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Reviewed, UniProtKB/Swiss-Prot O15111 (IKKA_HUMAN)

Last modified February 9, 2010. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Inhibitor of nuclear factor kappa-B kinase subunit alpha
      Short name=I-kappa-B kinase alpha
      Short name=IkBKA
      Short name=IKK-alpha
      Short name=IKK-A
      Short name=IkappaB kinase
    EC=2.7.11.10
Alternative name(s):
    I-kappa-B kinase 1
      Short name=IKK1
    Conserved helix-loop-helix ubiquitous kinase
    Nuclear factor NF-kappa-B inhibitor kinase alpha
      Short name=NFKBIKA
    Transcription factor 16
      Short name=TCF-16
Gene names
Name: CHUK
Synonyms: IKKA, TCF16
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length745 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Acts as part of the IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. 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. Also phosphorylates NCOA3. Phosphorylates 'Ser-10' of histone H3 at NF-kappa-B-regulated promoters during inflammatory responses triggered by cytokines. Ref.16

Catalytic activity

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

Enzyme regulation

Activated when phosphorylated and inactivated when dephosphorylated.

Subunit structure

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. 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. Directly interacts with IKK-gamma/NEMO and TRPC4AP By similarity. May interact with TRAF2. Interacts with NALP2. May interact with MAVS/IPS1. Interacts with ARRB1 and ARRB2. Ref.14 Ref.17 Ref.18 Ref.19

Subcellular location

Cytoplasm. Nucleus. Note: Shuttles between the cytoplasm and the nucleus. Ref.16

Tissue specificity

Widely expressed.

Post-translational modification

Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated. Ref.16 Ref.9 Ref.10 Ref.12

Sequence similarities

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

Contains 1 protein kinase domain.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 745745Inhibitor of nuclear factor kappa-B kinase subunit alpha
PRO_0000086011

Regions

Domain15 – 302288Protein kinase
Domain455 – 47622Leucine-zipper
Nucleotide binding21 – 299ATP By similarity
Region738 – 7436NEMO-binding

Sites

Active site1441Proton acceptor By similarity
Binding site441ATP By similarity

Amino acid modifications

Modified residue231Phosphothreonine; by PKB/AKT1 Ref.10
Modified residue1761Phosphoserine; by MAP3K14 Ref.9

Natural variations

Natural variant1261S → C: dbSNP rs34427437. Ref.21
VAR_040565
Natural variant1551V → A: dbSNP rs2230803. Ref.21
VAR_040566
Natural variant2681I → V: dbSNP rs2230804. Ref.21 Ref.3 Ref.5 Ref.6
VAR_021359

Experimental info

Mutagenesis231T → A: Loss of phosphorylation and decrease of kinase activity. Ref.10
Mutagenesis441K → A: Loss of kinase activity. Ref.3 Ref.1
Mutagenesis441K → M: Loss of autophosphorylation. Ref.3 Ref.1
Mutagenesis1761S → A: Loss of phosphorylation and of activity. Ref.9 Ref.3
Mutagenesis1761S → E: Full activation. Ref.9 Ref.3
Mutagenesis1791T → A: No change in phosphorylation. Ref.9
Mutagenesis1801S → A: No change in phosphorylation. Ref.9
Sequence conflict5431E → G in AAC51671. Ref.2
Sequence conflict6041L → R in AAC50713. Ref.7
Sequence conflict679 – 6802TS → AY in AAC50713. Ref.7
Sequence conflict6841P → A Ref.3
Sequence conflict6841P → A in AAC50713. Ref.7
Sequence conflict686 – 6872TS → DL in AAC50713. Ref.7

Sequences

Sequence LengthMass (Da)Tools
O15111-1 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 7A90B59BC98A56C2

FASTA74584,654
        10         20         30         40         50         60 
MERPPGLRPG AGGPWEMRER LGTGGFGNVC LYQHRELDLK IAIKSCRLEL STKNRERWCH 

        70         80         90        100        110        120 
EIQIMKKLNH ANVVKACDVP EELNILIHDV PLLAMEYCSG GDLRKLLNKP ENCCGLKESQ 

       130        140        150        160        170        180 
ILSLLSDIGS GIRYLHENKI IHRDLKPENI VLQDVGGKII HKIIDLGYAK DVDQGSLCTS 

       190        200        210        220        230        240 
FVGTLQYLAP ELFENKPYTA TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK 

       250        260        270        280        290        300 
CIFACEEMSG EVRFSSHLPQ PNSLCSLIVE PMENWLQLML NWDPQQRGGP VDLTLKQPRC 

       310        320        330        340        350        360 
FVLMDHILNL KIVHILNMTS AKIISFLLPP DESLHSLQSR IERETGINTG SQELLSETGI 

       370        380        390        400        410        420 
SLDPRKPASQ CVLDGVRGCD SYMVYLFDKS KTVYEGPFAS RSLSDCVNYI VQDSKIQLPI 

       430        440        450        460        470        480 
IQLRKVWAEA VHYVSGLKED YSRLFQGQRA AMLSLLRYNA NLTKMKNTLI SASQQLKAKL 

       490        500        510        520        530        540 
EFFHKSIQLD LERYSEQMTY GISSEKMLKA WKEMEEKAIH YAEVGVIGYL EDQIMSLHAE 

       550        560        570        580        590        600 
IMELQKSPYG RRQGDLMESL EQRAIDLYKQ LKHRPSDHSY SDSTEMVKII VHTVQSQDRV 

       610        620        630        640        650        660 
LKELFGHLSK LLGCKQKIID LLPKVEVALS NIKEADNTVM FMQGKRQKEI WHLLKIACTQ 

       670        680        690        700        710        720 
SSARSLVGSS LEGAVTPQTS AWLPPTSAEH DHSLSCVVTP QDGETSAQMI EENLNCLGHL 

       730        740 
STIIHEANEE QGNSMMNLDW SWLTE 

« Hide

References

« Hide 'large scale' references
[1]"Identification and characterization of an IkappaB kinase."
Regnier C.H., Song H.Y., Gao X., Goeddel D.V., Cao Z., Rothe M.
Cell 90:373-383(1997) [PubMed: 9244310] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF LYS-44.
Tissue: T-cell.
[2]"A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB."
DiDonato J.A., Hayakawa M., Rothwarf D.M., Zandi E., Karin M.
Nature 388:548-554(1997) [PubMed: 9252186] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[3]"IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation."
Mercurio F., Zhu H., Murray B.W., Shevchenko A., Bennett B.L., Li J.W., Young D.B., Barbosa M., Mann M., Manning A., Rao A.
Science 278:860-866(1997) [PubMed: 9346484] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, VARIANT VAL-268, MUTAGENESIS OF LYS-44 AND SER-176.
Tissue: Cervix carcinoma.
[4]"IkappaB kinase-alpha and -beta genes are coexpressed in adult and embryonic tissues but localized to different human chromosomes."
Hu M.C.-T., Wang Y.-P.
Gene 222:31-40(1998) [PubMed: 9813230] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Heart.
[5]SeattleSNPs variation discovery resource
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT VAL-268.
[6]"The DNA sequence and comparative analysis of human chromosome 10."
Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. expand/collapse author list , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
Nature 429:375-381(2004) [PubMed: 15164054] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT VAL-268.
[7]"CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine-threonine kinase catalytic domain."
Connelly M.A., Marcu K.B.
Cell. Mol. Biol. Res. 41:537-549(1995) [PubMed: 8777433] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 32-745.
Tissue: Cervix carcinoma.
[8]"IKAP is a scaffold protein of the IkappaB kinase complex."
Cohen L., Henzel W.J., Baeuerle P.A.
Nature 395:292-296(1998) [PubMed: 9751059] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH IKBKB; NFKBIA; RELA; IKBKAP AND MAP3K14.
[9]"NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176."
Ling L., Cao Z., Goeddel D.V.
Proc. Natl. Acad. Sci. U.S.A. 95:3792-3797(1998) [PubMed: 9520446] [Abstract]
Cited for: PHOSPHORYLATION AT SER-176, MUTAGENESIS OF SER-176; THR-179 AND SER-180.
[10]"NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase."
Ozes O.N., Mayo L.D., Gustin J.A., Pfeffer S.R., Pfeffer L.M., Donner D.B.
Nature 401:82-85(1999) [PubMed: 10485710] [Abstract]
Cited for: PHOSPHORYLATION AT THR-23, MUTAGENESIS OF THR-23.
[11]"Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation."
Delhase M., Hayakawa M., Chen Y., Karin M.
Science 284:309-313(1999) [PubMed: 10195894] [Abstract]
Cited for: IKKA-IKKB BINDING.
[12]"Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase."
Nemoto S., DiDonato J.A., Lin A.
Mol. Cell. Biol. 18:7336-7343(1998) [PubMed: 9819420] [Abstract]
Cited for: IKK PHOSPHORYLATION.
[13]"The I kappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection."
Jobin C., Sartor R.B.
Am. J. Physiol. 278:C451-C462(2000) [PubMed: 10712233] [Abstract]
Cited for: REVIEW.
[14]"Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator activity by I kappa B kinase."
Wu R.-C., Qin J., Hashimoto Y., Wong J., Xu J., Tsai S.Y., Tsai M.-J., O'Malley B.W.
Mol. Cell. Biol. 22:3549-3561(2002) [PubMed: 11971985] [Abstract]
Cited for: SUBUNIT OF A COMPLEX CONTAINING CREBBP; NCOA2; NCOA3; IKKB AND IKBKG.
[15]"Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation."
Tegethoff S., Behlke J., Scheidereit C.
Mol. Cell. Biol. 23:2029-2041(2003) [PubMed: 12612076] [Abstract]
Cited for: COMPOSITION OF THE IKK COMPLEX.
[16]"Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression."
Yamamoto Y., Verma U.N., Prajapati S., Kwak Y.T., Gaynor R.B.
Nature 423:655-659(2003) [PubMed: 12789342] [Abstract]
Cited for: SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
[17]"PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages."
Bruey J.-M., Bruey-Sedano N., Newman R., Chandler S., Stehlik C., Reed J.C.
J. Biol. Chem. 279:51897-51907(2004) [PubMed: 15456791] [Abstract]
Cited for: INTERACTION WITH NALP2.
[18]"beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha."
Witherow D.S., Garrison T.R., Miller W.E., Lefkowitz R.J.
Proc. Natl. Acad. Sci. U.S.A. 101:8603-8607(2004) [PubMed: 15173580] [Abstract]
Cited for: INTERACTION WITH ARRB1 AND ARRB2.
[19]"Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus."
Meylan E., Curran J., Hofmann K., Moradpour D., Binder M., Bartenschlager R., Tschopp J.
Nature 437:1167-1172(2005) [PubMed: 16177806] [Abstract]
Cited for: INTERACTION WITH MAVS.
[20]Colinge J., Superti-Furga G., Bennett K.L.
Submitted (OCT-2008) to UniProtKB
Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[21]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed: 17344846] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] CYS-126; ALA-155 AND VAL-268.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF012890 mRNA. Translation: AAC51662.1.
AF009225 mRNA. Translation: AAC51671.1.
AF080157 mRNA. Translation: AAD08996.1.
AY652653 Genomic DNA. Translation: AAT49098.1.
AL138921 Genomic DNA. Translation: CAH72401.1.
U22512 mRNA. Translation: AAC50713.1.
IPIIPI00005104.
RefSeqNP_001269.3.
UniGeneHs.198998

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3BRTX-ray2.25A/C732-745[»]
SMRO15111. Positions 20-289, 709-744.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-27526N.
IntActO15111. 41 interactions.
STRINGO15111.

PTM databases

PhosphoSiteO15111.

Proteomic databases

PRIDEO15111.

Genome annotation databases

EnsemblENST00000370397; ENSP00000359424; ENSG00000213341; Homo sapiens. [Genome view]
GeneID1147.
KEGGhsa:1147.
UCSCuc001kqp.1. human.

Organism-specific databases

CTD1147.
GeneCardsGC10M101938.
H-InvDBHIX0009119.
HGNCHGNC:1974. CHUK.
HPACAB004240.
CAB018564.
HPA001402.
MIM600664. gene.
PharmGKBPA26510.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG14699.
HOGENOMHBG358635.
HOVERGENO15111.
InParanoidO15111.

Enzyme and pathway databases

BRENDA2.7.11.10. 247.
Pathway_Interaction_DBnfkappabalternativepathway. Alternative NF-kappaB pathway.
bcr_5pathway. BCR signaling pathway.
nfkappabcanonicalpathway. Canonical NF-kappaB pathway.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
faspathway. FAS signaling pathway (CD95).
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
foxopathway. FoxO family signaling.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
il1pathway. IL1-mediated signaling events.
avb3_opn_pathway. Osteopontin-mediated events.
p75ntrpathway. p75(NTR)-mediated signaling.
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.
tnfpathway. TNF receptor signaling pathway.
trail_pathway. TRAIL signaling pathway.
ReactomeREACT_11061. Signalling by NGF.
REACT_6900. Signaling in Immune system.

Gene expression databases

ArrayExpressO15111.
BgeeO15111.
CleanExHS_CHUK.
GenevestigatorO15111.
GermOnlineENSG00000107566. Homo sapiens.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_prot_kinase-like_dom.
IPR008271. Ser/Thr_prot_kinase_AS.
IPR002290. Ser/Thr_prot_kinase_dom.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio4772.
SOURCESearch...

Entry information

Entry nameIKKA_HUMAN
AccessionPrimary (citable) accession number: O15111
Secondary accession number(s): O14666 expand/collapse secondary AC list , Q13132, Q5W0I4, Q92467
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: January 1, 1998
Last modified: February 9, 2010
This is version 114 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
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.

Relevant documents

Human chromosome 10

Human chromosome 10: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents