stress-activated MAPK cascade Source: Reactome
    30. toll-like receptor 10 signaling pathway Source: Reactome
    31. toll-like receptor 2 signaling pathway Source: BHF-UCL
    32. toll-like receptor 3 signaling pathway Source: Reactome
    33. toll-like receptor 4 signaling pathway Source: Reactome
    34. toll-like receptor 5 signaling pathway Source: Reactome
    35. toll-like receptor 9 signaling pathway Source: Reactome
    36. toll-like receptor signaling pathway Source: Reactome
    37. toll-like receptor TLR1:TLR2 signaling pathway Source: Reactome
    38. toll-like receptor TLR6:TLR2 signaling pathway Source: Reactome
    39. transmembrane receptor protein serine/threonine kinase signaling pathway Source: UniProtKB
    40. TRIF-dependent toll-like receptor signaling pathway Source: Reactome

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Immunity, Innate immunity

    Keywords - Ligandi

    ATP-binding, Magnesium, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.10.2. 2681.
    ReactomeiREACT_13415. p75NTR recruits signalling complexes.
    REACT_13696. NF-kB is activated and signals survival.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_21368. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_21399. activated TAK1 mediates p38 MAPK activation.
    REACT_22442. Interleukin-1 signaling.
    REACT_24918. IRAK1 recruits IKK complex.
    REACT_25024. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
    REACT_25120. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
    REACT_25222. MyD88 dependent cascade initiated on endosome.
    REACT_25354. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
    REACT_27215. MyD88 cascade initiated on plasma membrane.
    REACT_6788. MyD88:Mal cascade initiated on plasma membrane.
    REACT_75776. NOD1/2 Signaling Pathway.
    SignaLinkiP51617.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Interleukin-1 receptor-associated kinase 1 (EC:2.7.11.1)
    Short name:
    IRAK-1
    Gene namesi
    Name:IRAK1
    Synonyms:IRAK
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome X

    Organism-specific databases

    HGNCiHGNC:6112. IRAK1.

    Subcellular locationi

    Cytoplasm 1 Publication. Nucleus 1 Publication. Lipid droplet By similarity
    Note: Translocates to the nucleus when sumoylated. RSAD2/viperin recruits it to the lipid droplet By similarity.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: HPA
    2. cytosol Source: Reactome
    3. endosome membrane Source: Reactome
    4. interleukin-1 receptor complex Source: UniProtKB
    5. lipid particle Source: UniProtKB
    6. nucleus Source: HPA
    7. plasma membrane Source: Reactome

    Keywords - Cellular componenti

    Cytoplasm, Lipid droplet, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi209 – 2091T → A: Completely abolishes auto-phosphorylation in the kinase domain. 1 Publication
    Mutagenesisi239 – 2391K → S: Loss of kinase activity. 1 Publication
    Mutagenesisi387 – 3871T → A: Loss of kinase activity. 1 Publication

    Organism-specific databases

    Orphaneti93552. Pediatric systemic lupus erythematosus.
    536. Systemic lupus erythematosus.
    PharmGKBiPA29912.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 712712Interleukin-1 receptor-associated kinase 1PRO_0000086030Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei66 – 661Phosphothreonine; by PKC/PRKCI1 Publication
    Modified residuei131 – 1311Phosphoserine1 Publication
    Cross-linki134 – 134Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)2 Publications
    Cross-linki180 – 180Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)2 Publications
    Modified residuei209 – 2091Phosphothreonine; by IRAK41 Publication
    Modified residuei387 – 3871Phosphothreonine1 Publication

    Post-translational modificationi

    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.5 Publications
    Polyubiquitinated 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.3 Publications

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiP51617.
    PaxDbiP51617.
    PRIDEiP51617.

    PTM databases

    PhosphoSiteiP51617.

    Expressioni

    Tissue specificityi

    Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.1 Publication

    Gene expression databases

    ArrayExpressiP51617.
    BgeeiP51617.
    CleanExiHS_IRAK1.
    GenevestigatoriP51617.

    Organism-specific databases

    HPAiCAB004461.
    HPA054476.

    Interactioni

    Subunit structurei

    Homodimer 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.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    IRF4Q153062EBI-358664,EBI-751345
    IRF7Q929852EBI-358664,EBI-968267
    MYD88Q998362EBI-358664,EBI-447677
    PELI1Q96FA33EBI-358664,EBI-448369
    PELI2Q9HAT83EBI-358664,EBI-448407
    PIN1Q1352610EBI-358664,EBI-714158
    TIRAPP587532EBI-358664,EBI-528644
    TMEM173Q86WV62EBI-358664,EBI-2800345
    TRAF6Q9Y4K32EBI-358664,EBI-359276
    Unc93b1Q8VCW42EBI-358664,EBI-6116986From a different organism.
    Zc3h12aQ5D1E73EBI-358664,EBI-5326026From a different organism.

    Protein-protein interaction databases

    BioGridi109863. 85 interactions.
    DIPiDIP-397N.
    IntActiP51617. 26 interactions.
    MINTiMINT-97088.
    STRINGi9606.ENSP00000358997.

    Structurei

    3D structure databases

    ProteinModelPortaliP51617.
    SMRiP51617. Positions 18-102, 184-523.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini27 – 10680DeathAdd
    BLAST
    Domaini212 – 521310Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni110 – 211102ProST regionAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi649 – 6557Poly-Ser
    Compositional biasi688 – 6914Poly-Ser

    Domaini

    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.1 Publication

    Sequence similaritiesi

    Contains 1 death domain.Curated
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000015226.
    HOVERGENiHBG052144.
    InParanoidiP51617.
    KOiK04730.
    OMAiSPFCWPL.
    PhylomeDBiP51617.
    TreeFamiTF328924.

    Family and domain databases

    Gene3Di1.10.533.10. 1 hit.
    InterProiIPR011029. DEATH-like_dom.
    IPR000488. Death_domain.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00531. Death. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view]
    SUPFAMiSSF47986. SSF47986. 1 hit.
    SSF56112. SSF56112. 2 hits.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequences (4)i

    Sequence statusi: Complete.

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P51617-1) [UniParc]FASTAAdd to Basket

    Also known as: a

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV    50
    RDQTELRLCE RSGQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT 100
    AWHPPAPLPS PGTTAPRPSS IPAPAEAEAW SPRKLPSSAS TFLSPAFPGS 150
    QTHSGPELGL VPSPASLWPP PPSPAPSSTK PGPESSVSLL QGARPFPFCW 200
    PLCEISRGTH NFSEELKIGE GGFGCVYRAV MRNTVYAVKR LKENADLEWT 250
    AVKQSFLTEV EQLSRFRHPN IVDFAGYCAQ NGFYCLVYGF LPNGSLEDRL 300
    HCQTQACPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE 350
    RLTPKLGDFG LARFSRFAGS SPSQSSMVAR TQTVRGTLAY LPEEYIKTGR 400
    LAVDTDTFSF GVVVLETLAG QRAVKTHGAR TKYLKDLVEE EAEEAGVALR 450
    STQSTLQAGL AADAWAAPIA MQIYKKHLDP RPGPCPPELG LGLGQLACCC 500
    LHRRAKRRPP MTQVYERLEK LQAVVAGVPG HSEAASCIPP SPQENSYVSS 550
    TGRAHSGAAP WQPLAAPSGA SAQAAEQLQR GPNQPVESDE SLGGLSAALR 600
    SWHLTPSCPL DPAPLREAGC PQGDTAGESS WGSGPGSRPT AVEGLALGSS 650
    ASSSSEPPQI IINPARQKMV QKLALYEDGA LDSLQLLSSS SLPGLGLEQD 700
    RQGPEESDEF QS 712
    Length:712
    Mass (Da):76,537
    Last modified:December 1, 2000 - v2
    Checksum:iA7ADED75D3A3981D
    GO
    Isoform 2 (identifier: P51617-2) [UniParc]FASTAAdd to Basket

    Also known as: b

    The sequence of this isoform differs from the canonical sequence as follows:
         513-542: Missing.

    Note: Inactive.

    Show »
    Length:682
    Mass (Da):73,421
    Checksum:i687C7EB6064FA918
    GO
    Isoform 3 (identifier: P51617-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         45-45: F → FGGWRRAAGGREARGLLAPTPDAPRPA
         478-492: Missing.
         513-542: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:693
    Mass (Da):74,560
    Checksum:iD744A32E997E1246
    GO
    Isoform 4 (identifier: P51617-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         435-513: Missing.

    Show »
    Length:633
    Mass (Da):68,022
    Checksum:i419926E55C935F38
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti194 – 1941R → H.
    Corresponds to variant rs11465830 [ dbSNP | Ensembl ].
    VAR_051629
    Natural varianti196 – 1961F → S.1 Publication
    Corresponds to variant rs1059702 [ dbSNP | Ensembl ].
    VAR_051630
    Natural varianti203 – 2031C → S.
    Corresponds to variant rs10127175 [ dbSNP | Ensembl ].
    VAR_051631
    Natural varianti398 – 3981T → M.1 Publication
    Corresponds to variant rs56340948 [ dbSNP | Ensembl ].
    VAR_040573
    Natural varianti412 – 4121V → M in a glioblastoma multiforme sample; somatic mutation. 1 Publication
    VAR_040574
    Natural varianti421 – 4211Q → H in a breast pleomorphic lobular carcinoma sample; somatic mutation. 1 Publication
    VAR_040575
    Natural varianti532 – 5321S → L.2 Publications
    Corresponds to variant rs1059703 [ dbSNP | Ensembl ].
    VAR_040576
    Natural varianti619 – 6191G → S.1 Publication
    Corresponds to variant rs34112487 [ dbSNP | Ensembl ].
    VAR_040577
    Natural varianti625 – 6251T → M.1 Publication
    Corresponds to variant rs35638718 [ dbSNP | Ensembl ].
    VAR_040578
    Natural varianti638 – 6381R → W.1 Publication
    Corresponds to variant rs56082801 [ dbSNP | Ensembl ].
    VAR_040579
    Natural varianti690 – 6901S → G in a lung adenocarcinoma sample; somatic mutation. 1 Publication
    VAR_040580

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei45 – 451F → FGGWRRAAGGREARGLLAPT PDAPRPA in isoform 3. 1 PublicationVSP_011849
    Alternative sequencei435 – 51379Missing in isoform 4. 2 PublicationsVSP_041950Add
    BLAST
    Alternative sequencei478 – 49215Missing in isoform 3. 1 PublicationVSP_011850Add
    BLAST
    Alternative sequencei513 – 54230Missing in isoform 2 and isoform 3. 2 PublicationsVSP_011851Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L76191 mRNA. Translation: AAC41949.1.
    AF030876 Genomic DNA. Translation: AAC08756.1.
    AF346607 mRNA. Translation: AAK62888.1.
    DQ054788 mRNA. Translation: AAY88246.1.
    U52112 Genomic DNA. No translation available.
    CH471172 Genomic DNA. Translation: EAW72762.1.
    CH471172 Genomic DNA. Translation: EAW72763.1.
    CH471172 Genomic DNA. Translation: EAW72764.1.
    CH471172 Genomic DNA. Translation: EAW72765.1.
    BC054000 mRNA. Translation: AAH54000.1.
    BC014963 mRNA. Translation: AAH14963.1.
    CCDSiCCDS14740.1. [P51617-1]
    CCDS35443.1. [P51617-4]
    CCDS35444.1. [P51617-2]
    PIRiG02512.
    RefSeqiNP_001020413.1. NM_001025242.1. [P51617-2]
    NP_001020414.1. NM_001025243.1. [P51617-4]
    NP_001560.2. NM_001569.3. [P51617-1]
    UniGeneiHs.522819.

    Genome annotation databases

    EnsembliENST00000369974; ENSP00000358991; ENSG00000184216. [P51617-4]
    ENST00000369980; ENSP00000358997; ENSG00000184216. [P51617-1]
    ENST00000393687; ENSP00000377291; ENSG00000184216. [P51617-2]
    GeneIDi3654.
    KEGGihsa:3654.
    UCSCiuc004fjr.1. human. [P51617-2]
    uc004fjs.1. human. [P51617-1]
    uc004fjt.1. human. [P51617-4]

    Polymorphism databases

    DMDMi8928535.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L76191 mRNA. Translation: AAC41949.1 .
    AF030876 Genomic DNA. Translation: AAC08756.1 .
    AF346607 mRNA. Translation: AAK62888.1 .
    DQ054788 mRNA. Translation: AAY88246.1 .
    U52112 Genomic DNA. No translation available.
    CH471172 Genomic DNA. Translation: EAW72762.1 .
    CH471172 Genomic DNA. Translation: EAW72763.1 .
    CH471172 Genomic DNA. Translation: EAW72764.1 .
    CH471172 Genomic DNA. Translation: EAW72765.1 .
    BC054000 mRNA. Translation: AAH54000.1 .
    BC014963 mRNA. Translation: AAH14963.1 .
    CCDSi CCDS14740.1. [P51617-1 ]
    CCDS35443.1. [P51617-4 ]
    CCDS35444.1. [P51617-2 ]
    PIRi G02512.
    RefSeqi NP_001020413.1. NM_001025242.1. [P51617-2 ]
    NP_001020414.1. NM_001025243.1. [P51617-4 ]
    NP_001560.2. NM_001569.3. [P51617-1 ]
    UniGenei Hs.522819.

    3D structure databases

    ProteinModelPortali P51617.
    SMRi P51617. Positions 18-102, 184-523.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109863. 85 interactions.
    DIPi DIP-397N.
    IntActi P51617. 26 interactions.
    MINTi MINT-97088.
    STRINGi 9606.ENSP00000358997.

    Chemistry

    BindingDBi P51617.
    ChEMBLi CHEMBL3357.
    GuidetoPHARMACOLOGYi 2042.

    PTM databases

    PhosphoSitei P51617.

    Polymorphism databases

    DMDMi 8928535.

    Proteomic databases

    MaxQBi P51617.
    PaxDbi P51617.
    PRIDEi P51617.

    Protocols and materials databases

    DNASUi 3654.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000369974 ; ENSP00000358991 ; ENSG00000184216 . [P51617-4 ]
    ENST00000369980 ; ENSP00000358997 ; ENSG00000184216 . [P51617-1 ]
    ENST00000393687 ; ENSP00000377291 ; ENSG00000184216 . [P51617-2 ]
    GeneIDi 3654.
    KEGGi hsa:3654.
    UCSCi uc004fjr.1. human. [P51617-2 ]
    uc004fjs.1. human. [P51617-1 ]
    uc004fjt.1. human. [P51617-4 ]

    Organism-specific databases

    CTDi 3654.
    GeneCardsi GC0XM153277.
    H-InvDB HIX0017146.
    HGNCi HGNC:6112. IRAK1.
    HPAi CAB004461.
    HPA054476.
    MIMi 300283. gene.
    neXtProti NX_P51617.
    Orphaneti 93552. Pediatric systemic lupus erythematosus.
    536. Systemic lupus erythematosus.
    PharmGKBi PA29912.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000015226.
    HOVERGENi HBG052144.
    InParanoidi P51617.
    KOi K04730.
    OMAi SPFCWPL.
    PhylomeDBi P51617.
    TreeFami TF328924.

    Enzyme and pathway databases

    BRENDAi 2.7.10.2. 2681.
    Reactomei REACT_13415. p75NTR recruits signalling complexes.
    REACT_13696. NF-kB is activated and signals survival.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_21368. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
    REACT_21399. activated TAK1 mediates p38 MAPK activation.
    REACT_22442. Interleukin-1 signaling.
    REACT_24918. IRAK1 recruits IKK complex.
    REACT_25024. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
    REACT_25120. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
    REACT_25222. MyD88 dependent cascade initiated on endosome.
    REACT_25354. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
    REACT_27215. MyD88 cascade initiated on plasma membrane.
    REACT_6788. MyD88:Mal cascade initiated on plasma membrane.
    REACT_75776. NOD1/2 Signaling Pathway.
    SignaLinki P51617.

    Miscellaneous databases

    GeneWikii IRAK1.
    GenomeRNAii 3654.
    NextBioi 14289.
    PROi P51617.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P51617.
    Bgeei P51617.
    CleanExi HS_IRAK1.
    Genevestigatori P51617.

    Family and domain databases

    Gene3Di 1.10.533.10. 1 hit.
    InterProi IPR011029. DEATH-like_dom.
    IPR000488. Death_domain.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00531. Death. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SUPFAMi SSF47986. SSF47986. 1 hit.
    SSF56112. SSF56112. 2 hits.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "IRAK: a kinase associated with the interleukin-1 receptor."
      Cao Z., Henzel W.J., Gao X.
      Science 271:1128-1131(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, VARIANTS SER-196 AND LEU-532.
    2. "Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions."
      Reichwald K., Thiesen J., Wiehe T., Weitzel J., Poustka W.A., Rosenthal A., Platzer M., Stratling W.H., Kioschis P.
      Mamm. Genome 11:182-190(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
    3. "IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability."
      Jensen L.E., Whitehead A.S.
      J. Biol. Chem. 276:29037-29044(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, PHOSPHORYLATION.
    4. "A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling."
      Rao N., Nguyen S., Ngo K., Fung-Leung W.P.
      Mol. Cell. Biol. 25:6521-6532(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
    5. "The DNA sequence of the human X chromosome."
      Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.
      , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R.
      Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    7. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
      Tissue: Placenta.
    8. "MyD88: an adapter that recruits IRAK to the IL-1 receptor complex."
      Wesche H., Henzel W.J., Shillinglaw W., Li S., Cao Z.
      Immunity 7:837-847(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MYD88.
    9. "Tollip, a new component of the IL-1R1 pathway, links IRAK to the IL-1 receptor."
      Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C., Maschera B., Lewis A., Ray K., Tschopp J., Volpe F.
      Nat. Cell Biol. 2:346-351(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH TOLLIP.
    10. "IRAK4: a novel member of the IRAK family with the properties of an IRAK-kinase."
      Li S., Strelow A., Fontana E.J., Wesche H.
      Proc. Natl. Acad. Sci. U.S.A. 99:5567-5572(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH IRAK4.
    11. "Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex."
      Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X.
      J. Biol. Chem. 278:10952-10956(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PELI1 AND TRAF6.
    12. "Characterization of Pellino2, a substrate of IRAK1 and IRAK4."
      Strelow A., Kollewe C., Wesche H.
      FEBS Lett. 547:157-161(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF PELI2.
    13. "Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4."
      Burns K., Janssens S., Brissoni B., Olivos N., Beyaert R., Tschopp J.
      J. Exp. Med. 197:263-268(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION BY IRAK4.
    14. "Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein."
      Jensen L.E., Whitehead A.S.
      J. Immunol. 171:1500-1506(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PELI3.
    15. "Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C."
      Mamidipudi V., Lin C., Seibenhener M.L., Wooten M.W.
      J. Biol. Chem. 279:4161-4165(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT THR-66.
    16. "Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling."
      Kollewe C., Mackensen A.C., Neumann D., Knop J., Cao P., Li S., Wesche H., Martin M.U.
      J. Biol. Chem. 279:5227-5236(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-209 AND THR-387, DOMAIN, MUTAGENESIS OF THR-209 AND THR-387.
    17. "IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness."
      Qin J., Jiang Z., Qian Y., Casanova J.-L., Li X.
      J. Biol. Chem. 279:26748-26753(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, MUTAGENESIS OF LYS-239.
    18. "IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression."
      Huang Y., Li T., Sane D.C., Li L.
      J. Biol. Chem. 279:51697-51703(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF STAT3.
    19. "IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST 2 and induces T helper type 2-associated cytokines."
      Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K., Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F., Kastelein R.A.
      Immunity 23:479-490(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH IL1RL1.
    20. "Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction."
      Uematsu S., Sato S., Yamamoto M., Hirotani T., Kato H., Takeshita F., Matsuda M., Coban C., Ishii K.J., Kawai T., Takeuchi O., Akira S.
      J. Exp. Med. 201:915-923(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF IRF7.
    21. "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1."
      Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S., Kim I.H., Kim S.J., Park S.H.
      Nat. Immunol. 7:1057-1065(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION IN COMPLEX WITH IRAK4; MYD88; PELI1 AND TRAF6.
    22. "Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants."
      Su J., Richter K., Zhang C., Gu Q., Li L.
      Mol. Immunol. 44:900-905(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUMOYLATION, SUBCELLULAR LOCATION.
    23. "The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1."
      Ordureau A., Smith H., Windheim M., Peggie M., Carrick E., Morrice N., Cohen P.
      Biochem. J. 409:43-52(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF PELI1.
    24. "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
      Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
      Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    25. "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation."
      Conze D.B., Wu C.J., Thomas J.A., Landstrom A., Ashwell J.D.
      Mol. Cell. Biol. 28:3538-3547(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION AT LYS-134 AND LYS-180 BY TRAF6, INTERACTION WITH IKBKG/NEMO.
    26. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    27. "Direct activation of protein kinases by unanchored polyubiquitin chains."
      Xia Z.-P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W., Chen Z.J.
      Nature 461:114-119(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION.
    28. "IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal)."
      Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H., Morrice N., O'Neill L.A.
      J. Biol. Chem. 285:18276-18282(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF TIRAP.
    29. "IRAK1: a critical signaling mediator of innate immunity."
      Gottipati S., Rao N.L., Fung-Leung W.P.
      Cell. Signal. 20:269-276(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    30. "The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling."
      Moynagh P.N.
      Trends Immunol. 30:33-42(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    31. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    32. "Patterns of somatic mutation in human cancer genomes."
      Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
      , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
      Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS [LARGE SCALE ANALYSIS] MET-398; MET-412; HIS-421; LEU-532; SER-619; MET-625; TRP-638 AND GLY-690.

    Entry informationi

    Entry nameiIRAK1_HUMAN
    AccessioniPrimary (citable) accession number: P51617
    Secondary accession number(s): D3DWW3
    , D3DWW4, Q7Z5V4, Q96C06, Q96RL2
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: December 1, 2000
    Last modified: October 1, 2014
    This is version 154 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome X
      Human chromosome X: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

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