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UniProtKB - Q62406 (IRAK1_MOUSE)

Protein

Interleukin-1 receptor-associated kinase 1

Gene

Irak1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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

Mg2+

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei239ATPPROSITE-ProRule annotation1
Active sitei340Proton acceptorPROSITE-ProRule annotation1
Binding sitei358ATPPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi218 – 226ATPPROSITE-ProRule annotation9
Nucleotide bindingi342 – 345ATPPROSITE-ProRule annotation4

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.10.2 3474
ReactomeiR-MMU-1257604 PIP3 activates AKT signaling
R-MMU-209543 p75NTR recruits signalling complexes
R-MMU-209560 NF-kB is activated and signals survival
R-MMU-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-MMU-9020702 Interleukin-1 signaling
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 lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome X

Organism-specific databases

MGIiMGI:107420 Irak1

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

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)DescriptionActionsGraphical viewLength
Mutagenesisi66T → A: Abolishes dimerization. 1 Publication1
Mutagenesisi66T → E: Abolishes dimerization. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000860311 – 710Interleukin-1 receptor-associated kinase 1Add BLAST710

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei66Phosphothreonine; by PKC/PRKCIBy similarity1
Modified residuei131PhosphoserineBy 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 residuei553PhosphoserineBy 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

PRIDEiQ62406

PTM databases

iPTMnetiQ62406
PhosphoSitePlusiQ62406

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 Expressed in 285 organ(s), highest expression level in pancreas
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). Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity).By similarity5 Publications

Binary interactionsi

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi200627, 22 interactors
DIPiDIP-31491N
ELMiQ62406
IntActiQ62406, 28 interactors

Structurei

3D structure databases

ProteinModelPortaliQ62406
SMRiQ62406
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini27 – 106DeathAdd BLAST80
Domaini212 – 521Protein kinasePROSITE-ProRule annotationAdd BLAST310

Region

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

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

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.Curated

Phylogenomic databases

GeneTreeiENSGT00530000063073
HOGENOMiHOG000015226
HOVERGENiHBG052144
InParanoidiQ62406
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

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 11 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 11 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
B1AUW6B1AUW6_MOUSE
Interleukin-1 receptor-associated k...
Irak1
750Annotation score:
B1AUW8B1AUW8_MOUSE
Interleukin-1 receptor-associated k...
Irak1
631Annotation score:
Q8BR10Q8BR10_MOUSE
Interleukin-1 receptor-associated k...
Irak1
711Annotation score:
B1AUW9B1AUW9_MOUSE
Interleukin-1 receptor-associated k...
Irak1
683Annotation score:
F6THK7F6THK7_MOUSE
Interleukin-1 receptor-associated k...
Irak1
383Annotation score:
B1AUW1B1AUW1_MOUSE
Interleukin-1 receptor-associated k...
Irak1
147Annotation score:
F6TQF4F6TQF4_MOUSE
Interleukin-1 receptor-associated k...
Irak1
257Annotation score:
F6ZGQ1F6ZGQ1_MOUSE
Interleukin-1 receptor-associated k...
Irak1
128Annotation score:
F7ANU5F7ANU5_MOUSE
Interleukin-1 receptor-associated k...
Irak1
199Annotation score:
B1AUV9B1AUV9_MOUSE
Interleukin-1 receptor-associated k...
Irak1
146Annotation score:
There is more potential isoformShow all

Sequence cautioni

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

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti702P → L in AAO63013 (PubMed:10723722).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_011852691 – 710GLDLE…DEFQS → DFVDIDAIGIEAFMSELFIN HI in isoform 2. 1 PublicationAdd BLAST20

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 No translation available.
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

Similar proteinsi

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 No translation available.
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
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200627, 22 interactors
DIPiDIP-31491N
ELMiQ62406
IntActiQ62406, 28 interactors

PTM databases

iPTMnetiQ62406
PhosphoSitePlusiQ62406

Proteomic databases

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-1257604 PIP3 activates AKT signaling
R-MMU-209543 p75NTR recruits signalling complexes
R-MMU-209560 NF-kB is activated and signals survival
R-MMU-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-MMU-9020702 Interleukin-1 signaling
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
PROiPR:Q62406
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000031392 Expressed in 285 organ(s), highest expression level in pancreas
CleanExiMM_IRAK1
ExpressionAtlasiQ62406 baseline and differential
GenevisibleiQ62406 MM

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
ProtoNetiSearch...

Entry informationi

Entry nameiIRAK1_MOUSE
AccessioniPrimary (citable) accession number: Q62406
Secondary accession number(s): B1AUW4, Q6Y3Z5, Q6Y3Z6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: August 14, 2001
Last modified: September 12, 2018
This is version 176 of the entry and version 3 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. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  2. SIMILARITY comments
    Index of protein domains and families
  3. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
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