O15111 · IKKA_HUMAN
- ProteinInhibitor of nuclear factor kappa-B kinase subunit alpha
- GeneCHUK
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids745 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484).
Acts as a part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:18626576, PubMed:35952808, PubMed:9244310, PubMed:9252186, PubMed:9346484).
These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484).
In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484).
Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:21765415).
Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:20501937).
In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:17434128).
Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:12789342).
Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260).
Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity).
Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973).
Acts as a part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:18626576, PubMed:35952808, PubMed:9244310, PubMed:9252186, PubMed:9346484).
These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484).
In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484).
Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:21765415).
Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:20501937).
In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:17434128).
Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:12789342).
Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260).
Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity).
Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973).
Catalytic activity
- ATP + L-seryl-[I-kappa-B protein] = ADP + H+ + O-phospho-L-seryl-[I-kappa-B protein]
Activity regulation
Activated when phosphorylated and inactivated when dephosphorylated.
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
The subsequence LVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHLSTIIHEANEEQGNSMMNLDWSWLTE, which contains the IKKbetaNEMObind domain, shows transcriptional activator activity in a high-throughput recruitment assay.
Names & Taxonomy
Protein names
- Recommended nameInhibitor of nuclear factor kappa-B kinase subunit alpha
- EC number
- Short namesI-kappa-B kinase alpha; IKK-A; IKK-alpha; IkBKA; IkappaB kinase
- Alternative names
Gene names
- Community suggested namesCHUK
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO15111
- Secondary accessions
Proteomes
Organism-specific databases
Disease & Variants
Involvement in disease
Cocoon syndrome (COCOS)
- Note
- DescriptionA lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.
- See alsoMIM:613630
Bartsocas-Papas syndrome 2 (BPS2)
- Note
- DescriptionAn autosomal recessive, severe form of popliteal pterygium syndrome. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but they are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations.
- See alsoMIM:619339
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 23 | Loss of phosphorylation and decrease of kinase activity. | ||||
Sequence: T → A | ||||||
Mutagenesis | 44 | Loss of kinase activity. | ||||
Sequence: K → A | ||||||
Mutagenesis | 44 | Loss of autophosphorylation. | ||||
Sequence: K → M | ||||||
Natural variant | VAR_040565 | 126 | in dbSNP:rs34427437 | |||
Sequence: S → C | ||||||
Natural variant | VAR_040566 | 155 | in dbSNP:rs2230803 | |||
Sequence: V → A | ||||||
Mutagenesis | 176 | Loss of phosphorylation and of activity. | ||||
Sequence: S → A | ||||||
Mutagenesis | 176 | Full activation. | ||||
Sequence: S → E | ||||||
Mutagenesis | 179 | No change in phosphorylation. | ||||
Sequence: T → A | ||||||
Mutagenesis | 180 | No change in phosphorylation. | ||||
Sequence: S → A | ||||||
Natural variant | VAR_021359 | 268 | in dbSNP:rs2230804 | |||
Sequence: V → I |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 577 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000086011 | 1-745 | Inhibitor of nuclear factor kappa-B kinase subunit alpha | |||
Sequence: MERPPGLRPGAGGPWEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCHEIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTSFVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRCFVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGISLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPIIQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKLEFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAEIMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRVLKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQSSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHLSTIIHEANEEQGNSMMNLDWSWLTE | ||||||
Modified residue | 23 | Phosphothreonine; by PKB/AKT1 and SGK1 | ||||
Sequence: T | ||||||
Modified residue | 176 | Phosphoserine; by MAP3K14 | ||||
Sequence: S | ||||||
Modified residue | 179 | (Microbial infection) O-acetylthreonine; by Yersinia YopJ | ||||
Sequence: T | ||||||
Modified residue | 180 | Phosphoserine; by SGK1 | ||||
Sequence: S |
Post-translational modification
Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
Ubiquitinated by TRIM56 via 'Lys-63'-linked ubiquitination, promoting activation of CHUK/IKKA.
(Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits (PubMed:32935379).
The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076).
The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity).
Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985).
Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059).
Directly interacts with TRPC4AP (By similarity).
May interact with TRAF2 (PubMed:19150425).
Interacts with NALP2 (PubMed:15456791).
May interact with MAVS/IPS1 (PubMed:16177806).
Interacts with ARRB1 and ARRB2 (PubMed:15173580).
Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986).
Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171).
Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055).
Interacts with FOXO3 (PubMed:15084260).
Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375).
Interacts with LRRC14 (PubMed:27426725).
Interacts with SASH1 (PubMed:23776175).
Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).
The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076).
The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity).
Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985).
Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059).
Directly interacts with TRPC4AP (By similarity).
May interact with TRAF2 (PubMed:19150425).
Interacts with NALP2 (PubMed:15456791).
May interact with MAVS/IPS1 (PubMed:16177806).
Interacts with ARRB1 and ARRB2 (PubMed:15173580).
Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986).
Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171).
Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055).
Interacts with FOXO3 (PubMed:15084260).
Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375).
Interacts with LRRC14 (PubMed:27426725).
Interacts with SASH1 (PubMed:23776175).
Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).
(Microbial infection) Interacts with InlC of Listeria monocytogenes.
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 15-302 | Protein kinase | ||||
Sequence: WEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCHEIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTSFVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRCFV | ||||||
Region | 455-476 | Leucine-zipper | ||||
Sequence: LLRYNANLTKMKNTLISASQQL | ||||||
Region | 738-743 | NEMO-binding | ||||
Sequence: LDWSWL |
Domain
The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.
Sequence similarities
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length745
- Mass (Da)84,640
- Last updated2011-01-11 v2
- Checksum4EA55C6FFC66FA16
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 543 | in Ref. 2; AAC51671 | ||||
Sequence: E → G | ||||||
Sequence conflict | 604 | in Ref. 7; AAC50713 | ||||
Sequence: L → R | ||||||
Sequence conflict | 679-680 | in Ref. 7; AAC50713 | ||||
Sequence: TS → AY | ||||||
Sequence conflict | 684 | in Ref. 3; no nucleotide entry and 7; AAC50713 | ||||
Sequence: P → A | ||||||
Sequence conflict | 686-687 | in Ref. 7; AAC50713 | ||||
Sequence: TS → DL |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF012890 EMBL· GenBank· DDBJ | AAC51662.1 EMBL· GenBank· DDBJ | mRNA | ||
AF009225 EMBL· GenBank· DDBJ | AAC51671.1 EMBL· GenBank· DDBJ | mRNA | ||
AF080157 EMBL· GenBank· DDBJ | AAD08996.1 EMBL· GenBank· DDBJ | mRNA | ||
AY652653 EMBL· GenBank· DDBJ | AAT49098.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL138921 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
U22512 EMBL· GenBank· DDBJ | AAC50713.1 EMBL· GenBank· DDBJ | mRNA |