Reviewed, UniProtKB/Swiss-Prot O14920 (IKKB_HUMAN)

Names and origin

Protein names

Recommended name:
    Inhibitor of nuclear factor kappa-B kinase subunit beta
      Short name=I-kappa-B-kinase beta
      Short name=IkBKB
      Short name=IKK-beta
      Short name=IKK-B
    EC=2.7.11.10
Alternative name(s):
    I-kappa-B kinase 2
      Short name=IKK2
    Nuclear factor NF-kappa-B inhibitor kinase beta
      Short name=NFKBIKB

Gene names

Name:	IKBKB
Synonyms:	IKKB

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	756 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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. Also phosphorylates NCOA3.
Catalytic activity	ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].
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. Interacts with SQSTM1 through PRKCZ or PRKCI. Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6. May interact with MAVS/IPS1. Interacts with NALP2. Interacts with TICAM1. Interacts with Yersinia yopJ. Interacts with FAF1; the interaction disrupts the IKK complex formation. Interacts with ATM. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with NIBP; the interaction is direct. Ref.9 Ref.12 Ref.15 Ref.16 Ref.18 Ref.20 Ref.21 Ref.22 Ref.23
Subcellular location	Cytoplasm.
Tissue specificity	Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.
Post-translational modification	Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Ref.7 Ref.10 Ref.24 Ref.25 Yersinia yopJ may acetylate Ser/Thr residues, preventing phosphorylation and activation, which blocks the I-kappa-B signaling pathway. Ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues.
Sequence similarities	Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein S-nitrosylation Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	positive regulation of NF-kappaB transcription factor activity Inferred from direct assay. Source: MGI protein amino acid phosphorylation Ref.1 Non-traceable author statement. Source: UniProtKB
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro IkappaB kinase activity Inferred from electronic annotation. Source: EC identical protein binding Inferred from physical interaction. Source: IntAct transcription activator activity Ref.1 Ref.2 Ref.3 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-81266,EBI-81266
CHUK	O15111	3	EBI-81266,EBI-81249
Chuk	Q60680	1	EBI-81266,EBI-646245	From a different organism.
Chuk	Q60680-3	1	EBI-81266,EBI-646269	From a different organism.
IKBKG	Q9Y6K9	3	EBI-81266,EBI-81279
MAP3K1	Q13233	1	EBI-81266,EBI-49776
MAP3K14	Q99558	2	EBI-81266,EBI-358011
MAVS	Q7Z434	1	EBI-81266,EBI-995373
NCOA3	Q9Y6Q9	3	EBI-81266,EBI-81196
NFKBIA	P25963	3	EBI-81266,EBI-307386
Snap23	O09044	1	EBI-81266,EBI-1812522	From a different organism.
STAP2	Q9UGK3	3	EBI-81266,EBI-1553984
TSC1	Q92574	3	EBI-81266,EBI-1386638

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 756

756

Inhibitor of nuclear factor kappa-B kinase subunit beta

PRO_0000086013

Regions

Domain

15 – 300

286

Protein kinase

Domain

458 – 479

22

Leucine-zipper Potential

Nucleotide binding

21 – 29

9

ATP By similarity

Region

737 – 742

6

NEMO-binding

Sites

Active site

145

1

Proton acceptor By similarity

Binding site

44

1

ATP By similarity

Amino acid modifications

Modified residue

23

1

Phosphothreonine By similarity

Modified residue

177

1

Phosphoserine Ref.10

Modified residue

179

1

S-nitrosocysteine

Modified residue

181

1

Phosphoserine Ref.10

Modified residue

670

1

Phosphoserine; by autocatalysis Probable

Modified residue

672

1

Phosphoserine; by autocatalysis Probable

Modified residue

675

1

Phosphoserine; by autocatalysis Probable

Modified residue

682

1

Phosphoserine; by autocatalysis Probable

Modified residue

689

1

Phosphoserine; by autocatalysis Probable

Modified residue

692

1

Phosphoserine; by autocatalysis Probable

Modified residue

695

1

Phosphoserine; by autocatalysis Probable

Modified residue

697

1

Phosphoserine; by autocatalysis Probable

Modified residue

705

1

Phosphoserine; by autocatalysis Probable

Modified residue

733

1

Phosphoserine; by autocatalysis Probable

Modified residue

740

1

Phosphoserine; by autocatalysis Probable

Modified residue

750

1

Phosphoserine; by autocatalysis Probable

Cross-link

163

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.19

Natural variations

Natural variant

360

1

A → S in breast cancer samples; infiltrating ductal carcinoma; somatic mutation. Ref.26 Ref.27

VAR_035626

Natural variant

369

1

Q → R Ref.27

VAR_040567

Natural variant

526

1

R → Q: dbSNP rs2272736.

VAR_040568

Natural variant

554

1

R → W: dbSNP rs17875749. Ref.5

VAR_021124

Natural variant

710

1

A → T Ref.27

VAR_040569

Natural variant

734

1

F → L Ref.27

VAR_040570

Natural variant

736

1

A → T: dbSNP rs17611716.

VAR_051628

Experimental info

Mutagenesis

44

1

K → A: Loss of kinase activity and no effect on binding to NIK Ref.1 Ref.2

Mutagenesis

177

1

S → A: Decrease of activity Ref.1

Mutagenesis

177

1

S → E: Full activation Ref.1

Mutagenesis

181

1

S → A: Decrease of activity Ref.1

Mutagenesis

181

1

S → E: Full activation Ref.1

Sequence conflict

231 – 255

25

WHSKV…GTVKF → CVRMWPGTVAHSCNPSTLGG RGRWI Ref.6

Sequence conflict

425

1

Q → H Ref.1

Secondary structure

1

.

.

.

.

.

.

.

756

Helix Strand Turn

Details...

Helix

707 – 729

23

Helix

734 – 736

3

Helix

740 – 742

3

Sequences

	Sequence		Length	Mass (Da)
	O14920-1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: F9CADF671AE9E14E	FASTA	756	86,564
	10 20 30 40 50 60 MSWSPSLTTQ TCGAWEMKER LGTGGFGNVI RWHNQETGEQ IAIKQCRQEL SPRNRERWCL 70 80 90 100 110 120 EIQIMRRLTH PNVVAARDVP EGMQNLAPND LPLLAMEYCQ GGDLRKYLNQ FENCCGLREG 130 140 150 160 170 180 AILTLLSDIA SALRYLHENR IIHRDLKPEN IVLQQGEQRL IHKIIDLGYA KELDQGSLCT 190 200 210 220 230 240 SFVGTLQYLA PELLEQQKYT VTVDYWSFGT LAFECITGFR PFLPNWQPVQ WHSKVRQKSE 250 260 270 280 290 300 VDIVVSEDLN GTVKFSSSLP YPNNLNSVLA ERLEKWLQLM LMWHPRQRGT DPTYGPNGCF 310 320 330 340 350 360 KALDDILNLK LVHILNMVTG TIHTYPVTED ESLQSLKARI QQDTGIPEED QELLQEAGLA 370 380 390 400 410 420 LIPDKPATQC ISDGKLNEGH TLDMDLVFLF DNSKITYETQ ISPRPQPESV SCILQEPKRN 430 440 450 460 470 480 LAFFQLRKVW GQVWHSIQTL KEDCNRLQQG QRAAMMNLLR NNSCLSKMKN SMASMSQQLK 490 500 510 520 530 540 AKLDFFKTSI QIDLEKYSEQ TEFGITSDKL LLAWREMEQA VELCGRENEV KLLVERMMAL 550 560 570 580 590 600 QTDIVDLQRS PMGRKQGGTL DDLEEQAREL YRRLREKPRD QRTEGDSQEM VRLLLQAIQS 610 620 630 640 650 660 FEKKVRVIYT QLSKTVVCKQ KALELLPKVE EVVSLMNEDE KTVVRLQEKR QKELWNLLKI 670 680 690 700 710 720 ACSKVRGPVS GSPDSMNASR LSQPGQLMSQ PSTASNSLPE PAKKSEELVA EAHNLCTLLE 730 740 750 NAIQDTVREQ DQSFTALDWS WLQTEEEEHS CLEQAS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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, MUTAGENESIS OF LYS-44; SER-177 AND SER-181. Tissue: Cervix carcinoma.
[2]	"IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK." Woronicz J.D., Gao X., Cao Z., Rothe M., Goeddel D.V. Science 278:866-869(1997) [PubMed: 9346485] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF LYS-44.
[3]	"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.
[4]	"Assignment of IkappaB kinase beta (IKBKB) to human chromosome band 8p12-->p11 by in situ hybridization." Shindo M., Nakano H., Sakon S., Yagita H., Mihara M., Okumura K. Cytogenet. Cell Genet. 82:32-33(1998) [PubMed: 9763654] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], GENE MAPPING.
[5]	SeattleSNPs program for genomic applications Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT TRP-554.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-256. Tissue: Lung.
[7]	"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.
[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 CHUK; NFKBIA; RELA; IKBKAP AND MAP3K14.
[9]	"The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation." Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J. EMBO J. 18:3044-3053(1999) [PubMed: 10356400] [Abstract] Cited for: INTERACTION WITH SQSTM1; PRKCZ AND PRKCI.
[10]	"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: PHOSPHORYLATION AT SER-177; SER-181; SER-670; SER-672; SER-675; SER-682; SER-689; SER-692; SER-695; SER-697; SER-705; SER-733; SER-740 AND SER-750.
[11]	"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.
[12]	"Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases." Chariot A., Leonardi A., Muller J., Bonif M., Brown K., Siebenlist U. J. Biol. Chem. 277:37029-37036(2002) [PubMed: 12133833] [Abstract] Cited for: INTERACTION WITH IKBKG AND TANK.
[13]	"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: IDENTIFICATION IN A COMPLEX WITH CREBBP; NCOA2; NCOA3; IKKA AND IKBKG.
[14]	"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.
[15]	"Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways." Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B. J. Biol. Chem. 279:15652-15661(2004) [PubMed: 14739303] [Abstract] Cited for: INTERACTION WITH TICAM1.
[16]	"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.
[17]	"Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation." Reynaert N.L., Ckless K., Korn S.H., Vos N., Guala A.S., Wouters E.F., van der Vliet A., Janssen-Heininger Y.M. Proc. Natl. Acad. Sci. U.S.A. 101:8945-8950(2004) [PubMed: 15184672] [Abstract] Cited for: S-NITROSYLATION AT CYS-179.
[18]	"NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation." Hu W.-H., Pendergast J.S., Mo X.-M., Brambilla R., Bracchi-Ricard V., Li F., Walters W.M., Blits B., He L., Schaal S.M., Bethea J.R. J. Biol. Chem. 280:29233-29241(2005) [PubMed: 15951441] [Abstract] Cited for: INTERACTION WITH NIBP.
[19]	"Site-specific monoubiquitination of IkappaB kinase IKKbeta regulates its phosphorylation and persistent activation." Carter R.S., Pennington K.N., Arrate P., Oltz E.M., Ballard D.W. J. Biol. Chem. 280:43272-43279(2005) [PubMed: 16267042] [Abstract] Cited for: UBIQUITINATION AT LYS-163.
[20]	"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.
[21]	"Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation." Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., Orth K. Science 312:1211-1214(2006) [PubMed: 16728640] [Abstract] Cited for: INTERACTION WITH YOPJ, ACETYLATION.
[22]	"Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli." Wu Z.H., Shi Y., Tibbetts R.S., Miyamoto S. Science 311:1141-1146(2006) [PubMed: 16497931] [Abstract] Cited for: INTERACTION WITH ATM.
[23]	"FAF1 suppresses IkappaB kinase (IKK) activation by disrupting the IKK complex assembly." Park M.Y., Moon J.H., Lee K.S., Choi H.I., Chung J., Hong H.J., Kim E. J. Biol. Chem. 282:27572-27577(2007) [PubMed: 17684021] [Abstract] Cited for: INTERACTION WITH FAF1.
[24]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-672, MASS SPECTROMETRY.
[25]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-672, MASS SPECTROMETRY.
[26]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] SER-360.
[27]	"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. , 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.,