P51617 (IRAK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Gene names

Name:	IRAK1
Synonyms:	IRAK

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	712 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. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. 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 the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. Ref.3 Ref.12 Ref.15 Ref.17 Ref.18 Ref.20 Ref.23 Ref.28
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Subunit structure	Homodimer By similarity. Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation. Interacts with IL1RL1. Forms a complex with TRAF6, PELI1, IRAK4 and MYD88. Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex. The TRAF6-PELI1-IRAK1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate 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 IRAK1BP1 By similarity. Interacts (when polyubiquitinated) with IKBKG/NEMO. Interacts with RSAD2/viperin By similarity. Ref.8 Ref.9 Ref.10 Ref.11 Ref.14 Ref.19 Ref.21 Ref.25
Subcellular location	Cytoplasm. Nucleus. Lipid droplet By similarity. Note: Translocates to the nucleus when sumoylated. RSAD2/viperin recruits it to the lipid droplet By similarity. Ref.22
Tissue specificity	Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2. Ref.3
Domain	The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation. Ref.16
Post-translational modification	Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity. Ref.3 Ref.13 Ref.15 Ref.16 Polyubiquitinated after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation. Ref.22
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 Lipid droplet Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Magnesium Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Traceable author statement. Source: Reactome MyD88-dependent toll-like receptor signaling pathway Traceable author statement PubMed 10383454. Source: BHF-UCL TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome activation of MAPK activity Traceable author statement. Source: Reactome activation of NF-kappaB-inducing kinase activity Inferred from direct assay Ref.3. Source: UniProtKB cellular response to hypoxia Inferred from electronic annotation. Source: Compara innate immune response Traceable author statement. Source: Reactome interleukin-1-mediated signaling pathway Inferred from mutant phenotype PubMed 10383454. Source: BHF-UCL lipopolysaccharide-mediated signaling pathway Inferred from mutant phenotype PubMed 10383454. Source: BHF-UCL negative regulation of NF-kappaB transcription factor activity Inferred from mutant phenotype PubMed 10383454. Source: BHF-UCL nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome nucleotide-binding oligomerization domain containing signaling pathway Traceable author statement. Source: Reactome positive regulation of I-kappaB kinase/NF-kappaB cascade Traceable author statement. Source: Reactome positive regulation of NF-kappaB transcription factor activity Inferred from direct assay PubMed 10383454. Source: BHF-UCL 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 positive regulation of transcription, DNA-dependent Non-traceable author statement Ref.3. Source: UniProtKB protein autophosphorylation Non-traceable author statement Ref.3. Source: UniProtKB protein oligomerization Inferred from mutant phenotype PubMed 16831874. Source: UniProtKB regulation of cytokine-mediated signaling pathway Inferred from mutant phenotype PubMed 10383454. Source: BHF-UCL response to peptidoglycan Inferred from electronic annotation. Source: Compara toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Inferred from mutant phenotype PubMed 10383454. Source: BHF-UCL toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome transmembrane receptor protein serine/threonine kinase signaling pathway Non-traceable author statement Ref.3. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome endosome membrane Traceable author statement. Source: Reactome interleukin-1 receptor complex Non-traceable author statement Ref.9. Source: UniProtKB lipid particle Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW NF-kappaB-inducing kinase activity Traceable author statement Ref.1. Source: ProtInc protein homodimerization activity Non-traceable author statement Ref.3. Source: UniProtKB ubiquitin-protein ligase activity Traceable author statement. Source: Reactome
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IRAK2	O43187	3	EBI-358664,EBI-447733
IRAK3	Q9Y616	3	EBI-358664,EBI-447690
IRF4	Q15306	2	EBI-358664,EBI-751345
IRF7	Q92985	2	EBI-358664,EBI-968267
PELI2	Q9HAT8	2	EBI-358664,EBI-448407
PIN1	Q13526	10	EBI-358664,EBI-714158
TIRAP	P58753	2	EBI-358664,EBI-528644
TMEM173	Q86WV6	2	EBI-358664,EBI-2800345
TRAF6	Q9Y4K3	3	EBI-358664,EBI-359276
Unc93b1	Q8VCW4	2	EBI-358664,EBI-6116986	From a different organism.
Zc3h12a	Q5D1E7	3	EBI-358664,EBI-5326026	From a different organism.

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P51617-1)

Also known as: a;

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: P51617-2)

Also known as: b;

The sequence of this isoform differs from the canonical sequence as follows:
     513-542: Missing.

Note: Inactive.

Isoform 3 (identifier: P51617-3)

The sequence of this isoform differs from the canonical sequence as follows:
     45-45: F → FGGWRRAAGGREARGLLAPTPDAPRPA
     478-492: Missing.
     513-542: Missing.

Note: No experimental confirmation available.

Isoform 4 (identifier: P51617-4)

The sequence of this isoform differs from the canonical sequence as follows:
     435-513: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 712	712	Interleukin-1 receptor-associated kinase 1		PRO_0000086030
Regions
	Domain	27 – 106	80	Death
	Domain	212 – 521	310	Protein kinase
	Nucleotide binding	218 – 226	9	ATP By similarity
	Nucleotide binding	342 – 345	4	ATP By similarity
	Region	110 – 211	102	ProST region
	Compositional bias	649 – 655	7	Poly-Ser
	Compositional bias	688 – 691	4	Poly-Ser
Sites
	Active site	340	1	Proton acceptor By similarity
	Binding site	239	1	ATP
	Binding site	358	1	ATP By similarity
Amino acid modifications
	Modified residue	66	1	Phosphothreonine; by PKC/PRKCI Ref.15
	Modified residue	131	1	Phosphoserine Ref.24
	Modified residue	209	1	Phosphothreonine; by IRAK4 Probable
	Modified residue	387	1	Phosphothreonine Ref.16
Natural variations
	Alternative sequence	45	1	F → FGGWRRAAGGREARGLLAPT PDAPRPA in isoform 3.		VSP_011849
	Alternative sequence	435 – 513	79	Missing in isoform 4.		VSP_041950
	Alternative sequence	478 – 492	15	Missing in isoform 3.		VSP_011850
	Alternative sequence	513 – 542	30	Missing in isoform 2 and isoform 3.		VSP_011851
	Natural variant	194	1	R → H. Corresponds to variant rs11465830 [ dbSNP | Ensembl ].		VAR_051629
	Natural variant	196	1	F → S. Ref.1 Corresponds to variant rs1059702 [ dbSNP | Ensembl ].		VAR_051630
	Natural variant	203	1	C → S. Corresponds to variant rs10127175 [ dbSNP | Ensembl ].		VAR_051631
	Natural variant	398	1	T → M. Ref.32 Corresponds to variant rs56340948 [ dbSNP | Ensembl ].		VAR_040573
	Natural variant	412	1	V → M in a glioblastoma multiforme sample; somatic mutation. Ref.32		VAR_040574
	Natural variant	421	1	Q → H in a breast pleomorphic lobular carcinoma sample; somatic mutation. Ref.32		VAR_040575
	Natural variant	532	1	S → L. Ref.1 Ref.32 Corresponds to variant rs1059703 [ dbSNP | Ensembl ].		VAR_040576
	Natural variant	619	1	G → S. Ref.32 Corresponds to variant rs34112487 [ dbSNP | Ensembl ].		VAR_040577
	Natural variant	625	1	T → M. Ref.32 Corresponds to variant rs35638718 [ dbSNP | Ensembl ].		VAR_040578
	Natural variant	638	1	R → W. Ref.32 Corresponds to variant rs56082801 [ dbSNP | Ensembl ].		VAR_040579
	Natural variant	690	1	S → G in a lung adenocarcinoma sample; somatic mutation. Ref.32		VAR_040580
Experimental info
	Mutagenesis	209	1	T → A: Completely abolishes auto-phosphorylation in the kinase domain. Ref.16
	Mutagenesis	239	1	K → S: Loss of kinase activity. Ref.17
	Mutagenesis	387	1	T → A: Loss of kinase activity. Ref.16

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (a) [UniParc]. Last modified December 1, 2000. Version 2. Checksum: A7ADED75D3A3981D	FASTA	712	76,537
	10 20 30 40 50 60 MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE 70 80 90 100 110 120 RSGQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT AWHPPAPLPS PGTTAPRPSS 130 140 150 160 170 180 IPAPAEAEAW SPRKLPSSAS TFLSPAFPGS QTHSGPELGL VPSPASLWPP PPSPAPSSTK 190 200 210 220 230 240 PGPESSVSLL QGARPFPFCW PLCEISRGTH NFSEELKIGE GGFGCVYRAV MRNTVYAVKR 250 260 270 280 290 300 LKENADLEWT AVKQSFLTEV EQLSRFRHPN IVDFAGYCAQ NGFYCLVYGF LPNGSLEDRL 310 320 330 340 350 360 HCQTQACPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE RLTPKLGDFG 370 380 390 400 410 420 LARFSRFAGS SPSQSSMVAR TQTVRGTLAY LPEEYIKTGR LAVDTDTFSF GVVVLETLAG 430 440 450 460 470 480 QRAVKTHGAR TKYLKDLVEE EAEEAGVALR STQSTLQAGL AADAWAAPIA MQIYKKHLDP 490 500 510 520 530 540 RPGPCPPELG LGLGQLACCC LHRRAKRRPP MTQVYERLEK LQAVVAGVPG HSEAASCIPP 550 560 570 580 590 600 SPQENSYVSS TGRAHSGAAP WQPLAAPSGA SAQAAEQLQR GPNQPVESDE SLGGLSAALR 610 620 630 640 650 660 SWHLTPSCPL DPAPLREAGC PQGDTAGESS WGSGPGSRPT AVEGLALGSS ASSSSEPPQI 670 680 690 700 710 IINPARQKMV QKLALYEDGA LDSLQLLSSS SLPGLGLEQD RQGPEESDEF QS
	Isoform 2 (b) [UniParc]. Checksum: 687C7EB6064FA918	FASTA	682	73,421
	10 20 30 40 50 60 MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE 70 80 90 100 110 120 RSGQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT AWHPPAPLPS PGTTAPRPSS 130 140 150 160 170 180 IPAPAEAEAW SPRKLPSSAS TFLSPAFPGS QTHSGPELGL VPSPASLWPP PPSPAPSSTK 190 200 210 220 230 240 PGPESSVSLL QGARPFPFCW PLCEISRGTH NFSEELKIGE GGFGCVYRAV MRNTVYAVKR 250 260 270 280 290 300 LKENADLEWT AVKQSFLTEV EQLSRFRHPN IVDFAGYCAQ NGFYCLVYGF LPNGSLEDRL 310 320 330 340 350 360 HCQTQACPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE RLTPKLGDFG 370 380 390 400 410 420 LARFSRFAGS SPSQSSMVAR TQTVRGTLAY LPEEYIKTGR LAVDTDTFSF GVVVLETLAG 430 440 450 460 470 480 QRAVKTHGAR TKYLKDLVEE EAEEAGVALR STQSTLQAGL AADAWAAPIA MQIYKKHLDP 490 500 510 520 530 540 RPGPCPPELG LGLGQLACCC LHRRAKRRPP MTQENSYVSS TGRAHSGAAP WQPLAAPSGA 550 560 570 580 590 600 SAQAAEQLQR GPNQPVESDE SLGGLSAALR SWHLTPSCPL DPAPLREAGC PQGDTAGESS 610 620 630 640 650 660 WGSGPGSRPT AVEGLALGSS ASSSSEPPQI IINPARQKMV QKLALYEDGA LDSLQLLSSS 670 680 SLPGLGLEQD RQGPEESDEF QS
	Isoform 3 [UniParc]. Checksum: D744A32E997E1246	FASTA	693	74,560
	10 20 30 40 50 60 MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFGGWRR AAGGREARGL 70 80 90 100 110 120 LAPTPDAPRP AAALIVRDQT ELRLCERSGQ RTASVLWPWI NRNARVADLV HILTHLQLLR 130 140 150 160 170 180 ARDIITAWHP PAPLPSPGTT APRPSSIPAP AEAEAWSPRK LPSSASTFLS PAFPGSQTHS 190 200 210 220 230 240 GPELGLVPSP ASLWPPPPSP APSSTKPGPE SSVSLLQGAR PFPFCWPLCE ISRGTHNFSE 250 260 270 280 290 300 ELKIGEGGFG CVYRAVMRNT VYAVKRLKEN ADLEWTAVKQ SFLTEVEQLS RFRHPNIVDF 310 320 330 340 350 360 AGYCAQNGFY CLVYGFLPNG SLEDRLHCQT QACPPLSWPQ RLDILLGTAR AIQFLHQDSP 370 380 390 400 410 420 SLIHGDIKSS NVLLDERLTP KLGDFGLARF SRFAGSSPSQ SSMVARTQTV RGTLAYLPEE 430 440 450 460 470 480 YIKTGRLAVD TDTFSFGVVV LETLAGQRAV KTHGARTKYL KDLVEEEAEE AGVALRSTQS 490 500 510 520 530 540 TLQAGLAADA WAAPIAMQIY KKHLGQLACC CLHRRAKRRP PMTQENSYVS STGRAHSGAA 550 560 570 580 590 600 PWQPLAAPSG ASAQAAEQLQ RGPNQPVESD ESLGGLSAAL RSWHLTPSCP LDPAPLREAG 610 620 630 640 650 660 CPQGDTAGES SWGSGPGSRP TAVEGLALGS SASSSSEPPQ IIINPARQKM VQKLALYEDG 670 680 690 ALDSLQLLSS SSLPGLGLEQ DRQGPEESDE FQS
	Isoform 4 [UniParc]. Checksum: 419926E55C935F38	FASTA	633	68,022
	10 20 30 40 50 60 MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE 70 80 90 100 110 120 RSGQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT AWHPPAPLPS PGTTAPRPSS 130 140 150 160 170 180 IPAPAEAEAW SPRKLPSSAS TFLSPAFPGS QTHSGPELGL VPSPASLWPP PPSPAPSSTK 190 200 210 220 230 240 PGPESSVSLL QGARPFPFCW PLCEISRGTH NFSEELKIGE GGFGCVYRAV MRNTVYAVKR 250 260 270 280 290 300 LKENADLEWT AVKQSFLTEV EQLSRFRHPN IVDFAGYCAQ NGFYCLVYGF LPNGSLEDRL 310 320 330 340 350 360 HCQTQACPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE RLTPKLGDFG 370 380 390 400 410 420 LARFSRFAGS SPSQSSMVAR TQTVRGTLAY LPEEYIKTGR LAVDTDTFSF GVVVLETLAG 430 440 450 460 470 480 QRAVKTHGAR TKYLVYERLE KLQAVVAGVP GHSEAASCIP PSPQENSYVS STGRAHSGAA 490 500 510 520 530 540 PWQPLAAPSG ASAQAAEQLQ RGPNQPVESD ESLGGLSAAL RSWHLTPSCP LDPAPLREAG 550 560 570 580 590 600 CPQGDTAGES SWGSGPGSRP TAVEGLALGS SASSSSEPPQ IIINPARQKM VQKLALYEDG 610 620 630 ALDSLQLLSS SSLPGLGLEQ DRQGPEESDE FQS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"IRAK: a kinase associated with the interleukin-1 receptor." Cao Z., Henzel W.J., Gao X. Science 271:1128-1131(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, VARIANTS SER-196 AND LEU-532.
[2]	"Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions." Reichwald K., Thiesen J., Wiehe T., Weitzel J., Poustka W.A., Rosenthal A., Platzer M., Stratling W.H., Kioschis P. Mamm. Genome 11:182-190(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[3]	"IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability." Jensen L.E., Whitehead A.S. J. Biol. Chem. 276:29037-29044(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, PHOSPHORYLATION.
[4]	"A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling." Rao N., Nguyen S., Ngo K., Fung-Leung W.P. Mol. Cell. Biol. 25:6521-6532(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
[5]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases 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] (ISOFORMS 3 AND 4). Tissue: Placenta.
[8]	"MyD88: an adapter that recruits IRAK to the IL-1 receptor complex." Wesche H., Henzel W.J., Shillinglaw W., Li S., Cao Z. Immunity 7:837-847(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MYD88.
[9]	"Tollip, a new component of the IL-1R1 pathway, links IRAK to the IL-1 receptor." Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C., Maschera B., Lewis A., Ray K., Tschopp J., Volpe F. Nat. Cell Biol. 2:346-351(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TOLLIP.
[10]	"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: INTERACTION WITH IRAK4.
[11]	"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 PELI1 AND TRAF6.
[12]	"Characterization of Pellino2, a substrate of IRAK1 and IRAK4." Strelow A., Kollewe C., Wesche H. FEBS Lett. 547:157-161(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PELI2.
[13]	"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: PHOSPHORYLATION BY IRAK4.
[14]	"Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein." Jensen L.E., Whitehead A.S. J. Immunol. 171:1500-1506(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PELI3.
[15]	"Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C." Mamidipudi V., Lin C., Seibenhener M.L., Wooten M.W. J. Biol. Chem. 279:4161-4165(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT THR-66.
[16]	"Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling." Kollewe C., Mackensen A.C., Neumann D., Knop J., Cao P., Li S., Wesche H., Martin M.U. J. Biol. Chem. 279:5227-5236(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-209 AND THR-387, DOMAIN, MUTAGENESIS OF THR-209 AND THR-387.
[17]	"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-239.
[18]	"IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression." Huang Y., Li T., Sane D.C., Li L. J. Biol. Chem. 279:51697-51703(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF STAT3.
[19]	"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.
[20]	"Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction." Uematsu S., Sato S., Yamamoto M., Hirotani T., Kato H., Takeshita F., Matsuda M., Coban C., Ishii K.J., Kawai T., Takeuchi O., Akira S. J. Exp. Med. 201:915-923(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF IRF7.
[21]	"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 IRAK4; MYD88; PELI1 AND TRAF6.
[22]	"Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants." Su J., Richter K., Zhang C., Gu Q., Li L. Mol. Immunol. 44:900-905(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION, SUBCELLULAR LOCATION.
[23]	"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.
[24]	"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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[25]	"Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation." Conze D.B., Wu C.J., Thomas J.A., Landstrom A., Ashwell J.D. Mol. Cell. Biol. 28:3538-3547(2008) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION, INTERACTION WITH IKBKG/NEMO.
[26]	"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.
[27]	"Direct activation of protein kinases by unanchored polyubiquitin chains." Xia Z.-P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W., Chen Z.J. Nature 461:114-119(2009) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION.
[28]	"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.
[29]	"IRAK1: a critical signaling mediator of innate immunity." Gottipati S., Rao N.L., Fung-Leung W.P. Cell. Signal. 20:269-276(2008) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[30]	"The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling." Moynagh P.N. Trends Immunol. 30:33-42(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[31]	"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].
[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] MET-398; MET-412; HIS-421; LEU-532; SER-619; MET-625; TRP-638 AND GLY-690.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L76191 mRNA. Translation: AAC41949.1. AF030876 Genomic DNA. Translation: AAC08756.1. AF346607 mRNA. Translation: AAK62888.1. DQ054788 mRNA. Translation: AAY88246.1. U52112 Genomic DNA. No translation available. CH471172 Genomic DNA. Translation: EAW72762.1. CH471172 Genomic DNA. Translation: EAW72763.1. CH471172 Genomic DNA. Translation: EAW72764.1. CH471172 Genomic DNA. Translation: EAW72765.1. BC054000 mRNA. Translation: AAH54000.1. BC014963 mRNA. Translation: AAH14963.1.
IPI	IPI00293652. IPI00385328. IPI00472717.
PIR	G02512.
RefSeq	NP_001020413.1. NM_001025242.1. NP_001020414.1. NM_001025243.1. NP_001560.2. NM_001569.3.
UniGene	Hs.522819.
3D structure databases
ProteinModelPortal	P51617.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-397N.
IntAct	P51617. 22 interactions.
MINT	MINT-97088.
STRING	9606.ENSP00000358997.
PTM databases
PhosphoSite	P51617.
Polymorphism databases
DMDM	8928535.
Proteomic databases
PaxDb	P51617.
PRIDE	P51617.
Protocols and materials databases
DNASU	3654.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000369974; ENSP00000358991; ENSG00000184216. ENST00000369980; ENSP00000358997; ENSG00000184216. ENST00000393682; ENSP00000377287; ENSG00000184216. ENST00000393687; ENSP00000377291; ENSG00000184216. ENST00000594817; ENSP00000472045; ENSG00000268944. ENST00000596145; ENSP00000470203; ENSG00000268944. ENST00000596879; ENSP00000470669; ENSG00000268944. ENST00000600613; ENSP00000469066; ENSG00000268944.
GeneID	3654.
KEGG	hsa:3654.
UCSC	uc004fjr.1. human. uc004fjs.1. human.
Organism-specific databases
CTD	3654.
GeneCards	GC0XM153277.
H-InvDB	HIX0017146.
HGNC	HGNC:6112. IRAK1.
HPA	CAB004461.
MIM	300283. gene.
neXtProt	NX_P51617.
PharmGKB	PA29912.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000015226.
HOVERGEN	HBG052144.
InParanoid	P51617.
KO	K04730.
OMA	WPLCEIS.
OrthoDB	EOG4QNMWR.
PhylomeDB	P51617.
Enzyme and pathway databases
BRENDA	2.7.10.2. 2681.
Pathway_Interaction_DB	il1pathway. IL1-mediated signaling events. p75ntrpathway. p75(NTR)-mediated signaling.
Reactome	REACT_111102. Signal Transduction. REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines. REACT_6900. Immune System.
Gene expression databases
ArrayExpress	P51617.
Bgee	P51617.
CleanEx	HS_IRAK1.
Genevestigator	P51617.
GermOnline	ENSG00000184216. Homo sapiens.
Family and domain databases
Gene3D	1.10.533.10. 1 hit.
InterPro	IPR011029. DEATH-like_dom. IPR000488. Death_domain. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00531. Death. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
SUPFAM	SSF47986. DEATH_like. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS50017. DEATH_DOMAIN. False negative. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P51617.
ChEMBL	CHEMBL3357.
GenomeRNAi	3654.
NextBio	14289.
SOURCE	Search...

Entry information

Entry name

IRAK1_HUMAN

Accession

Primary (citable) accession number: P51617
Secondary accession number(s): D3DWW3 , D3DWW4, Q7Z5V4, Q96C06, Q96RL2

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	December 1, 2000
Last modified:	May 1, 2013
This is version 139 of the entry and version 2 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.