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Protein

Interleukin-1 receptor-associated kinase 4

Gene

Irak4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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. 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 (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei213 – 2131ATPPROSITE-ProRule annotation
Active sitei311 – 3111Proton acceptorPROSITE-ProRule annotation
Binding sitei329 – 3291ATPPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi192 – 2009ATPPROSITE-ProRule annotation
Nucleotide bindingi313 – 3164ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

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

ReactomeiR-MMU-446652. Interleukin-1 signaling.
R-MMU-975110. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
R-MMU-975138. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
R-MMU-975155. MyD88 dependent cascade initiated on endosome.

Names & Taxonomyi

Protein namesi
Recommended name:
Interleukin-1 receptor-associated kinase 4 (EC:2.7.11.1)
Short name:
IRAK-4
Gene namesi
Name:Irak4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:2182474. Irak4.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

Mice are strongly altered in their responses to viral and bacterial challenges due to a severe impairment of interleukin-1 and Toll-like receptor signaling pathways. Malt1 and Irak4 double knockout suggests an additional role of Irak4 in B-cell antigen receptor (BCR) mediated signaling pathway, since the double mutant inhibits B-cell proliferation.2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 459459Interleukin-1 receptor-associated kinase 4PRO_0000086036Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionineBy similarity
Modified residuei34 – 341N6-acetyllysineBy similarity
Modified residuei342 – 3421PhosphothreonineBy similarity
Modified residuei345 – 3451PhosphothreonineBy similarity
Modified residuei346 – 3461PhosphoserineBy similarity

Post-translational modificationi

Phosphorylated.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ8R4K2.
MaxQBiQ8R4K2.
PaxDbiQ8R4K2.
PRIDEiQ8R4K2.

PTM databases

iPTMnetiQ8R4K2.
PhosphoSiteiQ8R4K2.

Expressioni

Gene expression databases

BgeeiQ8R4K2.
CleanExiMM_IRAK4.
ExpressionAtlasiQ8R4K2. baseline and differential.
GenevisibleiQ8R4K2. MM.

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 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Irak3Q8K4B27EBI-3842721,EBI-646179
Myd88P223664EBI-3842721,EBI-525108

GO - Molecular functioni

  • interleukin-1 receptor binding Source: MGI

Protein-protein interaction databases

BioGridi234465. 5 interactions.
DIPiDIP-48996N.
IntActiQ8R4K2. 5 interactions.
STRINGi10090.ENSMUSP00000074471.

Structurei

Secondary structure

1
459
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi11 – 133Combined sources
Helixi16 – 2611Combined sources
Helixi28 – 303Combined sources
Helixi31 – 388Combined sources
Beta strandi44 – 485Combined sources
Helixi50 – 589Combined sources
Turni59 – 635Combined sources
Helixi66 – 749Combined sources
Helixi75 – 773Combined sources
Helixi81 – 9010Combined sources
Helixi94 – 1007Combined sources
Helixi102 – 1043Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1WH4NMR-A1-114[»]
2A9IX-ray1.70A1-113[»]
ProteinModelPortaliQ8R4K2.
SMRiQ8R4K2. Positions 1-458.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8R4K2.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini20 – 10485DeathAdd
BLAST
Domaini186 – 454269Protein kinasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG1187. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00530000063073.
HOGENOMiHOG000116550.
HOVERGENiHBG066836.
InParanoidiQ8R4K2.
KOiK04733.
OMAiFSFYELR.
OrthoDBiEOG7MD4Q1.
PhylomeDBiQ8R4K2.
TreeFamiTF351380.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR011029. DEATH-like_dom.
IPR017428. IL-1_rcpt-assoc_kin4.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF038189. IRAK4. 1 hit.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q8R4K2-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNKPLTPSTY IRNLNVGILR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ
60 70 80 90 100
FHIRRFEALL QTGKSPTCEL LFDWGTTNCT VGDLVDLLVQ IELFAPATLL
110 120 130 140 150
LPDAVPQTVK SLPPREAATV AQTHGPCQEK DRTSVMPMPK LEHSCEPPDS
160 170 180 190 200
SSPDNRSVES SDTRFHSFSF HELKSITNNF DEQPASAGGN RMGEGGFGVV
210 220 230 240 250
YKGCVNNTIV AVKKLGAMVE ISTEELKQQF DQEIKVMATC QHENLVELLG
260 270 280 290 300
FSSDSDNLCL VYAYMPNGSL LDRLSCLDGT PPLSWHTRCK VAQGTANGIR
310 320 330 340 350
FLHENHHIHR DIKSANILLD KDFTAKISDF GLARASARLA QTVMTSRIVG
360 370 380 390 400
TTAYMAPEAL RGEITPKSDI YSFGVVLLEL ITGLAAVDEN REPQLLLDIK
410 420 430 440 450
EEIEDEEKTI EDYTDEKMSD ADPASVEAMY SAASQCLHEK KNRRPDIAKV

QQLLQEMSA
Length:459
Mass (Da):50,872
Last modified:June 1, 2002 - v1
Checksum:iFC11AD06983B7AEB
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti321 – 3211K → R in AAH51676 (PubMed:15489334).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF445803 mRNA. Translation: AAM15773.1.
AK028837 mRNA. Translation: BAC26146.1.
BC051676 mRNA. Translation: AAH51676.1.
CCDSiCCDS27772.1.
RefSeqiNP_084202.2. NM_029926.5.
UniGeneiMm.422858.

Genome annotation databases

EnsembliENSMUST00000074936; ENSMUSP00000074471; ENSMUSG00000059883.
GeneIDi266632.
KEGGimmu:266632.
UCSCiuc007xjj.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF445803 mRNA. Translation: AAM15773.1.
AK028837 mRNA. Translation: BAC26146.1.
BC051676 mRNA. Translation: AAH51676.1.
CCDSiCCDS27772.1.
RefSeqiNP_084202.2. NM_029926.5.
UniGeneiMm.422858.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1WH4NMR-A1-114[»]
2A9IX-ray1.70A1-113[»]
ProteinModelPortaliQ8R4K2.
SMRiQ8R4K2. Positions 1-458.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi234465. 5 interactions.
DIPiDIP-48996N.
IntActiQ8R4K2. 5 interactions.
STRINGi10090.ENSMUSP00000074471.

PTM databases

iPTMnetiQ8R4K2.
PhosphoSiteiQ8R4K2.

Proteomic databases

EPDiQ8R4K2.
MaxQBiQ8R4K2.
PaxDbiQ8R4K2.
PRIDEiQ8R4K2.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000074936; ENSMUSP00000074471; ENSMUSG00000059883.
GeneIDi266632.
KEGGimmu:266632.
UCSCiuc007xjj.2. mouse.

Organism-specific databases

CTDi51135.
MGIiMGI:2182474. Irak4.

Phylogenomic databases

eggNOGiKOG1187. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00530000063073.
HOGENOMiHOG000116550.
HOVERGENiHBG066836.
InParanoidiQ8R4K2.
KOiK04733.
OMAiFSFYELR.
OrthoDBiEOG7MD4Q1.
PhylomeDBiQ8R4K2.
TreeFamiTF351380.

Enzyme and pathway databases

ReactomeiR-MMU-446652. Interleukin-1 signaling.
R-MMU-975110. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
R-MMU-975138. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
R-MMU-975155. MyD88 dependent cascade initiated on endosome.

Miscellaneous databases

EvolutionaryTraceiQ8R4K2.
PROiQ8R4K2.
SOURCEiSearch...

Gene expression databases

BgeeiQ8R4K2.
CleanExiMM_IRAK4.
ExpressionAtlasiQ8R4K2. baseline and differential.
GenevisibleiQ8R4K2. MM.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR011029. DEATH-like_dom.
IPR017428. IL-1_rcpt-assoc_kin4.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF038189. IRAK4. 1 hit.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "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: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: BALB/cJ.
  2. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Skin.
  3. "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].
    Strain: C57BL/6J.
    Tissue: Embryo.
  4. "Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4."
    Suzuki N., Suzuki S., Duncan G.S., Millar D.G., Wada T., Mirtsos C., Takada H., Wakeham A., Itie A., Li S., Penninger J.M., Wesche H., Ohashi P.S., Mak T.W., Yeh W.C.
    Nature 416:750-756(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  5. "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 IRAK1; MYD88; PELI1 AND TRAF6.
  6. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Spleen.
  7. "B cell antigen receptor-induced activation of an IRAK4-dependent signaling pathway revealed by a MALT1-IRAK4 double knockout mouse model."
    Dufner A., Schamel W.W.
    Cell Commun. Signal. 9:6-6(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  8. "Molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling."
    Lasker M.V., Gajjar M.M., Nair S.K.
    J. Immunol. 175:4175-4179(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 1-113.
  9. "Solution structure of the death domain of interleukin-1 receptor-associated kinase 4 (IRAK4) from Mus musculus."
    RIKEN structural genomics initiative (RSGI)
    Submitted (NOV-2004) to the PDB data bank
    Cited for: STRUCTURE BY NMR OF 1-114.

Entry informationi

Entry nameiIRAK4_MOUSE
AccessioniPrimary (citable) accession number: Q8R4K2
Secondary accession number(s): Q80WW1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: June 1, 2002
Last modified: June 8, 2016
This is version 131 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.