Q9NWZ3 (IRAK4_HUMAN) 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

Alternative name(s):
Renal carcinoma antigen NY-REN-64

Gene names

Name:

IRAK4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	460 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. Ref.1 Ref.9 Ref.11 Ref.15 Ref.16 Ref.18 Ref.23
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
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. Ref.1 Ref.8 Ref.13 Ref.14
Subcellular location	Cytoplasm Ref.26.
Post-translational modification	Phosphorylated By similarity. Ref.28 Ref.29 Ref.30
Involvement in disease	Recurrent isolated invasive pneumococcal disease 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.17 IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.12
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.
Biophysicochemical properties	Kinetic parameters: KM=650 µM for ATP (at pH 7.5) Ref.30 KM=1100 µM for substrate (at pH 7.5)

Ontologies

Keywords
Biological process	Immunity Innate immunity
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
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 MyD88-dependent toll-like receptor signaling pathway Traceable author statement Ref.27. Source: UniProtKB Toll signaling pathway Traceable author statement. Source: Reactome cytokine production Inferred from electronic annotation. Source: Compara cytokine-mediated signaling pathway Inferred from electronic annotation. Source: Compara innate immune response Traceable author statement Ref.27. Source: UniProtKB 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 toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome endosome membrane Traceable author statement. Source: Reactome plasma membrane Traceable author statement. Source: Reactome
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 experiment. Source: Reactome
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
PELI2	Q9HAT8	3	EBI-448378,EBI-448407
TIRAP	P58753	2	EBI-448378,EBI-528644

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9NWZ3-1)

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.

Isoform 2 (identifier: Q9NWZ3-2)

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

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

Nucleotide binding

313 – 316

4

ATP

Sites

Active site

311

1

Proton acceptor By similarity

Binding site

213

1

ATP

Binding site

329

1

ATP

Amino acid modifications

Modified residue

34

1

N6-acetyllysine Ref.22

Modified residue

342

1

Phosphothreonine Ref.29 Ref.30

Modified residue

345

1

Phosphothreonine Ref.28 Ref.29 Ref.30

Modified residue

346

1

Phosphoserine Ref.28 Ref.30

Natural variations

Alternative sequence

1 – 124

124

Missing in isoform 2.

VSP_041556

Natural variant

5

1

I → V. Ref.32
Corresponds to variant rs56312115 [ dbSNP | Ensembl ].

VAR_040588

Natural variant

98

1

S → R. Ref.5
Corresponds to variant rs4251469 [ dbSNP | Ensembl ].

VAR_019354

Natural variant

355

1

M → V. Ref.32

VAR_040589

Natural variant

390

1

H → R. Ref.5
Corresponds to variant rs4251583 [ dbSNP | Ensembl ].

VAR_019355

Natural variant

391

1

R → H. Ref.32
Corresponds to variant rs55944915 [ dbSNP | Ensembl ].

VAR_040590

Natural variant

428

1

A → T. Ref.5 Ref.32
Corresponds to variant rs4251545 [ dbSNP | Ensembl ].

VAR_019356

Experimental info

Mutagenesis

213

1

K → A: Loss of kinase activity. Ref.11

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

11 – 13

3

Helix

16 – 26

11

Helix

31 – 38

8

Beta strand

42 – 48

7

Helix

50 – 57

8

Helix

58 – 60

3

Turn

61 – 63

3

Helix

66 – 73

8

Turn

74 – 77

4

Helix

81 – 89

9

Turn

90 – 92

3

Helix

94 – 100

7

Beta strand

102 – 104

3

Beta strand

166 – 168

3

Helix

170 – 176

7

Turn

177 – 180

4

Turn

185 – 188

4

Beta strand

191 – 194

4

Beta strand

196 – 207

12

Beta strand

209 – 215

7

Turn

223 – 225

3

Helix

226 – 239

14

Beta strand

248 – 252

5

Beta strand

254 – 257

4

Beta strand

259 – 263

5

Helix

270 – 275

6

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

367 – 382

16

Beta strand

391 – 395

5

Helix

398 – 404

7

Helix

410 – 413

4

Helix

423 – 436

14

Turn

441 – 443

3

Helix

447 – 457

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 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
	Isoform 2 [UniParc]. Checksum: 6608D68A2EE4138C	FASTA	336	37,674
	10 20 30 40 50 60 MPFCDKDRTL MTPVQNLEQS YMPPDSSSPE NKSLEVSDTR FHSFSFYELK NVTNNFDERP 70 80 90 100 110 120 ISVGGNKMGE GGFGVVYKGY VNNTTVAVKK LAAMVDITTE ELKQQFDQEI KVMAKCQHEN 130 140 150 160 170 180 LVELLGFSSD GDDLCLVYVY MPNGSLLDRL SCLDGTPPLS WHMRCKIAQG AANGINFLHE 190 200 210 220 230 240 NHHIHRDIKS ANILLDEAFT AKISDFGLAR ASEKFAQTVM TSRIVGTTAY MAPEALRGEI 250 260 270 280 290 300 TPKSDIYSFG VVLLEIITGL PAVDEHREPQ LLLDIKEEIE DEEKTIEDYI DKKMNDADST 310 320 330 SVEAMYSVAS QCLHEKKNKR PDIKKVQQLL QEMTAS

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] (ISOFORM 1), 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), IDENTIFICATION AS A RENAL CANCER ANTIGEN.
[3]	"Human interleukin-1 receptor associated kinase 4 cDNA sequences." Chuang T.H., Ulevitch R.J. Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Spleen.
[4]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
[5]	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.
[6]	"The finished DNA sequence of human chromosome 12." Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A. Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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] (ISOFORM 1). Tissue: Brain.
[8]	"Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex." Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X. J. Biol. Chem. 278:10952-10956(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH IRAK1; PELI1 AND TRAF6.
[9]	"Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4." Burns K., Janssens S., Brissoni B., Olivos N., Beyaert R., Tschopp J. J. Exp. Med. 197:263-268(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF IRAK1.
[10]	"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] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN IRAK4D.
[11]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF LYS-213.
[12]	"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] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN IRAK4D.
[13]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH IL1RL1.
[14]	"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.
[15]	"Cross-talk between IRAK-4 and the NADPH oxidase." Pacquelet S., Johnson J.L., Ellis B.A., Brzezinska A.A., Lane W.S., Munafo D.B., Catz S.D. Biochem. J. 403:451-461(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF NCF1.
[16]	"IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression." Koziczak-Holbro M., Joyce C., Gluck A., Kinzel B., Muller M., Tschopp C., Mathison J.C., Davis C.N., Gram H. J. Biol. Chem. 282:13552-13560(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN TLR7 SIGNALING PATHWAY.
[17]	"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] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN IPD1.
[18]	"The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1." Ordureau A., Smith H., Windheim M., Peggie M., Carrick E., Morrice N., Cohen P. Biochem. J. 409:43-52(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PELI1.
[19]	"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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[20]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[21]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[22]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-34, MASS SPECTROMETRY.
[23]	"IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal)." Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H., Morrice N., O'Neill L.A. J. Biol. Chem. 285:18276-18282(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF TIRAP.
[24]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[25]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[26]	"Natural loss-of-function mutation of myeloid differentiation protein 88 disrupts its ability to form Myddosomes." Nagpal K., Plantinga T.S., Sirois C.M., Monks B.G., Latz E., Netea M.G., Golenbock D.T. J. Biol. Chem. 286:11875-11882(2011) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[27]	"What the Myddosome structure tells us about the initiation of innate immunity." Gay N.J., Gangloff M., O'Neill L.A. Trends Immunol. 32:104-109(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON MYDDOSOME.
[28]	"Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper." Wang Z., Liu J., Sudom A., Ayres M., Li S., Wesche H., Powers J.P., Walker N.P.C. Structure 14:1835-1844(2006) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 154-460 IN COMPLEX WITH INHIBITORS, PHOSPHORYLATION AT THR-345 AND SER-346.
[29]	"Crystal structures of the apo and inhibited IRAK4 kinase domain." Mol C.D., Arduini R.M., Baker D.P., Chien E.Y., Dougan D.R., Friedman J., Gibaja V., Hession C.A., Horne A. Submitted (DEC-2006) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 163-460, PHOSPHORYLATION AT THR-342 AND THR-345.
[30]	"Cutting Edge: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations." Kuglstatter A., Villasenor A.G., Shaw D., Lee S.W., Tsing S., Niu L., Song K.W., Barnett J.W., Browner M.F. J. Immunol. 178:2641-2645(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 160-460 IN COMPLEX WITH ATP ANALOGS, PHOSPHORYLATION AT THR-342; THR-345 AND SER-346, BIOPHYSICOCHEMICAL PROPERTIES.
[31]	"Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling." Lin S.-C., Lo Y.-C., Wu H. Nature 465:885-890(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) OF 4-106.
[32]	"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] [Europe PMC] [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.
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.

IPI

IPI00007641.
IPI00798404.

RefSeq

NP_001107654.1. NM_001114182.2.
NP_001138728.1. NM_001145256.1.
NP_001138729.1. NM_001145257.1.
NP_001138730.1. NM_001145258.1.
NP_057207.2. NM_016123.3.

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	[»]
3MOP	X-ray	3.40	G/H/I/J	4-106	[»]

ProteinModelPortal

Q9NWZ3.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-31351N.

IntAct

Q9NWZ3. 10 interactions.

MINT

MINT-1383671.

STRING

9606.ENSP00000349096.

Polymorphism databases

DMDM

50401181.

Proteomic databases

PaxDb

Q9NWZ3.

PRIDE

Q9NWZ3.

Protocols and materials databases

DNASU

51135.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000431837; ENSP00000390327; ENSG00000198001.
ENST00000440781; ENSP00000408734; ENSG00000198001.
ENST00000448290; ENSP00000390651; ENSG00000198001.
ENST00000551736; ENSP00000446490; ENSG00000198001.

GeneID

51135.

KEGG

hsa:51135.

UCSC

uc001rnt.3. human.

Organism-specific databases

CTD

51135.

GeneCards

GC12P044152.

HGNC

HGNC:17967. IRAK4.

HPA

CAB016685.
CAB022077.
HPA000924.

MIM

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

neXtProt

NX_Q9NWZ3.

Orphanet

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

PharmGKB

PA134914577.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000116550.

HOVERGEN

HBG066836.

InParanoid

Q9NWZ3.

KO

K04733.

OMA

MRCKIAQ.

OrthoDB

EOG457572.

PhylomeDB

Q9NWZ3.

Enzyme and pathway databases

Pathway_Interaction_DB

il1pathway. IL1-mediated signaling events.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q9NWZ3.

Bgee

Q9NWZ3.

CleanEx

HS_IRAK4.

Genevestigator

Q9NWZ3.

GermOnline

ENSG00000198001. Homo sapiens.

Family and domain databases

Gene3D

1.10.533.10. 1 hit.

InterPro

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

Pfam

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

BindingDB

Q9NWZ3.

ChEMBL

CHEMBL3778.

EvolutionaryTrace

Q9NWZ3.

GenomeRNAi

51135.

NextBio

53983.

SOURCE

Search...

Entry information

Entry name

IRAK4_HUMAN

Accession

Primary (citable) accession number: Q9NWZ3
Secondary accession number(s): Q69FE1, Q8TDF7, Q9Y589

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2004
Last sequence update:	October 1, 2000
Last modified:	May 1, 2013
This is version 123 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.