IRAK1_BOVIN
ID IRAK1_BOVIN Reviewed; 718 AA.
AC Q2LGB3;
DT 09-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 21-MAR-2006, sequence version 2.
DT 03-AUG-2022, entry version 119.
DE RecName: Full=Interleukin-1 receptor-associated kinase 1;
DE Short=IRAK-1;
DE EC=2.7.11.1;
GN Name=IRAK1;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary gland;
RX PubMed=16621030; DOI=10.1016/j.vetimm.2006.03.003;
RA Connor E.E., Cates E.A., Williams J.L., Bannerman D.D.;
RT "Cloning and radiation hybrid mapping of bovine toll-like receptor-4 (TLR-
RT 4) signaling molecules.";
RL Vet. Immunol. Immunopathol. 112:302-308(2006).
CC -!- FUNCTION: Serine/threonine-protein kinase that plays a critical role in
CC initiating innate immune response against foreign pathogens. Involved
CC in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly
CC recruited by MYD88 to the receptor-signaling complex upon TLR
CC activation. Association with MYD88 leads to IRAK1 phosphorylation by
CC IRAK4 and subsequent autophosphorylation and kinase activation.
CC Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and
CC PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then,
CC the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated
CC IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the
CC NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA
CC and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and
CC activation. Alternatively, phosphorylates TIRAP to promote its
CC ubiquitination and subsequent degradation. Phosphorylates the
CC interferon regulatory factor 7 (IRF7) to induce its activation and
CC translocation to the nucleus, resulting in transcriptional activation
CC of type I IFN genes, which drive the cell in an antiviral state. When
CC sumoylated, translocates to the nucleus and phosphorylates STAT3 (By
CC similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- SUBUNIT: Homodimer (By similarity). Forms a complex with TRAF6, PELI1,
CC IRAK4 and MYD88 (By similarity). Direct binding of SMAD6 to PELI1
CC prevents complex formation and hence negatively regulates IL1R-TLR
CC signaling and eventually NF-kappa-B-mediated gene expression (By
CC similarity). The TRAF6-PELI1-IRAK1-IRAK4-MYD88 complex recruits
CC MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (By
CC similarity). Interaction with MYD88 recruits IRAK1 to the stimulated
CC receptor complex (By similarity). Interacts with TOLLIP; this
CC interaction occurs in the cytosol prior to receptor activation (By
CC similarity). Interacts with IL1RL1 (By similarity). Interacts (when
CC polyubiquitinated) with IKBKG/NEMO (By similarity). Interacts with
CC RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity).
CC Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this
CC interaction increases the interaction between ZC3H12A and IKBKB/IKKB
CC (By similarity). Interacts with IRAK4 (By similarity). Interacts with
CC PELI3 (By similarity). Interacts with PELI1 and TRAF6 (By similarity).
CC Interacts with INAVA; the interaction takes place upon PRR stimulation
CC (By similarity). Interacts (via C-terminus) with NFATC4 (via N-
CC terminus) (By similarity). {ECO:0000250|UniProtKB:P51617,
CC ECO:0000250|UniProtKB:Q62406}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Lipid droplet {ECO:0000250}. Note=Translocates to the nucleus when
CC sumoylated. RSAD2/viperin recruits it to the lipid droplet (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: The ProST region is composed of many proline and serine
CC residues (more than 20 of each) and some threonines. This region is the
CC site of IRAK-1 hyperphosphorylation (By similarity). {ECO:0000250}.
CC -!- PTM: Following recruitment on the activated receptor complex,
CC phosphorylated on Thr-209, probably by IRAK4, resulting in a
CC conformational change of the kinase domain, allowing further
CC phosphorylations to take place. Thr-387 phosphorylation in the
CC activation loop is required to achieve full enzymatic activity (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta
CC by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin
CC chains linked through 'Lys-63'. Ubiquitination promotes interaction
CC with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation (By
CC similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily. {ECO:0000305}.
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DR EMBL; DQ319075; ABC47878.2; -; mRNA.
DR RefSeq; NP_001035645.1; NM_001040555.1.
DR AlphaFoldDB; Q2LGB3; -.
DR SMR; Q2LGB3; -.
DR STRING; 9913.ENSBTAP00000021407; -.
DR PaxDb; Q2LGB3; -.
DR PRIDE; Q2LGB3; -.
DR Ensembl; ENSBTAT00000021407; ENSBTAP00000021407; ENSBTAG00000016085.
DR GeneID; 533953; -.
DR KEGG; bta:533953; -.
DR CTD; 3654; -.
DR VEuPathDB; HostDB:ENSBTAG00000016085; -.
DR VGNC; VGNC:30264; IRAK1.
DR eggNOG; KOG1187; Eukaryota.
DR GeneTree; ENSGT00940000160502; -.
DR HOGENOM; CLU_000288_173_1_1; -.
DR InParanoid; Q2LGB3; -.
DR OMA; HFQTQAC; -.
DR OrthoDB; 684563at2759; -.
DR Proteomes; UP000009136; Chromosome X.
DR Bgee; ENSBTAG00000016085; Expressed in laryngeal cartilage and 104 other tissues.
DR ExpressionAtlas; Q2LGB3; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046982; F:protein heterodimerization activity; IEA:Ensembl.
DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IBA:GO_Central.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IBA:GO_Central.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IBA:GO_Central.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0001959; P:regulation of cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IBA:GO_Central.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IBA:GO_Central.
DR GO; GO:0060337; P:type I interferon signaling pathway; IEA:Ensembl.
DR CDD; cd08794; Death_IRAK1; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR035533; Death_IRAK1.
DR InterPro; IPR035536; IRAK1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24419:SF1; PTHR24419:SF1; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Cytoplasm; Immunity; Innate immunity; Isopeptide bond; Kinase;
KW Lipid droplet; Magnesium; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Ubl conjugation.
FT CHAIN 1..718
FT /note="Interleukin-1 receptor-associated kinase 1"
FT /id="PRO_0000269708"
FT DOMAIN 27..106
FT /note="Death"
FT DOMAIN 212..521
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 110..211
FT /note="ProST region"
FT /evidence="ECO:0000250"
FT REGION 146..188
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 534..554
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 569..594
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 631..662
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 692..718
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 162..181
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 538..554
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 576..594
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 340
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 218..226
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 239
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 342..345
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 358
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 66
FT /note="Phosphothreonine; by PKC/PRKCI"
FT /evidence="ECO:0000250|UniProtKB:P51617"
FT MOD_RES 209
FT /note="Phosphothreonine; by IRAK4"
FT /evidence="ECO:0000250|UniProtKB:P51617"
FT MOD_RES 375
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P51617"
FT MOD_RES 387
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P51617"
FT MOD_RES 556
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P51617"
FT CROSSLNK 134
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P51617"
FT CROSSLNK 180
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P51617"
SQ SEQUENCE 718 AA; 77397 MW; 3B364180697DB1F0 CRC64;
MAGGPGPGDP AVPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE
RSGQRTASVL WPWINRNARV ADLVRILTHL QLLRARDIIT AWHPPAPLLP PSTTSLTPSS
ISAPSEAAVP GHRKLPSLAS TFLSPAFPGS QTHSDPELCP GPSPAAHQPP LPSPAPSSTK
PSPESPMSLL PGAPSSSFCW PLHEICQGTH DFSEELKIGE GGFGCVYRAV MRNTVYAVKR
LKEEADLEWT TVKQSFQTEV QQLSRFRHPN IVDFAGYCAQ SGFYCLVYGF LPNGSLEDRL
HVQTQAWPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD VKSSNVLLDE RLMPKLGDFG
LARLSRFTGA NPGQSSSVAR TRTVRGTLAY LPEEYVKTGR LAVDTDTFSF GVVLLETLAG
QRAVRMHGAQ PKYLKDLVEE EAEEAGVTLK GTQTAVQGGP AADTWAALVA AQIYKKHLDP
RPGPCPPQLG LALGQLACCC LHRRAKRRPP MTQVYQTLEE LQVVVAGPCL ELEAASRSPP
SPQENSYVST SGSALSRASP WQPLAAPLGA QAQATDWPQK GANQPVESDE SVSDLSAALH
SWHLSPSCPA GPGAPSWVPA PFGQAACTQG GAARESSCGS GPGLQPTAVE GPLLGSSMSS
RPPQIVINPA RRKMLQKLAL YEDGVLDSLQ LLSSSSLPDS GQDLQDRQGP EERDEFRS
