Q8R4K2 (IRAK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Interleukin-1 receptor-associated kinase 4
Short name=IRAK-4
EC=2.7.11.1

Gene names

Name:

Irak4

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	459 AA.
Sequence status	Complete.
Protein existence	Evidence 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.

Ontologies

Keywords
Biological process	Immunity Innate immunity
Cellular component	Cytoplasm
Ligand	ATP-binding Magnesium Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Inferred from electronic annotation. Source: Compara cytokine production Inferred from direct assay PubMed 15292196. Source: MGI cytokine-mediated signaling pathway Inferred from direct assay PubMed 15292196. Source: MGI innate immune response Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of smooth muscle cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: InterPro protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 459

459

Interleukin-1 receptor-associated kinase 4

PRO_0000086036

Regions

Domain

20 – 104

85

Death

Domain

186 – 454

269

Protein kinase

Nucleotide binding

192 – 200

9

ATP By similarity

Nucleotide binding

313 – 316

4

ATP By similarity

Sites

Active site

311

1

Proton acceptor By similarity

Binding site

213

1

ATP By similarity

Binding site

329

1

ATP By similarity

Amino acid modifications

Modified residue

34

1

N6-acetyllysine By similarity

Modified residue

342

1

Phosphothreonine By similarity

Modified residue

345

1

Phosphothreonine By similarity

Modified residue

346

1

Phosphoserine By similarity

Experimental info

Sequence conflict

321

1

K → R in AAH51676. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

459

Helix Strand Turn

Details...

Helix

11 – 13

3

Helix

16 – 26

11

Helix

28 – 30

3

Helix

31 – 38

8

Beta strand

44 – 48

5

Helix

50 – 58

9

Turn

59 – 63

5

Helix

66 – 74

9

Helix

75 – 77

3

Helix

81 – 90

10

Helix

94 – 100

7

Helix

102 – 104

3

Sequences

	Sequence		Length	Mass (Da)
	Q8R4K2 [UniParc]. Last modified June 1, 2002. Version 1. Checksum: FC11AD06983B7AEB	FASTA	459	50,872
	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

References

	« Hide 'large scale' referencesShow '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. , 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.

IPI

IPI00153899.

RefSeq

NP_084202.2. NM_029926.5.

UniGene

Mm.422858.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1WH4	NMR	-	A	1-114	[»]
2A9I	X-ray	1.70	A	1-113	[»]

ProteinModelPortal

Q8R4K2.

SMR

Q8R4K2. Positions 1-458.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-48996N.

IntAct

Q8R4K2. 1 interaction.

PTM databases

PhosphoSite

Q8R4K2.

Proteomic databases

PaxDb

Q8R4K2.

PRIDE

Q8R4K2.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000074936; ENSMUSP00000074471; ENSMUSG00000059883.

GeneID

266632.

KEGG

mmu:266632.

UCSC

uc007xjj.2. mouse.

Organism-specific databases

CTD

51135.

MGI

MGI:2182474. Irak4.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00530000063073.

HOGENOM

HOG000116550.

HOVERGEN

HBG066836.

InParanoid

Q8R4K2.

KO

K04733.

OMA

FINIHIF.

OrthoDB

EOG457572.

Gene expression databases

ArrayExpress

Q8R4K2.

Bgee

Q8R4K2.

CleanEx

MM_IRAK4.

Genevestigator

Q8R4K2.

GermOnline

ENSMUSG00000059883. Mus musculus.

Family and domain databases

Gene3D

1.10.533.10. 1 hit.

InterPro

IPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR017428. Interleukin-1_rcpt-assoc_kin4.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
[Graphical view]

Pfam

PF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]

PIRSF

PIRSF038189. IRAK4. 1 hit.

SUPFAM

SSF47986. DEATH_like. 1 hit.
SSF56112. Kinase_like. 1 hit.

PROSITE

PS50017. DEATH_DOMAIN. False negative.
PS00107. PROTEIN_KINASE_ATP. False negative.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. False negative.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q8R4K2.

NextBio

392172.

SOURCE

Search...

Entry information

Entry name

IRAK4_MOUSE

Accession

Primary (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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program