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Protein

Interleukin-1 receptor-associated kinase 1

Gene

IRAK1

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

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 (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei239ATP1
Active sitei340Proton acceptor1
Binding sitei358ATP1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi218 – 226ATP9
Nucleotide bindingi342 – 345ATP4

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processImmunity, Innate immunity
LigandATP-binding, Magnesium, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Interleukin-1 receptor-associated kinase 1 (EC:2.7.11.1)
Short name:
IRAK-1
Gene namesi
Name:IRAK1
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Unplaced

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Lipid droplet, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002697081 – 718Interleukin-1 receptor-associated kinase 1Add BLAST718

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei66Phosphothreonine; by PKC/PRKCIBy similarity1
Cross-linki134Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki180Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei209Phosphothreonine; by IRAK4By similarity1
Modified residuei375PhosphoserineBy similarity1
Modified residuei387PhosphothreonineBy similarity1
Modified residuei556PhosphoserineBy similarity1

Post-translational modificationi

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 (By similarity).By similarity
Polyubiquitinated by TRAF6 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 (By similarity).By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ2LGB3.
PRIDEiQ2LGB3.

Interactioni

Subunit structurei

Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (By similarity). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (By similarity). The TRAF6-PELI1-IRAK1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (By similarity). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (By similarity). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (By similarity). Interacts with IL1RL1 (By similarity). Interacts (when polyubiquitinated) with IKBKG/NEMO (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with IRAK4 (By similarity). Interacts with PELI3 (By similarity). Interacts with PELI1 and TRAF6 (By similarity). Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity).By similarity

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000021407.

Structurei

3D structure databases

ProteinModelPortaliQ2LGB3.
SMRiQ2LGB3.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini27 – 106DeathAdd BLAST80
Domaini212 – 521Protein kinaseAdd BLAST310

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni110 – 211ProST regionBy similarityAdd BLAST102

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi104 – 194Pro-richAdd BLAST91
Compositional biasi693 – 696Poly-Ser4

Domaini

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 (By similarity).By similarity

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG1187. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000015226.
HOVERGENiHBG052144.
InParanoidiQ2LGB3.
KOiK04730.

Family and domain databases

CDDicd08794. Death_IRAK1. 1 hit.
InterProiView protein in InterPro
IPR011029. DEATH-like_dom_sf.
IPR000488. Death_domain.
IPR035533. Death_IRAK1.
IPR035536. IRAK1.
IPR011009. Kinase-like_dom_sf.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
PANTHERiPTHR24419:SF1. PTHR24419:SF1. 1 hit.
PfamiView protein in Pfam
PF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
SMARTiView protein in SMART
SM00220. S_TKc. 1 hit.
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 2 hits.
PROSITEiView protein in PROSITE
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.

Sequencei

Sequence statusi: Complete.

Q2LGB3-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAGGPGPGDP AVPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV
60 70 80 90 100
RDQTELRLCE RSGQRTASVL WPWINRNARV ADLVRILTHL QLLRARDIIT
110 120 130 140 150
AWHPPAPLLP PSTTSLTPSS ISAPSEAAVP GHRKLPSLAS TFLSPAFPGS
160 170 180 190 200
QTHSDPELCP GPSPAAHQPP LPSPAPSSTK PSPESPMSLL PGAPSSSFCW
210 220 230 240 250
PLHEICQGTH DFSEELKIGE GGFGCVYRAV MRNTVYAVKR LKEEADLEWT
260 270 280 290 300
TVKQSFQTEV QQLSRFRHPN IVDFAGYCAQ SGFYCLVYGF LPNGSLEDRL
310 320 330 340 350
HVQTQAWPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD VKSSNVLLDE
360 370 380 390 400
RLMPKLGDFG LARLSRFTGA NPGQSSSVAR TRTVRGTLAY LPEEYVKTGR
410 420 430 440 450
LAVDTDTFSF GVVLLETLAG QRAVRMHGAQ PKYLKDLVEE EAEEAGVTLK
460 470 480 490 500
GTQTAVQGGP AADTWAALVA AQIYKKHLDP RPGPCPPQLG LALGQLACCC
510 520 530 540 550
LHRRAKRRPP MTQVYQTLEE LQVVVAGPCL ELEAASRSPP SPQENSYVST
560 570 580 590 600
SGSALSRASP WQPLAAPLGA QAQATDWPQK GANQPVESDE SVSDLSAALH
610 620 630 640 650
SWHLSPSCPA GPGAPSWVPA PFGQAACTQG GAARESSCGS GPGLQPTAVE
660 670 680 690 700
GPLLGSSMSS RPPQIVINPA RRKMLQKLAL YEDGVLDSLQ LLSSSSLPDS
710
GQDLQDRQGP EERDEFRS
Length:718
Mass (Da):77,397
Last modified:March 21, 2006 - v2
Checksum:i3B364180697DB1F0
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
DQ319075 mRNA. Translation: ABC47878.2.
RefSeqiNP_001035645.1. NM_001040555.1.
UniGeneiBt.5221.

Genome annotation databases

GeneIDi533953.
KEGGibta:533953.

Similar proteinsi

Entry informationi

Entry nameiIRAK1_BOVIN
AccessioniPrimary (citable) accession number: Q2LGB3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 9, 2007
Last sequence update: March 21, 2006
Last modified: November 22, 2017
This is version 98 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families