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UniProtKB - O15111 (IKKA_HUMAN)

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Protein

Inhibitor of nuclear factor kappa-B kinase subunit alpha

Gene

CHUK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260).6 Publications

Catalytic activityi

ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].

Enzyme regulationi

Activated when phosphorylated and inactivated when dephosphorylated.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei44ATPPROSITE-ProRule annotation1
Active sitei144Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi21 – 29ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct
  • IkappaB kinase activity Source: UniProtKB
  • protein heterodimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • scaffold protein binding Source: MGI
View the complete GO annotation on QuickGO ...

GO - Biological processi

  • anatomical structure morphogenesis Source: ProtInc
  • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent Source: Reactome
  • cellular response to cadmium ion Source: CAFA
  • cellular response to reactive oxygen species Source: CAFA
  • cellular response to tumor necrosis factor Source: UniProtKB
  • cellular response to virus Source: CAFA
  • Fc-epsilon receptor signaling pathway Source: Reactome
  • I-kappaB kinase/NF-kappaB signaling Source: CAFA
  • I-kappaB phosphorylation Source: ProtInc
  • immune response Source: ProtInc
  • inflammatory response Source: UniProtKB
  • innate immune response Source: UniProtKB
  • interleukin-1-mediated signaling pathway Source: Reactome
  • MyD88-independent toll-like receptor signaling pathway Source: Reactome
  • negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • NIK/NF-kappaB signaling Source: CAFA
  • peptidyl-serine phosphorylation Source: GO_Central
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Reactome
  • positive regulation of interferon-alpha secretion Source: CAFA
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: CAFA
  • positive regulation of transcription by RNA polymerase II Source: UniProtKB
  • protein phosphorylation Source: UniProtKB
  • regulation of tumor necrosis factor-mediated signaling pathway Source: Reactome
  • response to acetate Source: Ensembl
  • response to amino acid Source: Ensembl
  • response to drug Source: Ensembl
  • response to hydroperoxide Source: Ensembl
  • response to lipopolysaccharide Source: Ensembl
  • response to toxic substance Source: Ensembl
  • response to virus Source: UniProtKB
  • Rho protein signal transduction Source: Ensembl
  • skeletal muscle contraction Source: Ensembl
  • stimulatory C-type lectin receptor signaling pathway Source: Reactome
  • stress-activated MAPK cascade Source: Reactome
  • striated muscle cell differentiation Source: Ensembl
  • T cell receptor signaling pathway Source: Reactome
  • TRIF-dependent toll-like receptor signaling pathway Source: Reactome
  • tumor necrosis factor-mediated signaling pathway Source: GO_Central
View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.10 2681
ReactomeiR-HSA-1169091 Activation of NF-kappaB in B cells
R-HSA-1236974 ER-Phagosome pathway
R-HSA-168638 NOD1/2 Signaling Pathway
R-HSA-168927 TICAM1, RIP1-mediated IKK complex recruitment
R-HSA-1810476 RIP-mediated NFkB activation via ZBP1
R-HSA-198323 AKT phosphorylates targets in the cytosol
R-HSA-202424 Downstream TCR signaling
R-HSA-2871837 FCERI mediated NF-kB activation
R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-HSA-5357905 Regulation of TNFR1 signaling
R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway
R-HSA-5602636 IKBKB deficiency causes SCID
R-HSA-5603027 IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)
R-HSA-5603029 IkBA variant leads to EDA-ID
R-HSA-5607761 Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764 CLEC7A (Dectin-1) signaling
R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-5676590 NIK-->noncanonical NF-kB signaling
R-HSA-5684264 MAP3K8 (TPL2)-dependent MAPK1/3 activation
R-HSA-9020702 Interleukin-1 signaling
R-HSA-933542 TRAF6 mediated NF-kB activation
R-HSA-933543 NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
R-HSA-937039 IRAK1 recruits IKK complex
R-HSA-937041 IKK complex recruitment mediated by RIP1
R-HSA-975144 IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation
SABIO-RKiO15111
SignaLinkiO15111
SIGNORiO15111

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
Transcription factor 16
Short name:
TCF-16
Gene namesi
Name:CHUK
Synonyms:IKKA, TCF16
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

EuPathDBiHostDB:ENSG00000213341.10
HGNCiHGNC:1974 CHUK
MIMi600664 gene
neXtProtiNX_O15111

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Cocoon syndrome (COCOS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease 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 also OMIM:613630

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi23T → A: Loss of phosphorylation and decrease of kinase activity. 1 Publication1
Mutagenesisi44K → A: Loss of kinase activity. 2 Publications1
Mutagenesisi44K → M: Loss of autophosphorylation. 2 Publications1
Mutagenesisi176S → A: Loss of phosphorylation and of activity. 2 Publications1
Mutagenesisi176S → E: Full activation. 2 Publications1
Mutagenesisi179T → A: No change in phosphorylation. 1 Publication1
Mutagenesisi180S → A: No change in phosphorylation. 1 Publication1

Organism-specific databases

DisGeNETi1147
MalaCardsiCHUK
MIMi613630 phenotype
OpenTargetsiENSG00000213341
PharmGKBiPA26510

Chemistry databases

ChEMBLiCHEMBL3476
DrugBankiDB06151 Acetylcysteine
DB00233 Aminosalicylic Acid
DB00244 Mesalazine
DB00795 Sulfasalazine
GuidetoPHARMACOLOGYi1989

Polymorphism and mutation databases

BioMutaiCHUK

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000860111 – 745Inhibitor of nuclear factor kappa-B kinase subunit alphaAdd BLAST745

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei23Phosphothreonine; by PKB/AKT1 and SGK12 Publications1
Modified residuei176Phosphoserine; by MAP3K141 Publication1
Modified residuei179O-acetylthreonine; by Yersinia yopJ1 Publication1
Modified residuei180Phosphoserine; by SGK11 Publication1

Post-translational modificationi

Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
(Microbial infection) Acetylation of Thr-179 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiO15111
MaxQBiO15111
PaxDbiO15111
PeptideAtlasiO15111
PRIDEiO15111
ProteomicsDBi48449

PTM databases

iPTMnetiO15111
PhosphoSitePlusiO15111

Expressioni

Tissue specificityi

Widely expressed.

Gene expression databases

BgeeiENSG00000213341
CleanExiHS_CHUK
GenevisibleiO15111 HS

Organism-specific databases

HPAiCAB004240
CAB018564
HPA001402

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, 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).By similarity14 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • protein heterodimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • scaffold protein binding Source: MGI
View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi107569, 138 interactors
ComplexPortaliCPX-3269 IkappaB kinase complex
CORUMiO15111
DIPiDIP-27526N
ELMiO15111
IntActiO15111, 84 interactors
MINTiO15111
STRINGi9606.ENSP00000359424

Chemistry databases

BindingDBiO15111

Structurei

Secondary structure

1745
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi735 – 737Combined sources3
Helixi741 – 743Combined sources3

3D structure databases

ProteinModelPortaliO15111
SMRiO15111
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO15111

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini15 – 302Protein kinasePROSITE-ProRule annotationAdd BLAST288

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni455 – 476Leucine-zipperAdd BLAST22
Regioni738 – 743NEMO-binding6

Domaini

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.1 Publication

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG4250 Eukaryota
ENOG410XRMU LUCA
GeneTreeiENSGT00910000144033
HOGENOMiHOG000038048
HOVERGENiHBG018241
InParanoidiO15111
KOiK04467
OMAiFVLMDHI
OrthoDBiEOG091G02VC
PhylomeDBiO15111
TreeFamiTF324269

Family and domain databases

InterProiView protein in InterPro
IPR022007 IKKbetaNEMObind
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF12179 IKKbetaNEMObind, 1 hit
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM01239 IKKbetaNEMObind, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequencei

Sequence statusi: Complete.

O15111-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MERPPGLRPG AGGPWEMRER LGTGGFGNVC LYQHRELDLK IAIKSCRLEL 
        60         70         80         90        100
STKNRERWCH EIQIMKKLNH ANVVKACDVP EELNILIHDV PLLAMEYCSG 
       110        120        130        140        150
GDLRKLLNKP ENCCGLKESQ ILSLLSDIGS GIRYLHENKI IHRDLKPENI 
       160        170        180        190        200
VLQDVGGKII HKIIDLGYAK DVDQGSLCTS FVGTLQYLAP ELFENKPYTA 
       210        220        230        240        250
TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK CIFACEEMSG 
       260        270        280        290        300
EVRFSSHLPQ PNSLCSLVVE PMENWLQLML NWDPQQRGGP VDLTLKQPRC 
       310        320        330        340        350
FVLMDHILNL KIVHILNMTS AKIISFLLPP 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 EFFHKSIQLD LERYSEQMTY 
       510        520        530        540        550
GISSEKMLKA WKEMEEKAIH YAEVGVIGYL EDQIMSLHAE IMELQKSPYG 
       560        570        580        590        600
RRQGDLMESL EQRAIDLYKQ LKHRPSDHSY SDSTEMVKII VHTVQSQDRV 
       610        620        630        640        650
LKELFGHLSK LLGCKQKIID LLPKVEVALS NIKEADNTVM FMQGKRQKEI 
       660        670        680        690        700
WHLLKIACTQ SSARSLVGSS LEGAVTPQTS AWLPPTSAEH DHSLSCVVTP 
       710        720        730        740 
QDGETSAQMI EENLNCLGHL STIIHEANEE QGNSMMNLDW SWLTE
Length:745
Mass (Da):84,640
Last modified:January 11, 2011 - v2
Checksum:i4EA55C6FFC66FA16
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti543E → G in AAC51671 (PubMed:9252186).Curated1
Sequence conflicti604L → R in AAC50713 (PubMed:8777433).Curated1
Sequence conflicti679 – 680TS → AY in AAC50713 (PubMed:8777433).Curated2
Sequence conflicti684P → A no nucleotide entry (PubMed:9346484).Curated1
Sequence conflicti684P → A in AAC50713 (PubMed:8777433).Curated1
Sequence conflicti686 – 687TS → DL in AAC50713 (PubMed:8777433).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040565126S → C1 PublicationCorresponds to variant dbSNP:rs34427437Ensembl.1
Natural variantiVAR_040566155V → A1 PublicationCorresponds to variant dbSNP:rs2230803Ensembl.1
Natural variantiVAR_021359268V → I6 PublicationsCorresponds to variant dbSNP:rs2230804Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF012890 mRNA Translation: AAC51662.1
AF009225 mRNA Translation: AAC51671.1
AF080157 mRNA Translation: AAD08996.1
AY652653 Genomic DNA Translation: AAT49098.1
AL138921 Genomic DNA No translation available.
U22512 mRNA Translation: AAC50713.1
CCDSiCCDS7488.1
RefSeqiNP_001269.3, NM_001278.4
UniGeneiHs.198998

Genome annotation databases

EnsembliENST00000370397; ENSP00000359424; ENSG00000213341
GeneIDi1147
KEGGihsa:1147
UCSCiuc001kqp.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiIKKA_HUMAN
AccessioniPrimary (citable) accession number: O15111
Secondary accession number(s): O14666
, Q13132, Q5W0I4, Q92467
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: January 11, 2011
Last modified: July 18, 2018
This is version 204 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

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