Q62406 · IRAK1_MOUSE

  • Protein
    Interleukin-1 receptor-associated kinase 1
  • Gene
    Irak1
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

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 (By similarity).

Catalytic activity

Cofactor

Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Features

Showing features for binding site, active site.

TypeIDPosition(s)Description
Binding site218-226ATP (UniProtKB | ChEBI)
Binding site239ATP (UniProtKB | ChEBI)
Active site340Proton acceptor
Binding site342-345ATP (UniProtKB | ChEBI)
Binding site358ATP (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentlipid droplet
Cellular Componentmembrane
Cellular Componentnucleus
Cellular Componentplasma membrane
Cellular Componentprotein-containing complex
Molecular FunctionATP binding
Molecular Functionheat shock protein binding
Molecular Functioninterleukin-1 receptor binding
Molecular Functionkinase activity
Molecular Functionprotein kinase activity
Molecular Functionprotein serine kinase activity
Molecular Functionprotein serine/threonine kinase activity
Biological Processcellular response to heat
Biological Processcellular response to lipopolysaccharide
Biological Processcytokine-mediated signaling pathway
Biological Processinnate immune response
Biological Processinterleukin-1-mediated signaling pathway
Biological Processintracellular signal transduction
Biological ProcessJNK cascade
Biological Processlipopolysaccharide-mediated signaling pathway
Biological Processnegative regulation of cholesterol efflux
Biological Processnegative regulation of DNA-templated transcription
Biological Processpositive regulation of canonical NF-kappaB signal transduction
Biological Processpositive regulation of JUN kinase activity
Biological Processpositive regulation of MAP kinase activity
Biological Processpositive regulation of smooth muscle cell proliferation
Biological Processresponse to lipopolysaccharide
Biological Processresponse to peptidoglycan
Biological ProcessToll signaling pathway
Biological Processtoll-like receptor 2 signaling pathway
Biological Processtoll-like receptor 4 signaling pathway

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Interleukin-1 receptor-associated kinase 1
  • EC number
  • Short names
    IRAK; IRAK-1
  • Alternative names
    • Pelle-like protein kinase (mPLK)

Gene names

    • Name
      Irak1
    • Synonyms
      Il1rak

Organism names

  • Taxonomic identifier
  • Strain
    • C57BL/6J
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q62406
  • Secondary accessions
    • B1AUW4
    • Q6Y3Z5
    • Q6Y3Z6

Proteomes

Organism-specific databases

Subcellular Location

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

Keywords

Phenotypes & Variants

Disruption phenotype

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

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis66Abolishes dimerization.
Mutagenesis66Abolishes dimerization.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 60 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

PTM/Processing

Features

Showing features for chain, modified residue, cross-link.

TypeIDPosition(s)Description
ChainPRO_00000860311-710Interleukin-1 receptor-associated kinase 1
Modified residue66Phosphothreonine; by PKC/PRKCI
Modified residue131Phosphoserine
Cross-link134Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link180Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Modified residue209Phosphothreonine; by IRAK4
Modified residue375Phosphoserine
Modified residue387Phosphothreonine
Modified residue553Phosphoserine

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 (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).

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

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

Developmental stage

Expressed from 11 dpc to 18 dpc.

Gene expression databases

Interaction

Subunit

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).
Interacts (via C-terminus) with NFATC4 (via N-terminus) (By similarity).

Binary interactions

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for domain, region, compositional bias.

TypeIDPosition(s)Description
Domain27-106Death
Region107-133Disordered
Region110-211ProST region
Compositional bias115-133Polar residues
Region169-190Disordered
Compositional bias172-189Polar residues
Domain212-521Protein kinase
Region527-655Disordered
Compositional bias536-559Polar residues
Compositional bias566-592Polar residues
Compositional bias598-655Polar residues
Region689-710Disordered

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 (By similarity).

Sequence similarities

Phylogenomic databases

Family and domain databases

Sequence & Isoform

Align isoforms (2)
  • Sequence status
    Complete

This entry describes 2 isoforms produced by Alternative splicing.

Q62406-1

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.

  • Length
    710
  • Mass (Da)
    77,269
  • Last updated
    2001-08-14 v3
  • Checksum
    8A501F002CD3EBD2
MAGGPGPGEPVVPGAQHFLYEVPPWVMCRFYKVMDALEPADWCQFAALIVRDQTELRLCERSEQRTASVLWPWINRNARVADLVHILTHLQLLRARDIITAWHPPAPVVPPSTAAPRPSSISAGSEAGDWSPRKLQSSASTFLSPAFPGSQTHSESELLQVPLPVSLGPPLPSSAPSSTKSSPESPVSGLQRAHPSPFCWPFCEISQGTCNFSEELRIGEGGFGCVYRAVMRNTTYAVKRLKEEADLEWTMVKQSFLTEVEQLSRFRHPNIVDFAGYCAESGLYCLVYGFLPNGSLEDQLHLQTQACSPLSWPQRLDILLGTARAIQFLHQDSPSLIHGDIKSSNVLLDERLMPKLGDFGLARFSRFAGAKASQSSTVARTSTVRGTLAYLPEEYIKTGRLAVDTDTFSFGVVILETLAGQRAVRTQGAKTKYLKDLIEDEAEEAGVTLKSTQPTLWVGVATDAWAAPIAAQIYKKHLDSRPGPCPPQLGLALAQLACCCMHRRAKKRPPMTQVYKRLEGLQAGPPWELEVAGHGSPSPQENSYMSTTGSAQSGDEPWQPLVVTTRAPAQAAQQLQRSPNQPVESDESVPGLSATLHSWHLTPGSHPSPASFREASCTQGGTTRESSVRSSPGFQPTTMEGSPTGSSSLLSSEPPQIIINPARQKMVQKLALYEEGVLDSLQLLSSGFFPGLDLEPEKSQGPEESDEFQS

Q62406-2

  • Name
    2
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical
    • 691-710: GLDLEPEKSQGPEESDEFQS → DFVDIDAIGIEAFMSELFINHI

Computationally mapped potential isoform sequences

There are 11 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
F6THK7F6THK7_MOUSEIrak1383
F6ZGQ1F6ZGQ1_MOUSEIrak1128
B1AUV9B1AUV9_MOUSEIrak1146
B1AUW1B1AUW1_MOUSEIrak1147
B1AUW6B1AUW6_MOUSEIrak1750
B1AUW8B1AUW8_MOUSEIrak1631
B1AUW9B1AUW9_MOUSEIrak1683
Q8BR10Q8BR10_MOUSEIrak1711
F7ANU5F7ANU5_MOUSEIrak1199
F7CUT1F7CUT1_MOUSEIrak1216
F6TQF4F6TQF4_MOUSEIrak1257

Sequence caution

The sequence AAD13224.1 differs from that shown. Reason: Erroneous initiation

Features

Showing features for compositional bias, alternative sequence, sequence conflict.

TypeIDPosition(s)Description
Compositional bias115-133Polar residues
Compositional bias172-189Polar residues
Compositional bias536-559Polar residues
Compositional bias566-592Polar residues
Compositional bias598-655Polar residues
Alternative sequenceVSP_011852691-710in isoform 2
Sequence conflict702in Ref. 2; AAO63013

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF103876
EMBL· GenBank· DDBJ
AAD13224.1
EMBL· GenBank· DDBJ
mRNA Different initiation
AY184363
EMBL· GenBank· DDBJ
AAO63013.1
EMBL· GenBank· DDBJ
mRNA
AY184364
EMBL· GenBank· DDBJ
AAO63014.1
EMBL· GenBank· DDBJ
mRNA
AL672002
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
U56773
EMBL· GenBank· DDBJ
AAC52694.2
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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. Our staff consists of biologists and biochemists that are not trained to give medical advice.
We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.
FeedbackHelp