Reviewed, UniProtKB/Swiss-Prot Q9NWZ3 (IRAK4_HUMAN)

Names and origin

Protein names

Recommended name:
    Interleukin-1 receptor-associated kinase 4
      Short name=IRAK-4
    EC=2.7.11.1
Alternative name(s):
    NY-REN-64 antigen

Gene names

Name:

IRAK4

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	460 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Required for the efficient recruitment of IRAK1 to the IL-1 receptor complex following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization. Phosphorylates IRAK1. Ref.1 Ref.7
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Subunit structure	IL-1 stimulation leads to the formation of a signaling complex which dissociates from the IL-1 receptor following the binding of PELI1. Interacts with IL1RL1. Ref.1 Ref.9
Involvement in disease	Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799]. Recurrent 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. Ref.10 Defects in IRAK4 are the cause of IRAK4 deficiency [MIM:607676]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. Ref.6 Ref.8
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
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Magnesium Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	I-kappaB kinase/NF-kappaB cascade Inferred from Experiment. Source: Reactome protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IL1RL1	Q01638	1	EBI-448378,EBI-993762
PELI2	Q9HAT8	2	EBI-448378,EBI-448407

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 460

460

Interleukin-1 receptor-associated kinase 4

PRO_0000086035

Regions

Domain

20 – 104

85

Death

Domain

186 – 454

269

Protein kinase

Nucleotide binding

192 – 200

9

ATP By similarity

Sites

Active site

311

1

Proton acceptor By similarity

Binding site

213

1

ATP

Amino acid modifications

Modified residue

3

1

N6-acetyllysine Ref.13

Modified residue

34

1

N6-acetyllysine Ref.13

Modified residue

152

1

Phosphoserine Ref.11

Natural variations

Natural variant

5

1

I → V: dbSNP rs56312115. Ref.14

VAR_040588

Natural variant

98

1

S → R: dbSNP rs4251469. Ref.4

VAR_019354

Natural variant

355

1

M → V

VAR_040589

Natural variant

390

1

H → R: dbSNP rs4251583. Ref.4

VAR_019355

Natural variant

391

1

R → H: dbSNP rs55944915. Ref.14

VAR_040590

Natural variant

428

1

A → T: dbSNP rs4251545. Ref.14 Ref.4

VAR_019356

Experimental info

Mutagenesis

213

1

K → A: Loss of kinase activity. Ref.7

Sequence conflict

81

1

V → A in AAM15772. Ref.1

Sequence conflict

432

1

V → G in AAD42884. Ref.2

Sequence conflict

437

1

L → R in AAD42884. Ref.2

Sequence conflict

444

1

R → S in AAD42884. Ref.2

Sequence conflict

451

1

Q → H in AAD42884. Ref.2

Secondary structure

1

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460

Helix Strand Turn

Details...

Helix

170 – 176

7

Turn

177 – 180

4

Helix

185 – 187

3

Beta strand

190 – 193

4

Beta strand

200 – 205

6

Beta strand

208 – 214

7

Helix

227 – 236

10

Helix

237 – 239

3

Beta strand

248 – 252

5

Beta strand

254 – 257

4

Beta strand

259 – 263

5

Helix

270 – 274

5

Helix

277 – 279

3

Helix

285 – 304

20

Helix

314 – 316

3

Beta strand

317 – 319

3

Beta strand

325 – 327

3

Helix

352 – 354

3

Helix

357 – 360

4

Helix

366 – 382

17

Beta strand

389 – 395

7

Helix

396 – 398

3

Helix

399 – 404

6

Helix

410 – 413

4

Helix

423 – 436

14

Helix

441 – 443

3

Helix

447 – 458

12

Sequences

	Sequence		Length	Mass (Da)
	Q9NWZ3-1 [UniParc]. Last modified October 1, 2000. Version 1. Checksum: 6C8156ADF25FF81E	FASTA	460	51,530
	10 20 30 40 50 60 MNKPITPSTY VRCLNVGLIR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ FHIRRFEALL 70 80 90 100 110 120 QTGKSPTSEL LFDWGTTNCT VGDLVDLLIQ NEFFAPASLL LPDAVPKTAN TLPSKEAITV 130 140 150 160 170 180 QQKQMPFCDK DRTLMTPVQN LEQSYMPPDS SSPENKSLEV SDTRFHSFSF YELKNVTNNF 190 200 210 220 230 240 DERPISVGGN KMGEGGFGVV YKGYVNNTTV AVKKLAAMVD ITTEELKQQF DQEIKVMAKC 250 260 270 280 290 300 QHENLVELLG FSSDGDDLCL VYVYMPNGSL LDRLSCLDGT PPLSWHMRCK IAQGAANGIN 310 320 330 340 350 360 FLHENHHIHR DIKSANILLD EAFTAKISDF GLARASEKFA QTVMTSRIVG TTAYMAPEAL 370 380 390 400 410 420 RGEITPKSDI YSFGVVLLEI ITGLPAVDEH REPQLLLDIK EEIEDEEKTI EDYIDKKMND 430 440 450 460 ADSTSVEAMY SVASQCLHEK KNKRPDIKKV QQLLQEMTAS

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: 11960013] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH IRAK1 AND TRAF6.
[2]	"Antigens recognized by autologous antibody in patients with renal-cell carcinoma." Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H., Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T., Old L.J. Int. J. Cancer 83:456-464(1999) [PubMed: 10508479] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], IDENTIFICATION AS A RENAL CANCER ANTIGEN.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	SeattleSNPs variation discovery resource Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-98; ARG-390 AND THR-428.
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[6]	"Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections." Medvedev A.E., Lentschat A., Kuhns D.B., Blanco J.C.G., Salkowski C., Zhang S., Arditi M., Gallin J.I., Vogel S.N. J. Exp. Med. 198:521-531(2003) [PubMed: 12925671] [Abstract] Cited for: INVOLVEMENT IN IRAK4 DEFICIENCY.
[7]	"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: 15084582] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF LYS-213.
[8]	"Pyogenic bacterial infections in humans with IRAK-4 deficiency." Picard C., Puel A., Bonnet M., Ku C.-L., Bustamante J., Yang K., Soudais C., Dupuis S., Feinberg J., Fieschi C., Elbim C., Hitchcock R., Lammas D., Davies G., Al-Ghonaium A., Al-Rayes H., Al-Jumaah S., Al-Hajjar S. , Al-Mohsen I.Z., Frayha H.H., Rucker R., Hawn T.R., Aderem A., Tufenkeji H., Haraguchi S., Day N.K., Good R.A., Gougerot-Pocidalo M.-A., Ozinsky A., Casanova J.-L. Science 299:2076-2079(2003) [PubMed: 12637671] [Abstract] Cited for: INVOLVEMENT IN IRAK4 DEFICIENCY.
[9]	"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: 16286016] [Abstract] Cited for: INTERACTION WITH IL1RL1.
[10]	"IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease." Ku C.-L., Picard C., Erdos M., Jeurissen A., Bustamante J., Puel A., von Bernuth H., Filipe-Santos O., Chang H.-H., Lawrence T., Raes M., Marodi L., Bossuyt X., Casanova J.-L. J. Med. Genet. 44:16-23(2007) [PubMed: 16950813] [Abstract] Cited for: INVOLVEMENT IN IPD1.
[11]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-152, MASS SPECTROMETRY.
[12]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[13]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-3 AND LYS-34, MASS SPECTROMETRY.
[14]	"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: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-5; VAL-355; HIS-391 AND THR-428.
+	Additional computationally mapped references.

Web resources

IRAK4base

IRAK4 mutation db

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF445802 mRNA. Translation: AAM15772.1.
AF155118 mRNA. Translation: AAD42884.1.
AK000528 mRNA. Translation: BAA91232.1.
AY186092 Genomic DNA. Translation: AAN75440.1.
BC013316 mRNA. Translation: AAH13316.1.

IPI

IPI00007641.

RefSeq

NP_001107654.1.
NP_057207.2.

UniGene

Hs.138499

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NRU	X-ray	2.00	A/B/C/D	154-460	[»]
2NRY	X-ray	2.15	A/B/C/D	154-460	[»]
2O8Y	X-ray	2.40	A/B	163-460	[»]
2OIB	X-ray	2.00	A/B/C/D	160-460	[»]
2OIC	X-ray	2.40	A/B/C/D	160-460	[»]
2OID	X-ray	2.30	A/B/C/D	160-460	[»]

SMR

Q9NWZ3. Positions 1-113.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9NWZ3. 6 interactions.

STRING

Q9NWZ3.

Proteomic databases

PRIDE

Q9NWZ3.

Genome annotation databases

Ensembl

ENST00000356669; ENSP00000349096; ENSG00000198001; Homo sapiens. [Genome view]
ENST00000448290; ENSP00000390651; ENSG00000198001; Homo sapiens. [Genome view]

GeneID

51135.

KEGG

hsa:51135.

UCSC

uc001rnt.2. human.

Organism-specific databases

CTD

51135.

GeneCards

GC12P042439.

H-InvDB

HIX0021737.

HGNC

HGNC:17967. IRAK4.

HPA

CAB016685.
CAB022077.
HPA000924.

MIM

606883. gene.
607676. phenotype.
610799. phenotype.

Orphanet

70592. Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency.

PharmGKB

PA134914577.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

HBG713523.

HOVERGEN

Q9NWZ3.

InParanoid

Q9NWZ3.

OMA

MRCKIAQ.

OrthoDB

EOG9DZ4FM.

PhylomeDB

Q9NWZ3.

Enzyme and pathway databases

BRENDA

2.7.11.1. 247.

Pathway_Interaction_DB

il1pathway. IL1-mediated signaling events.

Reactome

REACT_6900. Signaling in Immune system.

Gene expression databases

ArrayExpress

Q9NWZ3.

Bgee

Q9NWZ3.

CleanEx

HS_IRAK4.

Genevestigator

Q9NWZ3.

GermOnline

ENSG00000198001. Homo sapiens.

Family and domain databases

InterPro

IPR011029. DEATH-like.
IPR017428. Interleukin-1_rcpt-assoc_kin4.
IPR015787. Interleukin1_rcpt-assoc_kin4_C.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017442. Se/Thr_prot_kinase-like_dom.
[Graphical view]

PANTHER

PTHR23258:SF428. IRAK4. 1 hit.

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

PIRSF

PIRSF038189. IRAK4. 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 Resources

NextBio

53983.

SOURCE

Search...

Entry information

Entry name

IRAK4_HUMAN

Accession

Primary (citable) accession number: Q9NWZ3
Secondary accession number(s): Q8TDF7, Q9Y589

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2004
Last sequence update:	October 1, 2000
Last modified:	January 19, 2010
This is version 88 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.