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Q8R4K2 (IRAK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified May 29, 2013. Version 104. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
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Names and origin

Protein namesRecommended name:
Interleukin-1 receptor-associated kinase 4

Short name=IRAK-4
EC=2.7.11.1
Gene names
Name:Irak4
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length459 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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 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.

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Subunit structure

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. Ref.5

Subcellular location

Cytoplasm By similarity.

Post-translational modification

Phosphorylated By similarity.

Disruption phenotype

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. The Malt1-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. Ref.4 Ref.6

Sequence similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

Contains 1 death domain.

Contains 1 protein kinase domain.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 459459Interleukin-1 receptor-associated kinase 4
PRO_0000086036

Regions

Domain20 – 10485Death
Domain186 – 454269Protein kinase
Nucleotide binding192 – 2009ATP By similarity
Nucleotide binding313 – 3164ATP By similarity

Sites

Active site3111Proton acceptor By similarity
Binding site2131ATP By similarity
Binding site3291ATP By similarity

Amino acid modifications

Modified residue341N6-acetyllysine By similarity
Modified residue3421Phosphothreonine By similarity
Modified residue3451Phosphothreonine By similarity
Modified residue3461Phosphoserine By similarity

Experimental info

Sequence conflict3211K → R in AAH51676. Ref.3

Secondary structure

...................... 459
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q8R4K2 [UniParc].

Last modified June 1, 2002. Version 1.
Checksum: FC11AD06983B7AEB

FASTA45950,872
        10         20         30         40         50         60 
MNKPLTPSTY IRNLNVGILR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ FHIRRFEALL 

        70         80         90        100        110        120 
QTGKSPTCEL LFDWGTTNCT VGDLVDLLVQ IELFAPATLL LPDAVPQTVK SLPPREAATV 

       130        140        150        160        170        180 
AQTHGPCQEK DRTSVMPMPK LEHSCEPPDS SSPDNRSVES SDTRFHSFSF HELKSITNNF 

       190        200        210        220        230        240 
DEQPASAGGN RMGEGGFGVV YKGCVNNTIV AVKKLGAMVE ISTEELKQQF DQEIKVMATC 

       250        260        270        280        290        300 
QHENLVELLG FSSDSDNLCL VYAYMPNGSL LDRLSCLDGT PPLSWHTRCK VAQGTANGIR 

       310        320        330        340        350        360 
FLHENHHIHR DIKSANILLD KDFTAKISDF GLARASARLA QTVMTSRIVG TTAYMAPEAL 

       370        380        390        400        410        420 
RGEITPKSDI YSFGVVLLEL ITGLAAVDEN REPQLLLDIK EEIEDEEKTI EDYTDEKMSD 

       430        440        450 
ADPASVEAMY SAASQCLHEK KNRRPDIAKV QQLLQEMSA 

« Hide

References

« Hide 'large scale' references
[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/c.
[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. expand/collapse author list , 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]"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.
[7]"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.
[8]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF445803 mRNA. Translation: AAM15773.1.
AK028837 mRNA. Translation: BAC26146.1.
BC051676 mRNA. Translation: AAH51676.1.
IPIIPI00153899.
RefSeqNP_084202.2. NM_029926.5.
UniGeneMm.422858.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1WH4NMR-A1-114[»]
2A9IX-ray1.70A1-113[»]
ProteinModelPortalQ8R4K2.
SMRQ8R4K2. Positions 1-458.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-48996N.
IntActQ8R4K2. 1 interaction.

PTM databases

PhosphoSiteQ8R4K2.

Proteomic databases

PaxDbQ8R4K2.
PRIDEQ8R4K2.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000074936; ENSMUSP00000074471; ENSMUSG00000059883.
GeneID266632.
KEGGmmu:266632.
UCSCuc007xjj.2. mouse.

Organism-specific databases

CTD51135.
MGIMGI:2182474. Irak4.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00530000063073.
HOGENOMHOG000116550.
HOVERGENHBG066836.
InParanoidQ8R4K2.
KOK04733.
OMAFINIHIF.
OrthoDBEOG457572.

Gene expression databases

ArrayExpressQ8R4K2.
BgeeQ8R4K2.
CleanExMM_IRAK4.
GenevestigatorQ8R4K2.
GermOnlineENSMUSG00000059883. Mus musculus.

Family and domain databases

Gene3D1.10.533.10. 1 hit.
InterProIPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR017428. Interleukin-1_rcpt-assoc_kin4.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
[Graphical view]
PfamPF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF038189. IRAK4. 1 hit.
SUPFAMSSF47986. DEATH_like. 1 hit.
SSF56112. Kinase_like. 1 hit.
PROSITEPS50017. DEATH_DOMAIN. False negative.
PS00107. PROTEIN_KINASE_ATP. False negative.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. False negative.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ8R4K2.
NextBio392172.
SOURCESearch...

Entry information

Entry nameIRAK4_MOUSE
AccessionPrimary (citable) accession number: Q8R4K2
Secondary accession number(s): Q80WW1
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: June 1, 2002
Last modified: May 29, 2013
This is version 104 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families