UniProt Accession

 IRAK1_HUMAN; P51617; D3DWW3; D3DWW4; Q7Z5V4; Q96C06; Q96RL2 

Genbank Protein ID

 L76191; AF030876; AF346607; DQ054788; U52112; CH471172; CH471172; CH471172; CH471172; BC054000; BC014963 

Genbank Nucleotide ID

 AAC41949.1; AAC08756.1; AAK62888.1; AAY88246.1; EAW72762.1; EAW72763.1; EAW72764.1; EAW72765.1; AAH54000.1; AAH14963.1 

Protein Name

 Interleukin-1 receptor-associated kinase 1 

Protein Synonyms/Alias

 IRAK-1 

Gene Name

 IRAK1 

Gene Synonyms/Alias

 IRAK 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
239	RNTVYAVKRLKENAD	ubiquitination	[1]
242	VYAVKRLKENADLEW	ubiquitination	[2]
342	SLIHGDIKSSNVLLD	ubiquitination	[1, 2, 3, 4]
355	LDERLTPKLGDFGLA	ubiquitination	[2, 3, 4]
397	YLPEEYIKTGRLAVD	ubiquitination	[1, 2, 3, 4, 5, 6, 7]
435	GARTKYLKDLVEEEA	ubiquitination	[1, 2]

Reference

 [1] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [4] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [5] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [6] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [7] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
 Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
 Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965] 

Functional Description

 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. 

Sequence Annotation

 DOMAIN 27 106 Death.
 DOMAIN 212 521 Protein kinase.
 NP_BIND 218 226 ATP (By similarity).
 NP_BIND 342 345 ATP (By similarity).
 REGION 110 211 ProST region.
 ACT_SITE 340 340 Proton acceptor (By similarity).
 BINDING 239 239 ATP.
 BINDING 358 358 ATP (By similarity).
 MOD_RES 66 66 Phosphothreonine; by PKC/PRKCI.
 MOD_RES 131 131 Phosphoserine.
 MOD_RES 209 209 Phosphothreonine; by IRAK4 (Probable).
 MOD_RES 387 387 Phosphothreonine.  

Keyword

 Alternative splicing; ATP-binding; Complete proteome; Cytoplasm; Direct protein sequencing; Immunity; Innate immunity; Kinase; Lipid droplet; Magnesium; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Serine/threonine-protein kinase; Transferase; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 712 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0010008; C:endosome membrane; TAS:Reactome.
 GO:0045323; C:interleukin-1 receptor complex; NAS:UniProtKB.
 GO:0005811; C:lipid particle; ISS:UniProtKB.
 GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004704; F:NF-kappaB-inducing kinase activity; TAS:ProtInc.
 GO:0042803; F:protein homodimerization activity; NAS:UniProtKB.
 GO:0004842; F:ubiquitin-protein ligase activity; TAS:Reactome.
 GO:0000187; P:activation of MAPK activity; TAS:Reactome.
 GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IDA:UniProtKB.
 GO:0071456; P:cellular response to hypoxia; IEA:Compara.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:BHF-UCL.
 GO:0007254; P:JNK cascade; TAS:Reactome.
 GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:BHF-UCL.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:BHF-UCL.
 GO:0043066; P:negative regulation of apoptotic process; TAS:Reactome.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
 GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
 GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL.
 GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Compara.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Compara.
 GO:0045893; P:positive regulation of transcription, DNA-dependent; NAS:UniProtKB.
 GO:0046777; P:protein autophosphorylation; NAS:UniProtKB.
 GO:0051259; P:protein oligomerization; IMP:UniProtKB.
 GO:0001959; P:regulation of cytokine-mediated signaling pathway; IMP:BHF-UCL.
 GO:0032494; P:response to peptidoglycan; IEA:Compara.
 GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
 GO:0034134; P:toll-like receptor 2 signaling pathway; IMP:BHF-UCL.
 GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
 GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0007178; P:transmembrane receptor protein serine/threonine kinase signaling pathway; NAS:UniProtKB.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. 

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. 

Pfam

 PF00531; Death
 PF00069; Pkinase 

SMART

  

PROSITE

 PS50017; DEATH_DOMAIN
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS