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Protein

Inhibitor of nuclear factor kappa-B kinase subunit alpha

Gene

Chuk

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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.By similarity1 Publication

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

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
  • inflammatory response Source: GO_Central
  • innate immune response Source: GO_Central
  • 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 secretion 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 from RNA polymerase II promoter Source: UniProtKB
  • protein phosphorylation Source: MGI
  • response to muscle stretch Source: MGI
  • tumor necrosis factor-mediated signaling pathway Source: GO_Central

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.11.10. 3474.

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:99484. Chuk.

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

Disruption phenotypei

Mice show abnormal appearance and die within 4 hours after birth. The epidermal cells are highly proliferative with dysregulated epidermal differentiation.1 Publication

Chemistry databases

ChEMBLiCHEMBL5380.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000860121 – 745Inhibitor of nuclear factor kappa-B kinase subunit alphaAdd BLAST745

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei23Phosphothreonine; by PKB/AKT1 and SGK1By similarity1
Modified residuei176Phosphoserine; by MAP3K14By similarity1
Modified residuei180Phosphoserine; by SGK1By similarity1

Post-translational modificationi

Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ60680.
PaxDbiQ60680.
PeptideAtlasiQ60680.
PRIDEiQ60680.

PTM databases

iPTMnetiQ60680.
PhosphoSitePlusiQ60680.

Expressioni

Tissue specificityi

Ubiquitous only for isoform 1, isoforms 2 and 3 are expressed predominantly in brain and T-lymphocytes.

Developmental stagei

Maximally expressed at E7 day followed by E11, E15 and E17 days. In the limb development, its expression predominates in the limb buds at E12.5 day.

Gene expression databases

CleanExiMM_CHUK.

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, IKBKAP 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).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198709. 18 interactors.
CORUMiQ60680.
DIPiDIP-29719N.
IntActiQ60680. 31 interactors.
MINTiMINT-267529.
STRINGi10090.ENSMUSP00000026217.

Structurei

3D structure databases

ProteinModelPortaliQ60680.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini15 – 300Protein kinasePROSITE-ProRule annotationAdd BLAST286

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.

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.
HOGENOMiHOG000038048.
HOVERGENiHBG018241.
InParanoidiQ60680.
PhylomeDBiQ60680.

Family and domain databases

InterProiView protein in InterPro
IPR022007. IKKbetaNEMObind.
IPR011009. Kinase-like_dom.
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.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q60680-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        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
Length:745
Mass (Da):84,729
Last modified:November 1, 1996 - v1
Checksum:i3FEF5582AFF92233
GO
Isoform 2 (identifier: Q60680-2) [UniParc]FASTAAdd to basket
Also known as: Delta LH

The sequence of this isoform differs from the canonical sequence as follows:
     452-471: MLSLLRYNANLTKMKNTLIS → IFRKNVKSMERNGRKGHSLF
     472-745: Missing.

Show »
Length:471
Mass (Da):53,544
Checksum:i14F1EFF71B4A17EE
GO
Isoform 3 (identifier: Q60680-3) [UniParc]FASTAAdd to basket
Also known as: Delta H

The sequence of this isoform differs from the canonical sequence as follows:
     577-584: DHLYSDST → GKTLQSQY
     585-745: Missing.

Show »
Length:584
Mass (Da):66,805
Checksum:iD99BB8A6DF1CA4EB
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti236K → E in BAB31335 (PubMed:16141072).Curated1
Sequence conflicti400S → Y in BAB31335 (PubMed:16141072).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004866452 – 471MLSLL…NTLIS → IFRKNVKSMERNGRKGHSLF in isoform 2. CuratedAdd BLAST20
Alternative sequenceiVSP_004867472 – 745Missing in isoform 2. CuratedAdd BLAST274
Alternative sequenceiVSP_004868577 – 584DHLYSDST → GKTLQSQY in isoform 3. 2 Publications8
Alternative sequenceiVSP_004869585 – 745Missing in isoform 3. 2 PublicationsAdd BLAST161

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.
CCDSiCCDS29843.1. [Q60680-1]
PIRiI49101.
UniGeneiMm.3996.

Genome annotation databases

UCSCiuc008hpi.2. mouse. [Q60680-3]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiIKKA_MOUSE
AccessioniPrimary (citable) accession number: Q60680
Secondary accession number(s): Q80VU2, Q9D2X3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: November 1, 1996
Last modified: September 27, 2017
This is version 172 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families