Q62406 · IRAK1_MOUSE
- ProteinInterleukin-1 receptor-associated kinase 1
- GeneIrak1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids710 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Cofactor
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameInterleukin-1 receptor-associated kinase 1
- EC number
- Short namesIRAK; IRAK-1
- Alternative names
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ62406
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Translocates to the nucleus when sumoylated (By similarity).
RSAD2/viperin recruits it to the lipid droplet
RSAD2/viperin recruits it to the lipid droplet
Keywords
- Cellular component
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 66 | Abolishes dimerization. | ||||
Sequence: T → A | ||||||
Mutagenesis | 66 | Abolishes dimerization. | ||||
Sequence: T → E |
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.
PTM/Processing
Features
Showing features for chain, modified residue, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000086031 | 1-710 | Interleukin-1 receptor-associated kinase 1 | |||
Sequence: MAGGPGPGEPVVPGAQHFLYEVPPWVMCRFYKVMDALEPADWCQFAALIVRDQTELRLCERSEQRTASVLWPWINRNARVADLVHILTHLQLLRARDIITAWHPPAPVVPPSTAAPRPSSISAGSEAGDWSPRKLQSSASTFLSPAFPGSQTHSESELLQVPLPVSLGPPLPSSAPSSTKSSPESPVSGLQRAHPSPFCWPFCEISQGTCNFSEELRIGEGGFGCVYRAVMRNTTYAVKRLKEEADLEWTMVKQSFLTEVEQLSRFRHPNIVDFAGYCAESGLYCLVYGFLPNGSLEDQLHLQTQACSPLSWPQRLDILLGTARAIQFLHQDSPSLIHGDIKSSNVLLDERLMPKLGDFGLARFSRFAGAKASQSSTVARTSTVRGTLAYLPEEYIKTGRLAVDTDTFSFGVVILETLAGQRAVRTQGAKTKYLKDLIEDEAEEAGVTLKSTQPTLWVGVATDAWAAPIAAQIYKKHLDSRPGPCPPQLGLALAQLACCCMHRRAKKRPPMTQVYKRLEGLQAGPPWELEVAGHGSPSPQENSYMSTTGSAQSGDEPWQPLVVTTRAPAQAAQQLQRSPNQPVESDESVPGLSATLHSWHLTPGSHPSPASFREASCTQGGTTRESSVRSSPGFQPTTMEGSPTGSSSLLSSEPPQIIINPARQKMVQKLALYEEGVLDSLQLLSSGFFPGLDLEPEKSQGPEESDEFQS | ||||||
Modified residue | 66 | Phosphothreonine; by PKC/PRKCI | ||||
Sequence: T | ||||||
Modified residue | 131 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 134 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 180 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 209 | Phosphothreonine; by IRAK4 | ||||
Sequence: T | ||||||
Modified residue | 375 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 387 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 553 | Phosphoserine | ||||
Sequence: S |
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
- PTM
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).
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
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q62406 | Myd88 P22366 | 3 | EBI-448533, EBI-525108 | |
BINARY | Q62406 | Peli2 Q8BST6 | 2 | EBI-448533, EBI-448554 | |
BINARY | Q62406 | Tifa Q793I8 | 2 | EBI-448533, EBI-524817 | |
BINARY | Q62406 | Tollip Q9QZ06 | 2 | EBI-448533, EBI-74272 | |
BINARY | Q62406 | Traf2 P39429 | 2 | EBI-448533, EBI-520016 | |
BINARY | Q62406-1 | Aarsd1 Q3THG9 | 4 | EBI-488313, EBI-646572 | |
BINARY | Q62406-1 | Fbln2 P37889-1 | 10 | EBI-488313, EBI-645953 | |
BINARY | Q62406-1 | Traf6 P70196 | 4 | EBI-488313, EBI-448028 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 27-106 | Death | ||||
Sequence: MCRFYKVMDALEPADWCQFAALIVRDQTELRLCERSEQRTASVLWPWINRNARVADLVHILTHLQLLRARDIITAWHPPA | ||||||
Region | 107-133 | Disordered | ||||
Sequence: PVVPPSTAAPRPSSISAGSEAGDWSPR | ||||||
Region | 110-211 | ProST region | ||||
Sequence: PPSTAAPRPSSISAGSEAGDWSPRKLQSSASTFLSPAFPGSQTHSESELLQVPLPVSLGPPLPSSAPSSTKSSPESPVSGLQRAHPSPFCWPFCEISQGTCN | ||||||
Compositional bias | 115-133 | Polar residues | ||||
Sequence: APRPSSISAGSEAGDWSPR | ||||||
Region | 169-190 | Disordered | ||||
Sequence: PPLPSSAPSSTKSSPESPVSGL | ||||||
Compositional bias | 172-189 | Polar residues | ||||
Sequence: PSSAPSSTKSSPESPVSG | ||||||
Domain | 212-521 | Protein kinase | ||||
Sequence: FSEELRIGEGGFGCVYRAVMRNTTYAVKRLKEEADLEWTMVKQSFLTEVEQLSRFRHPNIVDFAGYCAESGLYCLVYGFLPNGSLEDQLHLQTQACSPLSWPQRLDILLGTARAIQFLHQDSPSLIHGDIKSSNVLLDERLMPKLGDFGLARFSRFAGAKASQSSTVARTSTVRGTLAYLPEEYIKTGRLAVDTDTFSFGVVILETLAGQRAVRTQGAKTKYLKDLIEDEAEEAGVTLKSTQPTLWVGVATDAWAAPIAAQIYKKHLDSRPGPCPPQLGLALAQLACCCMHRRAKKRPPMTQVYKRLEGL | ||||||
Region | 527-655 | Disordered | ||||
Sequence: WELEVAGHGSPSPQENSYMSTTGSAQSGDEPWQPLVVTTRAPAQAAQQLQRSPNQPVESDESVPGLSATLHSWHLTPGSHPSPASFREASCTQGGTTRESSVRSSPGFQPTTMEGSPTGSSSLLSSEPP | ||||||
Compositional bias | 536-559 | Polar residues | ||||
Sequence: SPSPQENSYMSTTGSAQSGDEPWQ | ||||||
Compositional bias | 566-592 | Polar residues | ||||
Sequence: RAPAQAAQQLQRSPNQPVESDESVPGL | ||||||
Compositional bias | 598-655 | Polar residues | ||||
Sequence: SWHLTPGSHPSPASFREASCTQGGTTRESSVRSSPGFQPTTMEGSPTGSSSLLSSEPP | ||||||
Region | 689-710 | Disordered | ||||
Sequence: FPGLDLEPEKSQGPEESDEFQS |
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
- Sequence statusComplete
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.
- Name1
- Length710
- Mass (Da)77,269
- Last updated2001-08-14 v3
- Checksum8A501F002CD3EBD2
Q62406-2
- Name2
- Differences from canonical
- 691-710: GLDLEPEKSQGPEESDEFQS → DFVDIDAIGIEAFMSELFINHI
Computationally mapped potential isoform sequences
There are 11 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
F6THK7 | F6THK7_MOUSE | Irak1 | 383 | ||
F6ZGQ1 | F6ZGQ1_MOUSE | Irak1 | 128 | ||
B1AUV9 | B1AUV9_MOUSE | Irak1 | 146 | ||
B1AUW1 | B1AUW1_MOUSE | Irak1 | 147 | ||
B1AUW6 | B1AUW6_MOUSE | Irak1 | 750 | ||
B1AUW8 | B1AUW8_MOUSE | Irak1 | 631 | ||
B1AUW9 | B1AUW9_MOUSE | Irak1 | 683 | ||
Q8BR10 | Q8BR10_MOUSE | Irak1 | 711 | ||
F7ANU5 | F7ANU5_MOUSE | Irak1 | 199 | ||
F7CUT1 | F7CUT1_MOUSE | Irak1 | 216 | ||
F6TQF4 | F6TQF4_MOUSE | Irak1 | 257 |
Sequence caution
Features
Showing features for compositional bias, alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 115-133 | Polar residues | ||||
Sequence: APRPSSISAGSEAGDWSPR | ||||||
Compositional bias | 172-189 | Polar residues | ||||
Sequence: PSSAPSSTKSSPESPVSG | ||||||
Compositional bias | 536-559 | Polar residues | ||||
Sequence: SPSPQENSYMSTTGSAQSGDEPWQ | ||||||
Compositional bias | 566-592 | Polar residues | ||||
Sequence: RAPAQAAQQLQRSPNQPVESDESVPGL | ||||||
Compositional bias | 598-655 | Polar residues | ||||
Sequence: SWHLTPGSHPSPASFREASCTQGGTTRESSVRSSPGFQPTTMEGSPTGSSSLLSSEPP | ||||||
Alternative sequence | VSP_011852 | 691-710 | in isoform 2 | |||
Sequence: GLDLEPEKSQGPEESDEFQS → DFVDIDAIGIEAFMSELFINHI | ||||||
Sequence conflict | 702 | in Ref. 2; AAO63013 | ||||
Sequence: P → L |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
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 |