UniProtKB - Q60680 (IKKA_MOUSE)
Inhibitor of nuclear factor kappa-B kinase subunit alpha
Chuk
Functioni
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. Acts as 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. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. 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. 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). 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. 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. 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. Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (PubMed:30988283).
Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (By similarity).
By similarity2 PublicationsCatalytic activityi
- EC:2.7.11.10
Activity regulationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 44 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 144 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 21 – 29 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- IkappaB kinase activity Source: UniProtKB-EC
- protein-containing complex binding Source: MGI
- protein heterodimerization activity Source: UniProtKB
- protein homodimerization activity Source: UniProtKB
- protein kinase activity Source: MGI
- protein serine/threonine kinase activity Source: UniProtKB
- scaffold protein binding Source: MGI
- transferrin receptor binding Source: MGI
GO - Biological processi
- cellular response to cadmium ion Source: MGI
- cellular response to reactive oxygen species Source: MGI
- cellular response to tumor necrosis factor Source: UniProtKB
- cellular response to virus Source: CAFA
- defense response to virus Source: CAFA
- I-kappaB kinase/NF-kappaB signaling Source: MGI
- I-kappaB phosphorylation Source: MGI
- lactation Source: MGI
- mammary gland alveolus development Source: MGI
- mammary gland epithelial cell proliferation Source: MGI
- morphogenesis of an epithelial sheet Source: MGI
- negative regulation of NF-kappaB transcription factor activity Source: MGI
- NIK/NF-kappaB signaling Source: MGI
- odontogenesis of dentin-containing tooth Source: MGI
- osteoclast differentiation Source: MGI
- peptidyl-serine phosphorylation Source: GO_Central
- positive regulation of I-kappaB kinase/NF-kappaB signaling Source: MGI
- positive regulation of interferon-alpha production Source: CAFA
- positive regulation of NF-kappaB transcription factor activity Source: GO_Central
- positive regulation of transcription, DNA-templated Source: MGI
- positive regulation of transcription by RNA polymerase II Source: UniProtKB
- protein phosphorylation Source: UniProtKB
- response to cholecystokinin Source: MGI
- response to lipopolysaccharide Source: MGI
- response to muscle stretch Source: MGI
- response to organic substance Source: MGI
- Rho protein signal transduction Source: MGI
- striated muscle cell differentiation Source: MGI
- tumor necrosis factor-mediated signaling pathway Source: GO_Central
Keywordsi
Molecular function | Kinase, Serine/threonine-protein kinase, Transferase |
Ligand | ATP-binding, Nucleotide-binding |
Enzyme and pathway databases
BRENDAi | 2.7.11.10, 3474 |
Reactomei | R-MMU-1169091, Activation of NF-kappaB in B cells R-MMU-168638, NOD1/2 Signaling Pathway R-MMU-1810476, RIP-mediated NFkB activation via ZBP1 R-MMU-198323, AKT phosphorylates targets in the cytosol R-MMU-202424, Downstream TCR signaling R-MMU-2871837, FCERI mediated NF-kB activation R-MMU-445989, TAK1 activates NFkB by phosphorylation and activation of IKKs complex R-MMU-5357905, Regulation of TNFR1 signaling R-MMU-5357956, TNFR1-induced NFkappaB signaling pathway R-MMU-5607761, Dectin-1 mediated noncanonical NF-kB signaling R-MMU-5607764, CLEC7A (Dectin-1) signaling R-MMU-5676590, NIK-->noncanonical NF-kB signaling R-MMU-5684264, MAP3K8 (TPL2)-dependent MAPK1/3 activation R-MMU-9020702, Interleukin-1 signaling R-MMU-933542, TRAF6 mediated NF-kB activation R-MMU-937039, IRAK1 recruits IKK complex R-MMU-937041, IKK complex recruitment mediated by RIP1 R-MMU-975144, IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation |
Names & Taxonomyi
Protein namesi | Recommended name: Inhibitor of nuclear factor kappa-B kinase subunit alpha (EC:2.7.11.10)Short name: I-kappa-B kinase alpha Short name: IKK-A Short name: IKK-alpha Short name: IkBKA Short name: IkappaB kinase Alternative name(s): Conserved helix-loop-helix ubiquitous kinase I-kappa-B kinase 1 Short name: IKK1 Nuclear factor NF-kappa-B inhibitor kinase alpha Short name: NFKBIKA |
Gene namesi | Name:Chuk Synonyms:Ikka |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:99484, Chuk |
Subcellular locationi
Cytosol
- cytosol Source: MGI
- IkappaB kinase complex Source: MGI
Nucleus
- nucleoplasm Source: MGI
Plasma Membrane
- CD40 receptor complex Source: BHF-UCL
- cytoplasmic side of plasma membrane Source: BHF-UCL
Other locations
- cytoplasm Source: MGI
- intracellular membrane-bounded organelle Source: MGI
Keywords - Cellular componenti
Cytoplasm, NucleusPathology & Biotechi
Disruption phenotypei
Chemistry databases
ChEMBLi | CHEMBL5380 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000086012 | 1 – 745 | Inhibitor of nuclear factor kappa-B kinase subunit alphaAdd BLAST | 745 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 23 | Phosphothreonine; by PKB/AKT1 and SGK1By similarity | 1 | |
Modified residuei | 176 | Phosphoserine; by MAP3K14By similarity | 1 | |
Modified residuei | 180 | Phosphoserine; by SGK1By similarity | 1 |
Post-translational modificationi
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | Q60680 |
MaxQBi | Q60680 |
PaxDbi | Q60680 |
PeptideAtlasi | Q60680 |
PRIDEi | Q60680 |
ProteomicsDBi | 267113 [Q60680-1] 267114 [Q60680-2] 267115 [Q60680-3] |
PTM databases
iPTMneti | Q60680 |
PhosphoSitePlusi | Q60680 |
Expressioni
Tissue specificityi
Developmental stagei
Interactioni
Subunit structurei
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. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (PubMed:20622870).
Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP.
Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (By similarity). Directly interacts with TRPC4AP (PubMed:14585990). May interact with TRAF2.
Interacts with NALP2. May interact with MAVS/IPS1 (By similarity).
Interacts with ARRB1 and ARRB2 (PubMed:18194271).
Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity.
Interacts with PIAS1; this interaction induces PIAS1 phosphorylation.
Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (By similarity).
Interacts with LRRC14 (By similarity).
Interacts with SASH1 (By similarity). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (By similarity).
By similarity4 PublicationsBinary interactionsi
Q60680
Isoform 1 [Q60680-1]
With | #Exp. | IntAct |
---|---|---|
Fam92a [Q8BP22] | 4 | EBI-646260,EBI-646638 |
Krt10 [P02535] | 6 | EBI-646260,EBI-646288 |
Pde4dip [B7ZNY0] | 4 | EBI-646260,EBI-659248 |
Isoform 2 [Q60680-2]
With | #Exp. | IntAct |
---|---|---|
MAP3K14 [Q99558] from Homo sapiens. | 3 | EBI-646264,EBI-358011 |
NFKBIA [P25963] from Homo sapiens. | 2 | EBI-646264,EBI-307386 |
GO - Molecular functioni
- protein heterodimerization activity Source: UniProtKB
- protein homodimerization activity Source: UniProtKB
- scaffold protein binding Source: MGI
- transferrin receptor binding Source: MGI
Protein-protein interaction databases
BioGRIDi | 198709, 23 interactors |
ComplexPortali | CPX-3270, IkappaB kinase complex |
CORUMi | Q60680 |
DIPi | DIP-29719N |
IntActi | Q60680, 33 interactors |
MINTi | Q60680 |
STRINGi | 10090.ENSMUSP00000026217 |
Miscellaneous databases
RNActi | Q60680, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 15 – 300 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 286 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 455 – 476 | Leucine-zipperAdd BLAST | 22 | |
Regioni | 738 – 743 | NEMO-binding | 6 |
Domaini
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG4250, Eukaryota |
InParanoidi | Q60680 |
PhylomeDBi | Q60680 |
Family and domain databases
InterProi | View protein in InterPro IPR041185, IKBKB_SDD IPR022007, IKKbetaNEMObind IPR011009, Kinase-like_dom_sf IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF18397, IKBKB_SDD, 1 hit PF12179, IKKbetaNEMObind, 1 hit PF00069, Pkinase, 1 hit |
SMARTi | View protein in SMART SM01239, IKKbetaNEMObind, 1 hit SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
s (3+)i Sequence
Sequence statusi: Complete.
This entry describes 3 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 3 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MERPPGLRPG AGGPWEMRER LGTGGFGNVS LYQHRELDLK IAIKSCRLEL
60 70 80 90 100
SSKNRERWCH EIQIMKKLDH ANVVKACDVP EELNFLINDV PLLAMEYCSG
110 120 130 140 150
GDLRKLLNKP ENCCGLKESQ ILSLLSDIGS GIRYLHENKI IHRDLKPENI
160 170 180 190 200
VLQDVGGKTI HKIIDLGYAK DVDQGSLCTS FVGTLQYLAP ELFENKPYTA
210 220 230 240 250
TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK CIFACEEMTG
260 270 280 290 300
EVRFSSHLPQ PNSLCSLIVE PMESWLQLML NWDPQQRGGP IDLTLKQPRC
310 320 330 340 350
FALMDHILNL KIVHILNMTS AKIISFLLPC DESLHSLQSR IERETGINTG
360 370 380 390 400
SQELLSETGI SLDPRKPASQ CVLDGVRGCD SYMVYLFDKS KTVYEGPFAS
410 420 430 440 450
RSLSDCVNYI VQDSKIQLPI IQLRKVWAEA VHYVSGLKED YSRLFQGQRA
460 470 480 490 500
AMLSLLRYNA NLTKMKNTLI SASQQLKAKL EFFRKSIQLD LERYSEQMTY
510 520 530 540 550
GISSEKMLKA WKEMEEKAIH YSEVGVIGYL EDQIMSLHTE IMELQKSPYG
560 570 580 590 600
RRQGDLMESL EQRAIDLYKQ LKHRPPDHLY SDSTEMVKII VHTVQSQDRV
610 620 630 640 650
LKELFGHLSK LLGCKQKIID LLPKVEVALS NIKEADNTVM FMQGKRQKEI
660 670 680 690 700
WHLLKIACTQ SSARSLVGSS LEGTVTPPVS AWLPPTLADR EHPLTCVVTP
710 720 730 740
QDGETLAQMI EENLNCLGHL STIIREANED QSSSLMSLDW SWLAE
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketE9QNL4 | E9QNL4_MOUSE | Inhibitor of nuclear factor kappa-B... | Chuk | 745 | Annotation score: | ||
E9Q605 | E9Q605_MOUSE | I-kappa-B kinase | Chuk | 719 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 236 | K → E in BAB31335 (PubMed:16141072).Curated | 1 | |
Sequence conflicti | 400 | S → Y in BAB31335 (PubMed:16141072).Curated | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_004866 | 452 – 471 | MLSLL…NTLIS → IFRKNVKSMERNGRKGHSLF in isoform 2. CuratedAdd BLAST | 20 | |
Alternative sequenceiVSP_004867 | 472 – 745 | Missing in isoform 2. CuratedAdd BLAST | 274 | |
Alternative sequenceiVSP_004868 | 577 – 584 | DHLYSDST → GKTLQSQY in isoform 3. 2 Publications | 8 | |
Alternative sequenceiVSP_004869 | 585 – 745 | Missing in isoform 3. 2 PublicationsAdd BLAST | 161 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U12473 mRNA Translation: AAC52589.1 AK018671 mRNA Translation: BAB31335.1 BC018243 mRNA Translation: AAH18243.1 |
CCDSi | CCDS29843.1 [Q60680-1] |
PIRi | I49101 |
Genome annotation databases
UCSCi | uc008hpi.2, mouse [Q60680-3] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U12473 mRNA Translation: AAC52589.1 AK018671 mRNA Translation: BAB31335.1 BC018243 mRNA Translation: AAH18243.1 |
CCDSi | CCDS29843.1 [Q60680-1] |
PIRi | I49101 |
3D structure databases
AlphaFoldDBi | Q60680 |
SMRi | Q60680 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 198709, 23 interactors |
ComplexPortali | CPX-3270, IkappaB kinase complex |
CORUMi | Q60680 |
DIPi | DIP-29719N |
IntActi | Q60680, 33 interactors |
MINTi | Q60680 |
STRINGi | 10090.ENSMUSP00000026217 |
Chemistry databases
ChEMBLi | CHEMBL5380 |
PTM databases
iPTMneti | Q60680 |
PhosphoSitePlusi | Q60680 |
Proteomic databases
EPDi | Q60680 |
MaxQBi | Q60680 |
PaxDbi | Q60680 |
PeptideAtlasi | Q60680 |
PRIDEi | Q60680 |
ProteomicsDBi | 267113 [Q60680-1] 267114 [Q60680-2] 267115 [Q60680-3] |
Genome annotation databases
UCSCi | uc008hpi.2, mouse [Q60680-3] |
Organism-specific databases
MGIi | MGI:99484, Chuk |
Phylogenomic databases
eggNOGi | KOG4250, Eukaryota |
InParanoidi | Q60680 |
PhylomeDBi | Q60680 |
Enzyme and pathway databases
BRENDAi | 2.7.11.10, 3474 |
Reactomei | R-MMU-1169091, Activation of NF-kappaB in B cells R-MMU-168638, NOD1/2 Signaling Pathway R-MMU-1810476, RIP-mediated NFkB activation via ZBP1 R-MMU-198323, AKT phosphorylates targets in the cytosol R-MMU-202424, Downstream TCR signaling R-MMU-2871837, FCERI mediated NF-kB activation R-MMU-445989, TAK1 activates NFkB by phosphorylation and activation of IKKs complex R-MMU-5357905, Regulation of TNFR1 signaling R-MMU-5357956, TNFR1-induced NFkappaB signaling pathway R-MMU-5607761, Dectin-1 mediated noncanonical NF-kB signaling R-MMU-5607764, CLEC7A (Dectin-1) signaling R-MMU-5676590, NIK-->noncanonical NF-kB signaling R-MMU-5684264, MAP3K8 (TPL2)-dependent MAPK1/3 activation R-MMU-9020702, Interleukin-1 signaling R-MMU-933542, TRAF6 mediated NF-kB activation R-MMU-937039, IRAK1 recruits IKK complex R-MMU-937041, IKK complex recruitment mediated by RIP1 R-MMU-975144, IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation |
Miscellaneous databases
ChiTaRSi | Chuk, mouse |
PROi | PR:Q60680 |
RNActi | Q60680, protein |
SOURCEi | Search... |
Family and domain databases
InterProi | View protein in InterPro IPR041185, IKBKB_SDD IPR022007, IKKbetaNEMObind IPR011009, Kinase-like_dom_sf IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF18397, IKBKB_SDD, 1 hit PF12179, IKKbetaNEMObind, 1 hit PF00069, Pkinase, 1 hit |
SMARTi | View protein in SMART SM01239, IKKbetaNEMObind, 1 hit SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | IKKA_MOUSE | |
Accessioni | Q60680Primary (citable) accession number: Q60680 Secondary accession number(s): Q80VU2, Q9D2X3 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | June 1, 2001 |
Last sequence update: | November 1, 1996 | |
Last modified: | May 25, 2022 | |
This is version 198 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- 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