IKKA_BOVIN
ID IKKA_BOVIN Reviewed; 740 AA.
AC Q95KV1; A7YWD1;
DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Inhibitor of nuclear factor kappa-B kinase subunit alpha;
DE Short=I-kappa-B kinase alpha;
DE Short=IKK-A;
DE Short=IKK-alpha;
DE Short=IkBKA;
DE EC=2.7.11.10;
DE AltName: Full=I-kappa-B kinase 1;
DE Short=IKK1;
DE AltName: Full=Nuclear factor NF-kappa-B inhibitor kinase alpha;
DE Short=NFKBIKA;
GN Name=CHUK; Synonyms=IKKA;
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], AND INTERACTION WITH IKBKB AND IKBKG.
RX PubMed=12459277; DOI=10.1016/s0378-1119(02)01011-9;
RA Rottenberg S., Schmuckli-Maurer J., Grimm S., Heussler V.T.,
RA Dobbelaere D.A.E.;
RT "Characterization of the bovine IkappaB kinases (IKK)alpha and IKKbeta, the
RT regulatory subunit NEMO and their substrate IkappaBalpha.";
RL Gene 299:293-300(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Ascending colon;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Serine kinase that plays an essential role in the NF-kappa-B
CC signaling pathway which is activated by multiple stimuli such as
CC inflammatory cytokines, bacterial or viral products, DNA damages or
CC other cellular stresses. Acts as part of the canonical IKK complex in
CC the conventional pathway of NF-kappa-B activation and phosphorylates
CC inhibitors of NF-kappa-B on serine residues. These modifications allow
CC polyubiquitination of the inhibitors and subsequent degradation by the
CC proteasome. In turn, free NF-kappa-B is translocated into the nucleus
CC and activates the transcription of hundreds of genes involved in immune
CC response, growth control, or protection against apoptosis. Negatively
CC regulates the pathway by phosphorylating the scaffold protein TAXBP1
CC and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing
CC complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and
CC RNF11). Therefore, CHUK plays a key role in the negative feedback of
CC NF-kappa-B canonical signaling to limit inflammatory gene activation.
CC As part of the non-canonical pathway of NF-kappa-B activation, the
CC MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100
CC associated with RelB, inducing its proteolytic processing to NFKB2/p52
CC and the formation of NF-kappa-B RelB-p52 complexes. In turn, these
CC complexes regulate genes encoding molecules involved in B-cell survival
CC and lymphoid organogenesis. Participates also in the negative feedback
CC of the non-canonical NF-kappa-B signaling pathway by phosphorylating
CC and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates
CC CREBBP and consequently increases both its transcriptional and histone
CC acetyltransferase activities. Modulates chromatin accessibility at NF-
CC kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10'
CC that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally,
CC phosphorylates the CREBBP-interacting protein NCOA3. Also
CC phosphorylates FOXO3 and may regulate this pro-apoptotic transcription
CC factor. Interacts with SASH1 (By similarity). Phosphorylates RIPK1 at
CC 'Ser-25' which represses its kinase activity and consequently prevents
CC TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates
CC AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with
CC ATG8 family proteins and its mitophagic activity (By similarity).
CC {ECO:0000250|UniProtKB:O15111, ECO:0000250|UniProtKB:Q60680}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-
CC seryl-[I-kappa-B protein]; Xref=Rhea:RHEA:19073, Rhea:RHEA-
CC COMP:13698, Rhea:RHEA-COMP:13699, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421,
CC ChEBI:CHEBI:456216; EC=2.7.11.10;
CC -!- ACTIVITY REGULATION: Activated when phosphorylated and inactivated when
CC dephosphorylated.
CC -!- SUBUNIT: Component of the I-kappa-B-kinase (IKK) core complex
CC consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-
CC beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The
CC IKK core complex seems to associate with regulatory or adapter proteins
CC to form a IKK-signalosome holo-complex (PubMed:12459277). The IKK
CC complex associates with TERF2IP/RAP1, leading to promote IKK-mediated
CC phosphorylation of RELA/p65. Part of a complex composed of NCOA2,
CC NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Part of a 70-90 kDa complex
CC at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and
CC MAP3K14. Directly interacts with TRPC4AP. May interact with TRAF2.
CC Interacts with NALP2. May interact with MAVS/IPS1. Interacts with ARRB1
CC and ARRB2. Interacts with NLRC5; prevents CHUK phosphorylation and
CC kinase activity. Interacts with PIAS1; this interaction induces PIAS1
CC phosphorylation. Interacts with ZNF268 isoform 2; the interaction is
CC further increased in a TNF-alpha-dependent manner (By similarity).
CC Interacts with IFIT5; the interaction synergizes the recruitment of IKK
CC to MAP3K7 and enhances IKK phosphorylation (By similarity). Interacts
CC with LRRC14 (By similarity). Directly interacts with DDX3X after the
CC physiological activation of the TLR7 and TLR8 pathways; this
CC interaction enhances CHUK autophosphorylation (By similarity).
CC {ECO:0000250|UniProtKB:O15111, ECO:0000250|UniProtKB:Q60680,
CC ECO:0000269|PubMed:12459277}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O15111}. Nucleus
CC {ECO:0000250|UniProtKB:O15111}. Note=Shuttles between the cytoplasm and
CC the nucleus. {ECO:0000250}.
CC -!- DOMAIN: The kinase domain is located in the N-terminal region. The
CC leucine zipper is important to allow homo- and hetero-dimerization. At
CC the C-terminal region is located the region responsible for the
CC interaction with NEMO/IKBKG (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by
CC MEKK1, and dephosphorylated by PP2A. Autophosphorylated (By
CC similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. I-kappa-B kinase subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; AJ414555; CAC93686.1; -; mRNA.
DR EMBL; BC134510; AAI34511.1; -; mRNA.
DR RefSeq; NP_776446.1; NM_174021.2.
DR AlphaFoldDB; Q95KV1; -.
DR SMR; Q95KV1; -.
DR BioGRID; 158442; 2.
DR DIP; DIP-44031N; -.
DR IntAct; Q95KV1; 2.
DR STRING; 9913.ENSBTAP00000009985; -.
DR PaxDb; Q95KV1; -.
DR PRIDE; Q95KV1; -.
DR Ensembl; ENSBTAT00000009985; ENSBTAP00000009985; ENSBTAG00000007591.
DR GeneID; 281073; -.
DR KEGG; bta:281073; -.
DR CTD; 1147; -.
DR VEuPathDB; HostDB:ENSBTAG00000007591; -.
DR VGNC; VGNC:27354; CHUK.
DR eggNOG; KOG4250; Eukaryota.
DR GeneTree; ENSGT00950000182937; -.
DR HOGENOM; CLU_000288_101_2_1; -.
DR InParanoid; Q95KV1; -.
DR OMA; RMMNLDW; -.
DR OrthoDB; 1013139at2759; -.
DR TreeFam; TF324269; -.
DR Proteomes; UP000009136; Chromosome 26.
DR Bgee; ENSBTAG00000007591; Expressed in spermatocyte and 105 other tissues.
DR ExpressionAtlas; Q95KV1; baseline.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0008385; C:IkappaB kinase complex; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008384; F:IkappaB kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IBA:GO_Central.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IBA:GO_Central.
DR Gene3D; 1.20.1270.250; -; 1.
DR InterPro; IPR041185; IKBKB_SDD.
DR InterPro; IPR046375; IKBKB_SDD_sf.
DR InterPro; IPR022007; IKKbetaNEMObind.
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 Pfam; PF18397; IKBKB_SDD; 1.
DR Pfam; PF12179; IKKbetaNEMObind; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM01239; IKKbetaNEMObind; 1.
DR SMART; SM00220; S_TKc; 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 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1..740
FT /note="Inhibitor of nuclear factor kappa-B kinase subunit
FT alpha"
FT /id="PRO_0000268159"
FT DOMAIN 15..302
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 455..476
FT /note="Leucine-zipper"
FT REGION 733..738
FT /note="NEMO-binding"
FT /evidence="ECO:0000250"
FT ACT_SITE 144
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 21..29
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 44
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 23
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:O15111"
FT MOD_RES 176
FT /note="Phosphoserine; by MAP3K14"
FT /evidence="ECO:0000250|UniProtKB:O15111"
FT MOD_RES 180
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15111"
SQ SEQUENCE 740 AA; 84344 MW; 01903BE11F44D176 CRC64;
MERPPGLRPG AGGPWEMRER LGTGGFGNVC LYQHRELDLK IAIKSCRLEL STKNRERWCH
EIQIMKKLNH ANVVKACDVP EELNFLINDV PLLAMEYCSG GDLRKLLNKP ENCCGLKESQ
ILSLLSDIGS GIRYLHENKI IHRDLKPENI VLQDVGGKIM HKIIDLGYAK DVDQGSLCTS
FVGTLQYLAP ELFENKPYTA TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK
CIFACEEMTG EVRFSSHLPQ PNSLCSLIVE PMENWLQLML NWDPQQRGGP VDLTLKQPRC
FVLMDHILNL KIVHILNMTS AKIISFLLPP DESLHSLQSR IERETGINTG SQELLSEMGI
SLDPRKPASQ CVLDGVRGCD SYMVYLFDKS KTVYEGPFAS RSLSDCVNYI VQDSKIQLPI
IQLRKVWAEA VHYVSGLKED YSRLFQGQRA AMLSLLRYNT NLTKMKNTLI SASQQLKAKL
EFFHKSIQLD LERYSEQMTY GISSEKMLKA WKEMEEKAIH YAEVGVIGYL EDQIMSLHTE
IMELQKSPYG RRQGDLMESL EQRAIDLYKQ LKHRPSDHSY SDSTEMVKII VHTVQSQDRV
LKELFGHLSK LLGCKQKIID LLPKVEMALS NIKEADSTVM FMQGKRQKEI WHLLKIACTQ
SSARSLVGSS LEGVTPQLPP TSAEREHPLS CVVTPQDGET LAQMIEENLN CLGHLSTIIH
EANEKQGNNM MSLDWSWLTE
