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Protein

Interleukin-1 receptor-associated kinase 1

Gene

Irak1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein 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 similarity1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei239 – 2391ATPPROSITE-ProRule annotation
Active sitei340 – 3401Proton acceptorPROSITE-ProRule annotation
Binding sitei358 – 3581ATPPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi218 – 2269ATPPROSITE-ProRule annotation
Nucleotide bindingi342 – 3454ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

  • activation of NF-kappaB-inducing kinase activity Source: MGI
  • cytokine-mediated signaling pathway Source: MGI
  • innate immune response Source: UniProtKB
  • interleukin-1-mediated signaling pathway Source: MGI
  • lipopolysaccharide-mediated signaling pathway Source: MGI
  • negative regulation of cholesterol efflux Source: UniProtKB
  • negative regulation of NF-kappaB transcription factor activity Source: MGI
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
  • positive regulation of JUN kinase activity Source: BHF-UCL
  • positive regulation of MAP kinase activity Source: BHF-UCL
  • positive regulation of NF-kappaB transcription factor activity Source: MGI
  • positive regulation of type I interferon production Source: MGI
  • protein autophosphorylation Source: MGI
  • protein oligomerization Source: MGI
  • regulation of cytokine-mediated signaling pathway Source: MGI
  • response to interleukin-1 Source: MGI
  • response to lipopolysaccharide Source: MGI
  • response to peptidoglycan Source: MGI
  • toll-like receptor 2 signaling pathway Source: MGI
  • toll-like receptor 4 signaling pathway Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Immunity, Innate immunity

Keywords - Ligandi

ATP-binding, Magnesium, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-168638. NOD1/2 Signaling Pathway.
R-MMU-209543. p75NTR recruits signalling complexes.
R-MMU-209560. NF-kB is activated and signals survival.
R-MMU-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-MMU-446652. Interleukin-1 signaling.
R-MMU-450302. activated TAK1 mediates p38 MAPK activation.
R-MMU-450321. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
R-MMU-937039. IRAK1 recruits IKK complex.
R-MMU-975110. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
R-MMU-975138. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
R-MMU-975144. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
R-MMU-975155. MyD88 dependent cascade initiated on endosome.

Names & Taxonomyi

Protein namesi
Recommended name:
Interleukin-1 receptor-associated kinase 1 (EC:2.7.11.1)
Short name:
IRAK
Short name:
IRAK-1
Alternative name(s):
Pelle-like protein kinase
Short name:
mPLK
Gene namesi
Name:Irak1
Synonyms:Il1rak
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome X

Organism-specific databases

MGIiMGI:107420. Irak1.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity
  • Lipid droplet 1 Publication

  • Note: Translocates to the nucleus when sumoylated (By similarity). RSAD2/viperin recruits it to the lipid droplet.By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • lipid particle Source: UniProtKB
  • membrane Source: UniProtKB
  • nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Lipid droplet, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice show a loss in TLR7- and TLR9-mediated IFN-alpha production in plasmacytoid dendritic cells demonstrating an important role in innate immune response.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi66 – 661T → A: Abolishes dimerization. 1 Publication
Mutagenesisi66 – 661T → E: Abolishes dimerization. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 710710Interleukin-1 receptor-associated kinase 1PRO_0000086031Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei66 – 661Phosphothreonine; by PKC/PRKCIBy similarity
Modified residuei131 – 1311PhosphoserineBy similarity
Cross-linki134 – 134Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki180 – 180Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei209 – 2091Phosphothreonine; by IRAK4By similarity
Modified residuei375 – 3751PhosphoserineBy similarity
Modified residuei387 – 3871PhosphothreonineBy similarity
Modified residuei553 – 5531PhosphoserineBy similarity

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

MaxQBiQ62406.
PRIDEiQ62406.

PTM databases

iPTMnetiQ62406.
PhosphoSiteiQ62406.

Expressioni

Tissue specificityi

Highly expressed in liver, followed by kidney and skeletal muscle.1 Publication

Developmental stagei

Expressed from E11 day to E18 day.1 Publication

Gene expression databases

BgeeiENSMUSG00000031392.
CleanExiMM_IRAK1.
ExpressionAtlasiQ62406. baseline and differential.
GenevisibleiQ62406. MM.

Interactioni

Subunit structurei

Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). 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-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 (PubMed:21435586). Interacts with IRAK1BP1 (PubMed:11096118). Interacts with PELI2 (PubMed:12370331). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (PubMed:22037600). Interacts with IRAK4 (By similarity). Interacts with PELI3 (By similarity). Interacts with PELI1 and TRAF6 (By similarity).By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Aarsd1Q3THG94EBI-488313,EBI-646572
Fbln2P37889-110EBI-488313,EBI-645953
Myd88P223662EBI-448533,EBI-525108
Peli2Q8BST62EBI-448533,EBI-448554
TifaQ793I82EBI-448533,EBI-524817
TollipQ9QZ062EBI-448533,EBI-74272
Traf2P394292EBI-448533,EBI-520016
Traf6P701964EBI-488313,EBI-448028

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200627. 23 interactions.
DIPiDIP-31491N.
IntActiQ62406. 27 interactions.

Structurei

3D structure databases

ProteinModelPortaliQ62406.
SMRiQ62406. Positions 18-102, 174-519.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini27 – 10680DeathAdd
BLAST
Domaini212 – 521310Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni110 – 211102ProST regionBy similarityAdd
BLAST

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

Contains 1 death domain.Curated
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

GeneTreeiENSGT00530000063073.
HOGENOMiHOG000015226.
HOVERGENiHBG052144.
InParanoidiQ62406.
KOiK04730.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q62406-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAGGPGPGEP VVPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV
60 70 80 90 100
RDQTELRLCE RSEQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT
110 120 130 140 150
AWHPPAPVVP PSTAAPRPSS ISAGSEAGDW SPRKLQSSAS TFLSPAFPGS
160 170 180 190 200
QTHSESELLQ VPLPVSLGPP LPSSAPSSTK SSPESPVSGL QRAHPSPFCW
210 220 230 240 250
PFCEISQGTC NFSEELRIGE GGFGCVYRAV MRNTTYAVKR LKEEADLEWT
260 270 280 290 300
MVKQSFLTEV EQLSRFRHPN IVDFAGYCAE SGLYCLVYGF LPNGSLEDQL
310 320 330 340 350
HLQTQACSPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE
360 370 380 390 400
RLMPKLGDFG LARFSRFAGA KASQSSTVAR TSTVRGTLAY LPEEYIKTGR
410 420 430 440 450
LAVDTDTFSF GVVILETLAG QRAVRTQGAK TKYLKDLIED EAEEAGVTLK
460 470 480 490 500
STQPTLWVGV ATDAWAAPIA AQIYKKHLDS RPGPCPPQLG LALAQLACCC
510 520 530 540 550
MHRRAKKRPP MTQVYKRLEG LQAGPPWELE VAGHGSPSPQ ENSYMSTTGS
560 570 580 590 600
AQSGDEPWQP LVVTTRAPAQ AAQQLQRSPN QPVESDESVP GLSATLHSWH
610 620 630 640 650
LTPGSHPSPA SFREASCTQG GTTRESSVRS SPGFQPTTME GSPTGSSSLL
660 670 680 690 700
SSEPPQIIIN PARQKMVQKL ALYEEGVLDS LQLLSSGFFP GLDLEPEKSQ
710
GPEESDEFQS
Length:710
Mass (Da):77,269
Last modified:August 14, 2001 - v3
Checksum:i8A501F002CD3EBD2
GO
Isoform 2 (identifier: Q62406-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     691-710: GLDLEPEKSQGPEESDEFQS → DFVDIDAIGIEAFMSELFINHI

Show »
Length:712
Mass (Da):77,558
Checksum:iE095D92487EA567C
GO

Sequence cautioni

The sequence AAD13224 differs from that shown. Reason: Erroneous initiation. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti702 – 7021P → L in AAO63013 (PubMed:10723722).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei691 – 71020GLDLE…DEFQS → DFVDIDAIGIEAFMSELFIN HI in isoform 2. 1 PublicationVSP_011852Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF103876 mRNA. Translation: AAD13224.1. Different initiation.
AY184363 mRNA. Translation: AAO63013.1.
AY184364 mRNA. Translation: AAO63014.1.
AL672002 Genomic DNA. Translation: CAM18735.1.
U56773 mRNA. Translation: AAC52694.2.
CCDSiCCDS30219.2. [Q62406-1]
CCDS53103.1. [Q62406-2]
RefSeqiNP_001171445.1. NM_001177974.1. [Q62406-1]
NP_001171447.1. NM_001177976.1. [Q62406-2]
NP_032389.2. NM_008363.2. [Q62406-1]
UniGeneiMm.38241.

Genome annotation databases

EnsembliENSMUST00000068286; ENSMUSP00000064448; ENSMUSG00000031392. [Q62406-1]
ENSMUST00000114352; ENSMUSP00000109992; ENSMUSG00000031392. [Q62406-1]
ENSMUST00000114360; ENSMUSP00000110000; ENSMUSG00000031392. [Q62406-2]
GeneIDi16179.
KEGGimmu:16179.
UCSCiuc009tnn.2. mouse. [Q62406-1]
uc012hkn.1. mouse. [Q62406-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF103876 mRNA. Translation: AAD13224.1. Different initiation.
AY184363 mRNA. Translation: AAO63013.1.
AY184364 mRNA. Translation: AAO63014.1.
AL672002 Genomic DNA. Translation: CAM18735.1.
U56773 mRNA. Translation: AAC52694.2.
CCDSiCCDS30219.2. [Q62406-1]
CCDS53103.1. [Q62406-2]
RefSeqiNP_001171445.1. NM_001177974.1. [Q62406-1]
NP_001171447.1. NM_001177976.1. [Q62406-2]
NP_032389.2. NM_008363.2. [Q62406-1]
UniGeneiMm.38241.

3D structure databases

ProteinModelPortaliQ62406.
SMRiQ62406. Positions 18-102, 174-519.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200627. 23 interactions.
DIPiDIP-31491N.
IntActiQ62406. 27 interactions.

PTM databases

iPTMnetiQ62406.
PhosphoSiteiQ62406.

Proteomic databases

MaxQBiQ62406.
PRIDEiQ62406.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000068286; ENSMUSP00000064448; ENSMUSG00000031392. [Q62406-1]
ENSMUST00000114352; ENSMUSP00000109992; ENSMUSG00000031392. [Q62406-1]
ENSMUST00000114360; ENSMUSP00000110000; ENSMUSG00000031392. [Q62406-2]
GeneIDi16179.
KEGGimmu:16179.
UCSCiuc009tnn.2. mouse. [Q62406-1]
uc012hkn.1. mouse. [Q62406-2]

Organism-specific databases

CTDi3654.
MGIiMGI:107420. Irak1.

Phylogenomic databases

GeneTreeiENSGT00530000063073.
HOGENOMiHOG000015226.
HOVERGENiHBG052144.
InParanoidiQ62406.
KOiK04730.

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-168638. NOD1/2 Signaling Pathway.
R-MMU-209543. p75NTR recruits signalling complexes.
R-MMU-209560. NF-kB is activated and signals survival.
R-MMU-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-MMU-446652. Interleukin-1 signaling.
R-MMU-450302. activated TAK1 mediates p38 MAPK activation.
R-MMU-450321. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
R-MMU-937039. IRAK1 recruits IKK complex.
R-MMU-975110. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
R-MMU-975138. TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
R-MMU-975144. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
R-MMU-975155. MyD88 dependent cascade initiated on endosome.

Miscellaneous databases

ChiTaRSiIrak1. mouse.
PROiQ62406.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000031392.
CleanExiMM_IRAK1.
ExpressionAtlasiQ62406. baseline and differential.
GenevisibleiQ62406. MM.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiIRAK1_MOUSE
AccessioniPrimary (citable) accession number: Q62406
Secondary accession number(s): B1AUW4, Q6Y3Z5, Q6Y3Z6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: August 14, 2001
Last modified: September 7, 2016
This is version 160 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.