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Protein

Interleukin-1 receptor-associated kinase 4

Gene

IRAK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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 (PubMed:17878374). 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.9 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Kineticsi

  1. KM=650 µM for ATP (at pH 7.5)1 Publication
  2. KM=1100 µM for substrate (at pH 7.5)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei213ATP1
    Active sitei311Proton acceptorPROSITE-ProRule annotation1
    Binding sitei329ATP1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi192 – 200ATPPROSITE-ProRule annotation9
    Nucleotide bindingi313 – 316ATP4

    GO - Molecular functioni

    GO - Biological processi

    • cytokine production Source: Ensembl
    • innate immune response Source: UniProtKB
    • interleukin-1-mediated signaling pathway Source: GO_Central
    • JNK cascade Source: Ensembl
    • MyD88-dependent toll-like receptor signaling pathway Source: UniProtKB
    • neutrophil mediated immunity Source: UniProtKB
    • neutrophil migration Source: UniProtKB
    • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
    • positive regulation of NF-kappaB transcription factor activity Source: GO_Central
    • positive regulation of smooth muscle cell proliferation Source: Ensembl
    • toll-like receptor 9 signaling pathway Source: Reactome
    • toll-like receptor signaling pathway Source: UniProtKB

    Keywordsi

    Molecular functionKinase, Serine/threonine-protein kinase, Transferase
    Biological processImmunity, Innate immunity
    LigandATP-binding, Magnesium, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiR-HSA-1257604 PIP3 activates AKT signaling
    R-HSA-166058 MyD88:Mal cascade initiated on plasma membrane
    R-HSA-5603037 IRAK4 deficiency (TLR5)
    R-HSA-5603041 IRAK4 deficiency (TLR2/4)
    R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
    R-HSA-9020702 Interleukin-1 signaling
    R-HSA-975110 TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling
    R-HSA-975138 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
    R-HSA-975155 MyD88 dependent cascade initiated on endosome
    R-HSA-975871 MyD88 cascade initiated on plasma membrane
    SignaLinkiQ9NWZ3
    SIGNORiQ9NWZ3

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Interleukin-1 receptor-associated kinase 4 (EC:2.7.11.1)
    Short name:
    IRAK-4
    Alternative name(s):
    Renal carcinoma antigen NY-REN-64
    Gene namesi
    Name:IRAK4
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 12

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000198001.13
    HGNCiHGNC:17967 IRAK4
    MIMi606883 gene
    neXtProtiNX_Q9NWZ3

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Involvement in diseasei

    Recurrent isolated invasive pneumococcal disease 1 (IPD1)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionRecurrent 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.
    See also OMIM:610799
    IRAK4 deficiency (IRAK4D)6 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionCauses extracellular pyogenic bacterial and fungal infections in otherwise healthy children.
    See also OMIM:607676
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_07288812R → C in IRAK4D; no effect on inhibition of NF-kappa-B complex activation; loss of interaction with MYD88; decreases protein stability. 2 PublicationsCorresponds to variant dbSNP:rs377584435EnsemblClinVar.1
    Natural variantiVAR_072892298G → D in IRAK4D; decreases inhibition of NF-kappa-B complex activation; impairs neutrophil migration and phagocytosis. 3 PublicationsCorresponds to variant dbSNP:rs568782766Ensembl.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi213K → A: Loss of kinase activity. 1 Publication1

    Organism-specific databases

    DisGeNETi51135
    MalaCardsiIRAK4
    MIMi607676 phenotype
    610799 phenotype
    OpenTargetsiENSG00000198001
    Orphaneti70592 Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency
    PharmGKBiPA134914577

    Chemistry databases

    ChEMBLiCHEMBL3778
    DrugBankiDB08590 1-(3-HYDROXYPROPYL)-2-[(3-NITROBENZOYL)AMINO]-1H-BENZIMIDAZOL-5-YL PIVALATE
    GuidetoPHARMACOLOGYi2045

    Polymorphism and mutation databases

    BioMutaiIRAK4
    DMDMi50401181

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000860351 – 460Interleukin-1 receptor-associated kinase 4Add BLAST460

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei1N-acetylmethionineCombined sources1
    Modified residuei34N6-acetyllysineCombined sources1
    Modified residuei342Phosphothreonine2 Publications1
    Modified residuei345Phosphothreonine3 Publications1
    Modified residuei346Phosphoserine2 Publications1

    Post-translational modificationi

    Phosphorylated.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiQ9NWZ3
    MaxQBiQ9NWZ3
    PaxDbiQ9NWZ3
    PeptideAtlasiQ9NWZ3
    PRIDEiQ9NWZ3
    ProteomicsDBi83000
    83001 [Q9NWZ3-2]

    PTM databases

    iPTMnetiQ9NWZ3
    PhosphoSitePlusiQ9NWZ3

    Expressioni

    Gene expression databases

    BgeeiENSG00000198001
    CleanExiHS_IRAK4
    ExpressionAtlasiQ9NWZ3 baseline and differential
    GenevisibleiQ9NWZ3 HS

    Organism-specific databases

    HPAiCAB016685
    CAB022077

    Interactioni

    Subunit structurei

    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. 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 IL1RL1.7 Publications

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi119322, 26 interactors
    DIPiDIP-31351N
    IntActiQ9NWZ3, 15 interactors
    MINTiQ9NWZ3
    STRINGi9606.ENSP00000390651

    Chemistry databases

    BindingDBiQ9NWZ3

    Structurei

    Secondary structure

    1460
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi11 – 13Combined sources3
    Helixi16 – 26Combined sources11
    Helixi31 – 38Combined sources8
    Beta strandi42 – 48Combined sources7
    Helixi50 – 57Combined sources8
    Helixi58 – 60Combined sources3
    Turni61 – 63Combined sources3
    Helixi66 – 73Combined sources8
    Turni74 – 77Combined sources4
    Helixi81 – 89Combined sources9
    Turni90 – 92Combined sources3
    Helixi94 – 100Combined sources7
    Beta strandi102 – 104Combined sources3
    Beta strandi164 – 167Combined sources4
    Helixi170 – 176Combined sources7
    Turni177 – 180Combined sources4
    Helixi185 – 187Combined sources3
    Beta strandi191 – 194Combined sources4
    Beta strandi195 – 197Combined sources3
    Beta strandi199 – 205Combined sources7
    Beta strandi208 – 214Combined sources7
    Beta strandi218 – 220Combined sources3
    Helixi224 – 239Combined sources16
    Beta strandi248 – 252Combined sources5
    Beta strandi254 – 257Combined sources4
    Beta strandi259 – 263Combined sources5
    Helixi270 – 275Combined sources6
    Helixi277 – 279Combined sources3
    Helixi285 – 304Combined sources20
    Helixi314 – 316Combined sources3
    Beta strandi317 – 319Combined sources3
    Beta strandi325 – 327Combined sources3
    Beta strandi349 – 351Combined sources3
    Helixi352 – 354Combined sources3
    Helixi357 – 360Combined sources4
    Helixi367 – 382Combined sources16
    Beta strandi391 – 395Combined sources5
    Helixi396 – 398Combined sources3
    Helixi399 – 404Combined sources6
    Helixi410 – 413Combined sources4
    Helixi423 – 436Combined sources14
    Helixi441 – 443Combined sources3
    Helixi447 – 457Combined sources11

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2NRUX-ray2.00A/B/C/D154-460[»]
    2NRYX-ray2.15A/B/C/D154-460[»]
    2O8YX-ray2.40A/B163-460[»]
    2OIBX-ray2.00A/B/C/D160-460[»]
    2OICX-ray2.40A/B/C/D160-460[»]
    2OIDX-ray2.30A/B/C/D160-460[»]
    3MOPX-ray3.40G/H/I/J4-106[»]
    4RMZX-ray2.20A/B154-460[»]
    4U97X-ray2.65A/B154-460[»]
    4U9AX-ray2.80A/B154-460[»]
    4XS2X-ray2.73A/B/C/D160-460[»]
    4Y73X-ray2.14A/B/C/D160-460[»]
    4YO6X-ray2.32A/B/C/D160-460[»]
    4YP8X-ray2.64A/B/C/D160-460[»]
    4ZTLX-ray2.39A/B/C/D160-460[»]
    4ZTMX-ray2.66A/B/C/D160-460[»]
    4ZTNX-ray2.23A/B/C/D160-460[»]
    5K72X-ray2.22A/B/C/D160-460[»]
    5K75X-ray2.03A/B/C/D160-460[»]
    5K76X-ray2.74A/B160-460[»]
    5K7GX-ray2.23A/B/C/D160-460[»]
    5K7IX-ray2.31A/B160-460[»]
    5KX7X-ray2.80A/B160-460[»]
    5KX8X-ray2.67A/B/C/D160-460[»]
    5T1SX-ray2.30A/B/C/D160-460[»]
    5T1TX-ray2.34A/B/C/D160-460[»]
    5UIQX-ray2.64A/B/C/D154-460[»]
    5UIRX-ray2.64A/B154-460[»]
    5UISX-ray2.50A/B/C/D154-460[»]
    5UITX-ray1.84A/B154-460[»]
    5UIUX-ray2.02A/B154-460[»]
    5W84X-ray2.90A/B160-460[»]
    5W85X-ray2.25A/B160-460[»]
    ProteinModelPortaliQ9NWZ3
    SMRiQ9NWZ3
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9NWZ3

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini20 – 104DeathAdd BLAST85
    Domaini186 – 454Protein kinasePROSITE-ProRule annotationAdd BLAST269

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiKOG1187 Eukaryota
    COG0515 LUCA
    GeneTreeiENSGT00530000063073
    HOGENOMiHOG000116550
    HOVERGENiHBG066836
    InParanoidiQ9NWZ3
    KOiK04733
    OMAiAQTVMTS
    OrthoDBiEOG091G0YKT
    PhylomeDBiQ9NWZ3
    TreeFamiTF351380

    Family and domain databases

    CDDicd08793 Death_IRAK4, 1 hit
    InterProiView protein in InterPro
    IPR011029 DEATH-like_dom_sf
    IPR017428 IRAK4
    IPR037970 IRAK4_Death
    IPR011009 Kinase-like_dom_sf
    IPR000719 Prot_kinase_dom
    IPR001245 Ser-Thr/Tyr_kinase_cat_dom
    PfamiView protein in Pfam
    PF07714 Pkinase_Tyr, 1 hit
    PIRSFiPIRSF038189 IRAK4, 1 hit
    SMARTiView protein in SMART
    SM00220 S_TKc, 1 hit
    SUPFAMiSSF47986 SSF47986, 1 hit
    SSF56112 SSF56112, 1 hit
    PROSITEiView protein in PROSITE
    PS50011 PROTEIN_KINASE_DOM, 1 hit

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q9NWZ3-1) [UniParc]FASTAAdd to basket

    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

            10         20         30         40         50
    MNKPITPSTY VRCLNVGLIR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ
    60 70 80 90 100
    FHIRRFEALL QTGKSPTSEL LFDWGTTNCT VGDLVDLLIQ NEFFAPASLL
    110 120 130 140 150
    LPDAVPKTAN TLPSKEAITV QQKQMPFCDK DRTLMTPVQN LEQSYMPPDS
    160 170 180 190 200
    SSPENKSLEV SDTRFHSFSF YELKNVTNNF DERPISVGGN KMGEGGFGVV
    210 220 230 240 250
    YKGYVNNTTV AVKKLAAMVD ITTEELKQQF DQEIKVMAKC QHENLVELLG
    260 270 280 290 300
    FSSDGDDLCL VYVYMPNGSL LDRLSCLDGT PPLSWHMRCK IAQGAANGIN
    310 320 330 340 350
    FLHENHHIHR DIKSANILLD EAFTAKISDF GLARASEKFA QTVMTSRIVG
    360 370 380 390 400
    TTAYMAPEAL RGEITPKSDI YSFGVVLLEI ITGLPAVDEH REPQLLLDIK
    410 420 430 440 450
    EEIEDEEKTI EDYIDKKMND ADSTSVEAMY SVASQCLHEK KNKRPDIKKV
    460
    QQLLQEMTAS
    Length:460
    Mass (Da):51,530
    Last modified:October 1, 2000 - v1
    Checksum:i6C8156ADF25FF81E
    GO
    Isoform 2 (identifier: Q9NWZ3-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-124: Missing.

    Show »
    Length:336
    Mass (Da):37,674
    Checksum:i6608D68A2EE4138C
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti81V → A in AAM15772 (PubMed:11960013).Curated1
    Sequence conflicti432V → G in AAD42884 (PubMed:10508479).Curated1
    Sequence conflicti437L → R in AAD42884 (PubMed:10508479).Curated1
    Sequence conflicti444R → S in AAD42884 (PubMed:10508479).Curated1
    Sequence conflicti451Q → H in AAD42884 (PubMed:10508479).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_0405885I → V Polymorphism; no effect on inhibition of NF-kappa-B activation; no effect on interaction with MYD88. 2 PublicationsCorresponds to variant dbSNP:rs56312115Ensembl.1
    Natural variantiVAR_07288812R → C in IRAK4D; no effect on inhibition of NF-kappa-B complex activation; loss of interaction with MYD88; decreases protein stability. 2 PublicationsCorresponds to variant dbSNP:rs377584435EnsemblClinVar.1
    Natural variantiVAR_07288920R → W Polymorphism; increases inhibition of NF-kappa-B complex activation; decreases interaction with MYD88; decreases protein stability. 1 PublicationCorresponds to variant dbSNP:rs143625818Ensembl.1
    Natural variantiVAR_07289026I → T Polymorphism; no effect on inhibition of NF-kappa-B activation; no effect on interaction with MYD88. 1 PublicationCorresponds to variant dbSNP:rs138116867Ensembl.1
    Natural variantiVAR_07289139I → V Polymorphism; no effect on inhibition of NF-kappa-B activation; no effect on interaction with MYD88. 1 PublicationCorresponds to variant dbSNP:rs113588409Ensembl.1
    Natural variantiVAR_01935498S → R Polymorphism; no effect on inhibition of NF-kappa-B activation; no effect on interaction with MYD88. 2 PublicationsCorresponds to variant dbSNP:rs4251469Ensembl.1
    Natural variantiVAR_072892298G → D in IRAK4D; decreases inhibition of NF-kappa-B complex activation; impairs neutrophil migration and phagocytosis. 3 PublicationsCorresponds to variant dbSNP:rs568782766Ensembl.1
    Natural variantiVAR_040589355M → V1 PublicationCorresponds to variant dbSNP:rs142376871Ensembl.1
    Natural variantiVAR_019355390H → R1 PublicationCorresponds to variant dbSNP:rs4251583Ensembl.1
    Natural variantiVAR_040590391R → H Found in a patient with IRAK4D in association with C-12; probable neutral polymorphism. 2 PublicationsCorresponds to variant dbSNP:rs55944915EnsemblClinVar.1
    Natural variantiVAR_019356428A → T2 PublicationsCorresponds to variant dbSNP:rs4251545EnsemblClinVar.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0415561 – 124Missing in isoform 2. 2 PublicationsAdd BLAST124

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF445802 mRNA Translation: AAM15772.1
    AF155118 mRNA Translation: AAD42884.1
    AY340964 mRNA Translation: AAR02360.1
    AY340965 mRNA Translation: AAR02361.1
    AY340966 mRNA Translation: AAR02362.1
    AY340967 mRNA Translation: AAR02363.1
    AK000528 mRNA Translation: BAA91232.1
    AK299944 mRNA Translation: BAG61774.1
    AY186092 Genomic DNA Translation: AAN75440.1
    AC093012 Genomic DNA No translation available.
    BC013316 mRNA Translation: AAH13316.1
    CCDSiCCDS44862.1 [Q9NWZ3-2]
    CCDS8744.1 [Q9NWZ3-1]
    RefSeqiNP_001107654.1, NM_001114182.2 [Q9NWZ3-1]
    NP_001138728.1, NM_001145256.1 [Q9NWZ3-2]
    NP_001138729.1, NM_001145257.1 [Q9NWZ3-2]
    NP_001138730.1, NM_001145258.1 [Q9NWZ3-2]
    NP_057207.2, NM_016123.3 [Q9NWZ3-1]
    XP_005269000.1, XM_005268943.3 [Q9NWZ3-1]
    XP_005269001.1, XM_005268944.4 [Q9NWZ3-1]
    XP_005269002.1, XM_005268945.4 [Q9NWZ3-1]
    XP_005269004.1, XM_005268947.4
    XP_005269005.1, XM_005268948.2
    XP_005269006.1, XM_005268949.2 [Q9NWZ3-2]
    XP_006719501.1, XM_006719438.3 [Q9NWZ3-1]
    XP_006719502.1, XM_006719439.2
    XP_011536733.1, XM_011538431.2 [Q9NWZ3-1]
    XP_011536734.1, XM_011538432.1
    XP_011536735.1, XM_011538433.2 [Q9NWZ3-1]
    XP_016874879.1, XM_017019390.1 [Q9NWZ3-1]
    XP_016874880.1, XM_017019391.1
    UniGeneiHs.138499

    Genome annotation databases

    EnsembliENST00000431837; ENSP00000390327; ENSG00000198001 [Q9NWZ3-2]
    ENST00000440781; ENSP00000408734; ENSG00000198001 [Q9NWZ3-2]
    ENST00000551736; ENSP00000446490; ENSG00000198001 [Q9NWZ3-1]
    ENST00000613694; ENSP00000479889; ENSG00000198001 [Q9NWZ3-1]
    GeneIDi51135
    KEGGihsa:51135
    UCSCiuc001rnt.4 human [Q9NWZ3-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiIRAK4_HUMAN
    AccessioniPrimary (citable) accession number: Q9NWZ3
    Secondary accession number(s): Q69FE1, Q8TDF7, Q9Y589
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2004
    Last sequence update: October 1, 2000
    Last modified: June 20, 2018
    This is version 175 of the entry and version 1 of the sequence. See 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

    3D-structure, Complete proteome, Reference proteome

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