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Q62406 (IRAK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 115. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Interleukin-1 receptor-associated kinase 1
Short name=IRAK
Short name=IRAK-1
EC=2.7.11.1
Alternative name(s):
Pelle-like protein kinase
Short name=mPLK
Gene names
Name:Irak1
Synonyms:Il1rak
OrganismMus musculus (Mouse)
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length710 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.4

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

Subunit structure

Homodimer By similarity. Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation. Interacts with MYD88; this interaction recruits IRAK1 to the stimulated receptor complex. Interacts with IL1RL1. Interacts with IRAK1BP1 By similarity. Associates with TRAF6, PELI1 and IRAK4; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Interacts (when polyubiquitinated) with IKBKG/NEMO By similarity. Ref.5 Ref.6 Ref.7

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Note: Translocates to the nucleus when sumoylated By similarity.

Tissue specificity

Highly expressed in liver, followed by kidney and skeletal muscle. Ref.4

Developmental stage

Expressed from E11 day to E18 day. Ref.4

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.

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. Ref.4

Polyubiquitinated 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.

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. Ref.8

Sequence similarities

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

Contains 1 death domain.

Contains 1 protein kinase domain.

Sequence caution

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

Ontologies

Keywords
   Biological processImmunity
Innate immunity
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Magnesium
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological processinnate immune response

Inferred from expression pattern. Source: UniProtKB

interleukin-1-mediated signaling pathway

Inferred from direct assay. Source: MGI

lipopolysaccharide-mediated signaling pathway

Inferred from direct assay. Source: MGI

negative regulation of cholesterol efflux

Inferred from mutant phenotype. Source: UniProtKB

negative regulation of transcription, DNA-dependent

Inferred from mutant phenotype. Source: UniProtKB

positive regulation of JUN kinase activity

Inferred from mutant phenotype. Source: BHF-UCL

positive regulation of NF-kappaB transcription factor activity

Inferred from direct assay. Source: MGI

protein autophosphorylation

Inferred from direct assay. Source: MGI

response to peptidoglycan

Inferred from direct assay. Source: MGI

toll-like receptor 2 signaling pathway

Inferred from direct assay. Source: MGI

toll-like receptor 4 signaling pathway

Inferred from direct assay. Source: MGI

   Cellular componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

membrane fraction

Inferred from direct assay. Source: UniProtKB

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

interleukin-1 receptor binding

Inferred from physical interaction. Source: MGI

protein binding

Inferred from physical interaction Ref.7. Source: IntAct

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: 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.
Isoform 2 (identifier: Q62406-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 710710Interleukin-1 receptor-associated kinase 1
PRO_0000086031

Regions

Domain27 – 10680Death
Domain212 – 521310Protein kinase
Nucleotide binding218 – 2269ATP By similarity
Nucleotide binding342 – 3454ATP By similarity
Region110 – 211102ProST region By similarity

Sites

Active site3401Proton acceptor By similarity
Binding site2391ATP By similarity
Binding site3581ATP By similarity

Amino acid modifications

Modified residue661Phosphothreonine; by PKC/PRKCI By similarity
Modified residue1311Phosphoserine By similarity
Modified residue2091Phosphothreonine; by IRAK4 By similarity
Modified residue3771Phosphothreonine By similarity
Modified residue3871Phosphothreonine By similarity

Natural variations

Alternative sequence691 – 71020GLDLE…DEFQS → DFVDIDAIGIEAFMSELFIN HI in isoform 2.
VSP_011852

Experimental info

Mutagenesis661T → A: Abolishes dimerization. Ref.6
Mutagenesis661T → E: Abolishes dimerization. Ref.6
Sequence conflict7021P → L in AAO63013. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified August 14, 2001. Version 3.
Checksum: 8A501F002CD3EBD2

FASTA71077,269
        10         20         30         40         50         60 
MAGGPGPGEP VVPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE 

        70         80         90        100        110        120 
RSEQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT AWHPPAPVVP PSTAAPRPSS 

       130        140        150        160        170        180 
ISAGSEAGDW SPRKLQSSAS TFLSPAFPGS QTHSESELLQ VPLPVSLGPP LPSSAPSSTK 

       190        200        210        220        230        240 
SSPESPVSGL QRAHPSPFCW PFCEISQGTC NFSEELRIGE GGFGCVYRAV MRNTTYAVKR 

       250        260        270        280        290        300 
LKEEADLEWT MVKQSFLTEV EQLSRFRHPN IVDFAGYCAE SGLYCLVYGF LPNGSLEDQL 

       310        320        330        340        350        360 
HLQTQACSPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE RLMPKLGDFG 

       370        380        390        400        410        420 
LARFSRFAGA KASQSSTVAR TSTVRGTLAY LPEEYIKTGR LAVDTDTFSF GVVILETLAG 

       430        440        450        460        470        480 
QRAVRTQGAK TKYLKDLIED EAEEAGVTLK STQPTLWVGV ATDAWAAPIA AQIYKKHLDS 

       490        500        510        520        530        540 
RPGPCPPQLG LALAQLACCC MHRRAKKRPP MTQVYKRLEG LQAGPPWELE VAGHGSPSPQ 

       550        560        570        580        590        600 
ENSYMSTTGS AQSGDEPWQP LVVTTRAPAQ AAQQLQRSPN QPVESDESVP GLSATLHSWH 

       610        620        630        640        650        660 
LTPGSHPSPA SFREASCTQG GTTRESSVRS SPGFQPTTME GSPTGSSSLL SSEPPQIIIN 

       670        680        690        700        710 
PARQKMVQKL ALYEEGVLDS LQLLSSGFFP GLDLEPEKSQ GPEESDEFQS

« Hide

Isoform 2 [UniParc].

Checksum: E095D92487EA567C
Show »

FASTA71277,558

References

« Hide 'large scale' references
[1]"Cloning of mouse IRAK."
Kopp E.B., Ghosh S.
Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions."
Reichwald K., Thiesen J., Wiehe T., Weitzel J., Poustka W.A., Rosenthal A., Platzer M., Stratling W.H., Kioschis P.
Mamm. Genome 11:182-190(2000) [PubMed: 10723722] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
[3]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6.
[4]"Developmental and tissue-specific expression of mouse pelle-like protein kinase."
Trofimova M., Sprenkle A.B., Green M., Sturgill T.W., Goebl M.G., Harrington M.A.
J. Biol. Chem. 271:17609-17612(1996) [PubMed: 8663605] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 34-710 (ISOFORM 1), FUNCTION, DEVELOPMENTAL STAGE, TISSUE SPECIFICITY, AUTOPHOSPHORYLATION.
Tissue: Embryo.
[5]"SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity."
Vig E., Green M., Liu Y., Yu K.-Y., Kwon H.-J., Tian J., Goebl M.G., Harrington M.A.
J. Biol. Chem. 276:7859-7866(2001) [PubMed: 11096118] [Abstract]
Cited for: INTERACTION WITH IRAK1BP1.
[6]"Identification of threonine 66 as a functionally critical residue of the interleukin-1 receptor-associated kinase."
Ross K., Yang L., Dower S., Volpe F., Guesdon F.
J. Biol. Chem. 277:37414-37421(2002) [PubMed: 12138165] [Abstract]
Cited for: DIMERIZATION, MUTAGENESIS OF THR-66.
[7]"Mouse pellino-2 modulates IL-1 and lipopolysaccharide signaling."
Yu K.-Y., Kwon H.-J., Norman D.A.M., Vig E., Goebl M.G., Harrington M.A.
J. Immunol. 169:4075-4078(2002) [PubMed: 12370331] [Abstract]
Cited for: INTERACTION WITH PELI2.
[8]"Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction."
Uematsu S., Sato S., Yamamoto M., Hirotani T., Kato H., Takeshita F., Matsuda M., Coban C., Ishii K.J., Kawai T., Takeuchi O., Akira S.
J. Exp. Med. 201:915-923(2005) [PubMed: 15767370] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		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.
IPIIPI00125866.
IPI00474424.
RefSeqNP_001171445.1. NM_001177974.1.
NP_001171447.1. NM_001177976.1.
NP_032389.2. NM_008363.2.
UniGeneMm.38241.

3D structure databases

ProteinModelPortalQ62406.
SMRQ62406. Positions 17-103, 196-521.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-31491N.
IntActQ62406. 24 interactions.
STRINGQ62406.

PTM databases

PhosphoSiteQ62406.

Proteomic databases

PRIDEQ62406.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000068286; ENSMUSP00000064448; ENSMUSG00000031392.
ENSMUST00000114352; ENSMUSP00000109992; ENSMUSG00000031392.
ENSMUST00000114360; ENSMUSP00000110000; ENSMUSG00000031392.
GeneID16179.
KEGGmmu:16179.
UCSCuc012hkn.1. mouse.

Organism-specific databases

CTD3654.
MGIMGI:107420. Irak1.

Phylogenomic databases

HOVERGENHBG052144.

Enzyme and pathway databases

BRENDA2.7.10.2. 3474.

Gene expression databases

ArrayExpressQ62406.
BgeeQ62406.
CleanExMM_IRAK1.
GenevestigatorQ62406.
GermOnlineENSMUSG00000031392. Mus musculus.

Family and domain databases

InterProIPR000488. Death.
IPR011029. DEATH-like.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
Gene3DG3DSA:1.10.533.10. DEATH_like. 1 hit.
KOK04730.
PfamPF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMSSF47986. DEATH_like. 1 hit.
SSF56112. Kinase_like. 1 hit.
PROSITEPS50017. DEATH_DOMAIN. False negative.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio289049.
SOURCESearch...

Entry information

Entry nameIRAK1_MOUSE
AccessionPrimary (citable) accession number: Q62406
Secondary accession number(s): B1AUW4, Q6Y3Z5, Q6Y3Z6
Entry history
Integrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: August 14, 2001
Last modified: January 25, 2012
This is version 115 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

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