IKKA_HUMAN
ID IKKA_HUMAN Reviewed; 745 AA.
AC O15111; O14666; Q13132; Q5W0I4; Q92467;
DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 2.
DT 03-AUG-2022, entry version 230.
DE RecName: Full=Inhibitor of nuclear factor kappa-B kinase subunit alpha;
DE Short=I-kappa-B kinase alpha;
DE Short=IKK-A;
DE Short=IKK-alpha;
DE Short=IkBKA;
DE Short=IkappaB kinase;
DE EC=2.7.11.10 {ECO:0000269|PubMed:9244310, ECO:0000269|PubMed:9252186, ECO:0000269|PubMed:9346484};
DE AltName: Full=Conserved helix-loop-helix ubiquitous kinase;
DE AltName: Full=I-kappa-B kinase 1;
DE Short=IKK1;
DE AltName: Full=Nuclear factor NF-kappa-B inhibitor kinase alpha;
DE Short=NFKBIKA;
DE AltName: Full=Transcription factor 16;
DE Short=TCF-16;
GN Name=CHUK; Synonyms=IKKA, TCF16;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF
RP LYS-44, AND VARIANT ILE-268.
RC TISSUE=T-cell;
RX PubMed=9244310; DOI=10.1016/s0092-8674(00)80344-x;
RA Regnier C.H., Song H.Y., Gao X., Goeddel D.V., Cao Z., Rothe M.;
RT "Identification and characterization of an IkappaB kinase.";
RL Cell 90:373-383(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC
RP ACTIVITY, AND VARIANT ILE-268.
RX PubMed=9252186; DOI=10.1038/41493;
RA DiDonato J.A., Hayakawa M., Rothwarf D.M., Zandi E., Karin M.;
RT "A cytokine-responsive IkappaB kinase that activates the transcription
RT factor NF-kappaB.";
RL Nature 388:548-554(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC
RP ACTIVITY, AND MUTAGENESIS OF LYS-44 AND SER-176.
RC TISSUE=Cervix carcinoma;
RX PubMed=9346484; DOI=10.1126/science.278.5339.860;
RA Mercurio F., Zhu H., Murray B.W., Shevchenko A., Bennett B.L., Li J.W.,
RA Young D.B., Barbosa M., Mann M., Manning A., Rao A.;
RT "IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-
RT kappaB activation.";
RL Science 278:860-866(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ILE-268.
RC TISSUE=Heart;
RX PubMed=9813230; DOI=10.1016/s0378-1119(98)00462-4;
RA Hu M.C.-T., Wang Y.-P.;
RT "IkappaB kinase-alpha and -beta genes are coexpressed in adult and
RT embryonic tissues but localized to different human chromosomes.";
RL Gene 222:31-40(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ILE-268.
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 32-745, AND VARIANT ILE-268.
RC TISSUE=Cervix carcinoma;
RX PubMed=8777433;
RA Connelly M.A., Marcu K.B.;
RT "CHUK, a new member of the helix-loop-helix and leucine zipper families of
RT interacting proteins, contains a serine-threonine kinase catalytic
RT domain.";
RL Cell. Mol. Biol. Res. 41:537-549(1995).
RN [8]
RP PROTEIN SEQUENCE OF 169-181, INACTIVATION BY YERSINIA YOPJ (MICROBIAL
RP INFECTION), ACETYLATION AT THR-179 (MICROBIAL INFECTION), AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=17116858; DOI=10.1073/pnas.0608995103;
RA Mittal R., Peak-Chew S.Y., McMahon H.T.;
RT "Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by
RT YopJ inhibits signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18574-18579(2006).
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH IKBKB; NFKBIA; RELA; ELP1 AND MAP3K14.
RX PubMed=9751059; DOI=10.1038/26254;
RA Cohen L., Henzel W.J., Baeuerle P.A.;
RT "IKAP is a scaffold protein of the IkappaB kinase complex.";
RL Nature 395:292-296(1998).
RN [10]
RP PHOSPHORYLATION AT SER-176, AND MUTAGENESIS OF SER-176; THR-179 AND
RP SER-180.
RX PubMed=9520446; DOI=10.1073/pnas.95.7.3792;
RA Ling L., Cao Z., Goeddel D.V.;
RT "NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-
RT 176.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:3792-3797(1998).
RN [11]
RP PHOSPHORYLATION AT THR-23, AND MUTAGENESIS OF THR-23.
RX PubMed=10485710; DOI=10.1038/43466;
RA Ozes O.N., Mayo L.D., Gustin J.A., Pfeffer S.R., Pfeffer L.M., Donner D.B.;
RT "NF-kappaB activation by tumour necrosis factor requires the Akt serine-
RT threonine kinase.";
RL Nature 401:82-85(1999).
RN [12]
RP INTERACTION WITH IKBKB.
RX PubMed=10195894; DOI=10.1126/science.284.5412.309;
RA Delhase M., Hayakawa M., Chen Y., Karin M.;
RT "Positive and negative regulation of IkappaB kinase activity through
RT IKKbeta subunit phosphorylation.";
RL Science 284:309-313(1999).
RN [13]
RP IKK PHOSPHORYLATION.
RX PubMed=9819420; DOI=10.1128/mcb.18.12.7336;
RA Nemoto S., DiDonato J.A., Lin A.;
RT "Coordinate regulation of IkappaB kinases by mitogen-activated protein
RT kinase kinase kinase 1 and NF-kappaB-inducing kinase.";
RL Mol. Cell. Biol. 18:7336-7343(1998).
RN [14]
RP REVIEW.
RX PubMed=10712233; DOI=10.1152/ajpcell.2000.278.3.c451;
RA Jobin C., Sartor R.B.;
RT "The I kappa B/NF-kappa B system: a key determinant of mucosal inflammation
RT and protection.";
RL Am. J. Physiol. 278:C451-C462(2000).
RN [15]
RP SUBUNIT OF A COMPLEX CONTAINING CREBBP; NCOA2; NCOA3; IKBKB AND IKBKG.
RX PubMed=11971985; DOI=10.1128/mcb.22.10.3549-3561.2002;
RA Wu R.-C., Qin J., Hashimoto Y., Wong J., Xu J., Tsai S.Y., Tsai M.-J.,
RA O'Malley B.W.;
RT "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator activity by
RT I kappa B kinase.";
RL Mol. Cell. Biol. 22:3549-3561(2002).
RN [16]
RP COMPOSITION OF THE IKK COMPLEX.
RX PubMed=12612076; DOI=10.1128/mcb.23.6.2029-2041.2003;
RA Tegethoff S., Behlke J., Scheidereit C.;
RT "Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is
RT obligatory for IKK complex activity and NF-kappaB activation.";
RL Mol. Cell. Biol. 23:2029-2041(2003).
RN [17]
RP SUBCELLULAR LOCATION, AND FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
RX PubMed=12789342; DOI=10.1038/nature01576;
RA Yamamoto Y., Verma U.N., Prajapati S., Kwak Y.T., Gaynor R.B.;
RT "Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced
RT gene expression.";
RL Nature 423:655-659(2003).
RN [18]
RP FUNCTION, AND INTERACTION WITH FOXO3.
RX PubMed=15084260; DOI=10.1016/s0092-8674(04)00302-2;
RA Hu M.C., Lee D.F., Xia W., Golfman L.S., Ou-Yang F., Yang J.Y., Zou Y.,
RA Bao S., Hanada N., Saso H., Kobayashi R., Hung M.C.;
RT "IkappaB kinase promotes tumorigenesis through inhibition of forkhead
RT FOXO3a.";
RL Cell 117:225-237(2004).
RN [19]
RP INTERACTION WITH NALP2.
RX PubMed=15456791; DOI=10.1074/jbc.m406741200;
RA Bruey J.-M., Bruey-Sedano N., Newman R., Chandler S., Stehlik C.,
RA Reed J.C.;
RT "PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-
RT kappaB and caspase-1 activation in macrophages.";
RL J. Biol. Chem. 279:51897-51907(2004).
RN [20]
RP INTERACTION WITH ARRB1 AND ARRB2.
RX PubMed=15173580; DOI=10.1073/pnas.0402851101;
RA Witherow D.S., Garrison T.R., Miller W.E., Lefkowitz R.J.;
RT "beta-Arrestin inhibits NF-kappaB activity by means of its interaction with
RT the NF-kappaB inhibitor IkappaBalpha.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:8603-8607(2004).
RN [21]
RP INTERACTION WITH MAVS.
RX PubMed=16177806; DOI=10.1038/nature04193;
RA Meylan E., Curran J., Hofmann K., Moradpour D., Binder M.,
RA Bartenschlager R., Tschopp J.;
RT "Cardif is an adaptor protein in the RIG-I antiviral pathway and is
RT targeted by hepatitis C virus.";
RL Nature 437:1167-1172(2005).
RN [22]
RP INTERACTION WITH PIAS1.
RX PubMed=17540171; DOI=10.1016/j.cell.2007.03.056;
RA Liu B., Yang Y., Chernishof V., Loo R.R., Jang H., Tahk S., Yang R.,
RA Mink S., Shultz D., Bellone C.J., Loo J.A., Shuai K.;
RT "Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1
RT to restrict inflammation and immunity.";
RL Cell 129:903-914(2007).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF CREBBP.
RX PubMed=17434128; DOI=10.1016/j.molcel.2007.02.019;
RA Huang W.C., Ju T.K., Hung M.C., Chen C.C.;
RT "Phosphorylation of CBP by IKKalpha promotes cell growth by switching the
RT binding preference of CBP from p53 to NF-kappaB.";
RL Mol. Cell 26:75-87(2007).
RN [24]
RP REVIEW, AND DOMAIN.
RX PubMed=18626576; DOI=10.1007/s12026-008-8025-1;
RA Solt L.A., May M.J.;
RT "The IkappaB kinase complex: master regulator of NF-kappaB signaling.";
RL Immunol. Res. 42:3-18(2008).
RN [25]
RP PHOSPHORYLATION AT THR-23 AND SER-180 BY SGK1.
RX PubMed=19088076; DOI=10.1074/jbc.m805055200;
RA Tai D.J., Su C.C., Ma Y.L., Lee E.H.;
RT "SGK1 phosphorylation of IkappaB Kinase alpha and p300 Up-regulates NF-
RT kappaB activity and increases N-Methyl-D-aspartate receptor NR2A and NR2B
RT expression.";
RL J. Biol. Chem. 284:4073-4089(2009).
RN [26]
RP INTERACTION WITH TRAF2.
RX PubMed=19150425; DOI=10.1016/j.molcel.2008.11.023;
RA Li S., Wang L., Dorf M.E.;
RT "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-
RT linked polyubiquitination.";
RL Mol. Cell 33:30-42(2009).
RN [27]
RP FUNCTION, AND INTERACTION WITH NLRC5.
RX PubMed=20434986; DOI=10.1016/j.cell.2010.03.040;
RA Cui J., Zhu L., Xia X., Wang H.Y., Legras X., Hong J., Ji J., Shen P.,
RA Zheng S., Chen Z.J., Wang R.F.;
RT "NLRC5 negatively regulates the NF-kappaB and type I interferon signaling
RT pathways.";
RL Cell 141:483-496(2010).
RN [28]
RP INTERACTION WITH L.MONOCYTOGENES INLC (MICROBIAL INFECTION).
RX PubMed=20855622; DOI=10.1073/pnas.1007765107;
RA Gouin E., Adib-Conquy M., Balestrino D., Nahori M.A., Villiers V.,
RA Colland F., Dramsi S., Dussurget O., Cossart P.;
RT "The Listeria monocytogenes InlC protein interferes with innate immune
RT responses by targeting the I{kappa}B kinase subunit IKK{alpha}.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:17333-17338(2010).
RN [29]
RP INVOLVEMENT IN COCOS.
RX PubMed=20961246; DOI=10.1056/nejmoa0911698;
RA Lahtela J., Nousiainen H.O., Stefanovic V., Tallila J., Viskari H.,
RA Karikoski R., Gentile M., Saloranta C., Varilo T., Salonen R., Kestila M.;
RT "Mutant CHUK and severe fetal encasement malformation.";
RL N. Engl. J. Med. 363:1631-1637(2010).
RN [30]
RP FUNCTION IN MAP3K14 PHOSPHORYLATION.
RX PubMed=20501937; DOI=10.1126/scisignal.2000778;
RA Razani B., Zarnegar B., Ytterberg A.J., Shiba T., Dempsey P.W., Ware C.F.,
RA Loo J.A., Cheng G.;
RT "Negative feedback in noncanonical NF-kappaB signaling modulates NIK
RT stability through IKKalpha-mediated phosphorylation.";
RL Sci. Signal. 3:RA41-RA41(2010).
RN [31]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [32]
RP FUNCTION IN PHOSPHORYLATION OF TAX1BP1.
RX PubMed=21765415; DOI=10.1038/ni.2066;
RA Shembade N., Pujari R., Harhaj N.S., Abbott D.W., Harhaj E.W.;
RT "The kinase IKKalpha inhibits activation of the transcription factor NF-
RT kappaB by phosphorylating the regulatory molecule TAX1BP1.";
RL Nat. Immunol. 12:834-843(2011).
RN [33]
RP INTERACTION WITH ZNF268, AND SUBUNIT.
RX PubMed=23091055; DOI=10.1074/jbc.m112.399923;
RA Wang W., Guo M., Hu L., Cai J., Zeng Y., Luo J., Shu Z., Li W., Huang Z.;
RT "The zinc finger protein ZNF268 is overexpressed in human cervical cancer
RT and contributes to tumorigenesis via enhancing NF-kappaB signaling.";
RL J. Biol. Chem. 287:42856-42866(2012).
RN [34]
RP INTERACTION WITH SASH1.
RX PubMed=23776175; DOI=10.4049/jimmunol.1200583;
RA Dauphinee S.M., Clayton A., Hussainkhel A., Yang C., Park Y.J.,
RA Fuller M.E., Blonder J., Veenstra T.D., Karsan A.;
RT "SASH1 is a scaffold molecule in endothelial TLR4 signaling.";
RL J. Immunol. 191:892-901(2013).
RN [35]
RP INTERACTION WITH IFIT5.
RX PubMed=26334375; DOI=10.1016/j.cellsig.2015.08.018;
RA Zheng C., Zheng Z., Zhang Z., Meng J., Liu Y., Ke X., Hu Q., Wang H.;
RT "IFIT5 positively regulates NF-kappaB signaling through synergizing the
RT recruitment of IkappaB kinase (IKK) to TGF-beta-activated kinase 1
RT (TAK1).";
RL Cell. Signal. 27:2343-2354(2015).
RN [36]
RP INTERACTION WITH LRRC14.
RX PubMed=27426725; DOI=10.1016/j.yexcr.2016.07.011;
RA Wu C., Yang Y., Ou J., Zhu L., Zhao W., Cui J.;
RT "LRRC14 attenuates Toll-like receptor-mediated NF-kappa-B signaling through
RT disruption of IKK complex.";
RL Exp. Cell Res. 347:65-73(2016).
RN [37]
RP INTERACTION WITH DDX3X, AND SUBCELLULAR LOCATION.
RX PubMed=30341167; DOI=10.1042/bcj20180163;
RA Fullam A., Gu L., Hoehn Y., Schroeder M.;
RT "DDX3 directly facilitates IKKalpha activation and regulates downstream
RT signalling pathways.";
RL Biochem. J. 475:3595-3607(2018).
RN [38]
RP FUNCTION.
RX PubMed=30217973; DOI=10.1038/s41467-018-05722-3;
RA Di Rita A., Peschiaroli A., D'Acunzo P., Strobbe D., Hu Z., Gruber J.,
RA Nygaard M., Lambrughi M., Melino G., Papaleo E., Dengjel J., El Alaoui S.,
RA Campanella M., Doetsch V., Rogov V.V., Strappazzon F., Cecconi F.;
RT "HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating
RT AMBRA1 activation via IKKalpha.";
RL Nat. Commun. 9:3755-3755(2018).
RN [39]
RP IDENTIFICATION IN THE IKK COMPLEX.
RX PubMed=32935379; DOI=10.15252/embj.2020105139;
RA Chathuranga K., Kim T.H., Lee H., Park J.S., Kim J.H., Chathuranga W.A.G.,
RA Ekanayaka P., Choi Y.J., Lee C.H., Kim C.J., Jung J.U., Lee J.S.;
RT "Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2.";
RL EMBO J. 39:e105139-e105139(2020).
RN [40]
RP INVOLVEMENT IN BPS2.
RX PubMed=25691407; DOI=10.1002/ajmg.a.36896;
RA Leslie E.J., O'Sullivan J., Cunningham M.L., Singh A., Goudy S.L.,
RA Ababneh F., Alsubaie L., Ch'ng G.S., van der Laar I.M., Hoogeboom A.J.,
RA Dunnwald M., Kapoor S., Jiramongkolchai P., Standley J., Manak J.R.,
RA Murray J.C., Dixon M.J.;
RT "Expanding the genetic and phenotypic spectrum of popliteal pterygium
RT disorders.";
RL Am. J. Med. Genet. A 167A:545-552(2015).
RN [41]
RP VARIANTS [LARGE SCALE ANALYSIS] CYS-126; ALA-155 AND ILE-268.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 732-745.
RX PubMed=18462684; DOI=10.1016/j.str.2008.02.012;
RA Rushe M., Silvian L., Bixler S., Chen L.L., Cheung A., Bowes S., Cuervo H.,
RA Berkowitz S., Zheng T., Guckian K., Pellegrini M., Lugovskoy A.;
RT "Structure of a NEMO/IKK-associating domain reveals architecture of the
RT interaction site.";
RL Structure 16:798-808(2008).
CC -!- FUNCTION: Serine kinase that plays an essential role in the NF-kappa-B
CC signaling pathway which is activated by multiple stimuli such as
CC inflammatory cytokines, bacterial or viral products, DNA damages or
CC other cellular stresses (PubMed:9244310, PubMed:9252186,
CC PubMed:9346484, PubMed:18626576). Acts as part of the canonical IKK
CC complex in the conventional pathway of NF-kappa-B activation and
CC phosphorylates inhibitors of NF-kappa-B on serine residues
CC (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576).
CC These modifications allow polyubiquitination of the inhibitors and
CC subsequent degradation by the proteasome (PubMed:9244310,
CC PubMed:9252186, PubMed:9346484, PubMed:18626576). In turn, free NF-
CC kappa-B is translocated into the nucleus and activates the
CC transcription of hundreds of genes involved in immune response, growth
CC control, or protection against apoptosis (PubMed:9244310,
CC PubMed:9252186, PubMed:9346484, PubMed:18626576). Negatively regulates
CC the pathway by phosphorylating the scaffold protein TAXBP1 and thus
CC promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex
CC (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11)
CC (PubMed:21765415). Therefore, CHUK plays a key role in the negative
CC feedback of NF-kappa-B canonical signaling to limit inflammatory gene
CC activation. As part of the non-canonical pathway of NF-kappa-B
CC activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates
CC NFKB2/p100 associated with RelB, inducing its proteolytic processing to
CC NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes
CC (PubMed:20501937). In turn, these complexes regulate genes encoding
CC molecules involved in B-cell survival and lymphoid organogenesis.
CC Participates also in the negative feedback of the non-canonical NF-
CC kappa-B signaling pathway by phosphorylating and destabilizing
CC MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently
CC increases both its transcriptional and histone acetyltransferase
CC activities (PubMed:17434128). Modulates chromatin accessibility at NF-
CC kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10'
CC that are subsequently acetylated at 'Lys-14' by CREBBP
CC (PubMed:12789342). Additionally, phosphorylates the CREBBP-interacting
CC protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-
CC apoptotic transcription factor (PubMed:15084260). Phosphorylates RIPK1
CC at 'Ser-25' which represses its kinase activity and consequently
CC prevents TNF-mediated RIPK1-dependent cell death (By similarity).
CC Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1
CC interaction with ATG8 family proteins and its mitophagic activity
CC (PubMed:30217973). {ECO:0000250|UniProtKB:Q60680,
CC ECO:0000269|PubMed:12789342, ECO:0000269|PubMed:15084260,
CC ECO:0000269|PubMed:17434128, ECO:0000269|PubMed:20434986,
CC ECO:0000269|PubMed:20501937, ECO:0000269|PubMed:21765415,
CC ECO:0000269|PubMed:30217973, ECO:0000269|PubMed:9244310,
CC ECO:0000269|PubMed:9252186, ECO:0000269|PubMed:9346484,
CC ECO:0000303|PubMed:18626576}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-
CC seryl-[I-kappa-B protein]; Xref=Rhea:RHEA:19073, Rhea:RHEA-
CC COMP:13698, Rhea:RHEA-COMP:13699, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421,
CC ChEBI:CHEBI:456216; EC=2.7.11.10;
CC Evidence={ECO:0000269|PubMed:9244310, ECO:0000269|PubMed:9252186,
CC ECO:0000269|PubMed:9346484};
CC -!- ACTIVITY REGULATION: Activated when phosphorylated and inactivated when
CC dephosphorylated.
CC -!- SUBUNIT: Component of the I-kappa-B-kinase (IKK) core complex
CC consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-
CC beta/IKBKB dimers are associated with four gamma/IKBKG subunits
CC (PubMed:32935379). The IKK core complex seems to associate with
CC regulatory or adapter proteins to form a IKK-signalosome holo-complex
CC (PubMed:10195894, PubMed:12612076). The IKK complex associates with
CC TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of
CC RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3,
CC CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90
CC kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1
CC and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By
CC similarity). May interact with TRAF2 (PubMed:19150425). Interacts with
CC NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806).
CC Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5;
CC prevents CHUK phosphorylation and kinase activity (PubMed:20434986).
CC Interacts with PIAS1; this interaction induces PIAS1 phosphorylation
CC (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is
CC further increased in a TNF-alpha-dependent manner (PubMed:23091055).
CC Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the
CC interaction synergizes the recruitment of IKK to MAP3K7 and enhances
CC IKK phosphorylation (PubMed:26334375). Interacts with LRRC14
CC (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly
CC interacts with DDX3X after the physiological activation of the TLR7 and
CC TLR8 pathways; this interaction enhances CHUK autophosphorylation
CC (PubMed:30341167). {ECO:0000250|UniProtKB:Q60680,
CC ECO:0000269|PubMed:10195894, ECO:0000269|PubMed:11971985,
CC ECO:0000269|PubMed:12612076, ECO:0000269|PubMed:15084260,
CC ECO:0000269|PubMed:15173580, ECO:0000269|PubMed:15456791,
CC ECO:0000269|PubMed:16177806, ECO:0000269|PubMed:17540171,
CC ECO:0000269|PubMed:19150425, ECO:0000269|PubMed:20434986,
CC ECO:0000269|PubMed:23091055, ECO:0000269|PubMed:23776175,
CC ECO:0000269|PubMed:26334375, ECO:0000269|PubMed:27426725,
CC ECO:0000269|PubMed:30341167, ECO:0000269|PubMed:32935379,
CC ECO:0000269|PubMed:9751059}.
CC -!- SUBUNIT: (Microbial infection) Interacts with InlC of Listeria
CC monocytogenes. {ECO:0000269|PubMed:20855622}.
CC -!- INTERACTION:
CC O15111; Q16543: CDC37; NbExp=5; IntAct=EBI-81249, EBI-295634;
CC O15111; P46527: CDKN1B; NbExp=4; IntAct=EBI-81249, EBI-519280;
CC O15111; Q13451: FKBP5; NbExp=2; IntAct=EBI-81249, EBI-306914;
CC O15111; P07900: HSP90AA1; NbExp=3; IntAct=EBI-81249, EBI-296047;
CC O15111; O14920: IKBKB; NbExp=17; IntAct=EBI-81249, EBI-81266;
CC O15111; Q9Y6K9: IKBKG; NbExp=27; IntAct=EBI-81249, EBI-81279;
CC O15111; Q92985: IRF7; NbExp=4; IntAct=EBI-81249, EBI-968267;
CC O15111; Q99558: MAP3K14; NbExp=12; IntAct=EBI-81249, EBI-358011;
CC O15111; Q5TCX8: MAP3K21; NbExp=2; IntAct=EBI-81249, EBI-1057380;
CC O15111; P01106: MYC; NbExp=3; IntAct=EBI-81249, EBI-447544;
CC O15111; P19838: NFKB1; NbExp=3; IntAct=EBI-81249, EBI-300010;
CC O15111; P25963: NFKBIA; NbExp=15; IntAct=EBI-81249, EBI-307386;
CC O15111; Q04206: RELA; NbExp=2; IntAct=EBI-81249, EBI-73886;
CC O15111; Q15796: SMAD2; NbExp=2; IntAct=EBI-81249, EBI-1040141;
CC O15111; Q86VP1: TAX1BP1; NbExp=2; IntAct=EBI-81249, EBI-529518;
CC O15111; P03129: E7; Xeno; NbExp=2; IntAct=EBI-81249, EBI-866453;
CC O15111; Q07857: E7; Xeno; NbExp=2; IntAct=EBI-81249, EBI-9690349;
CC O15111; Q6TY28: E7; Xeno; NbExp=2; IntAct=EBI-81249, EBI-9690312;
CC O15111; Q6TY35: E7; Xeno; NbExp=2; IntAct=EBI-81249, EBI-9690239;
CC O15111; Q80901: E7; Xeno; NbExp=2; IntAct=EBI-81249, EBI-9690278;
CC O15111; Q8B5B5: E7; Xeno; NbExp=2; IntAct=EBI-81249, EBI-9690330;
CC O15111; P71451: inlC; Xeno; NbExp=3; IntAct=EBI-81249, EBI-21019720;
CC O15111; Q77M19: P; Xeno; NbExp=2; IntAct=EBI-81249, EBI-6149376;
CC O15111; P24772: VACWR196; Xeno; NbExp=3; IntAct=EBI-81249, EBI-4291651;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12789342,
CC ECO:0000269|PubMed:30341167}. Nucleus {ECO:0000269|PubMed:12789342}.
CC Note=Shuttles between the cytoplasm and the nucleus.
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DOMAIN: The kinase domain is located in the N-terminal region. The
CC leucine zipper is important to allow homo- and hetero-dimerization. At
CC the C-terminal region is located the region responsible for the
CC interaction with NEMO/IKBKG. {ECO:0000269|PubMed:18626576}.
CC -!- PTM: Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by
CC MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
CC -!- PTM: (Microbial infection) Acetylation of Thr-179 by Yersinia YopJ
CC prevents phosphorylation and activation, thus blocking the I-kappa-B
CC signaling pathway. {ECO:0000269|PubMed:17116858}.
CC -!- DISEASE: Cocoon syndrome (COCOS) [MIM:613630]: A lethal syndrome
CC characterized by multiple fetal malformations including defective face
CC and seemingly absent limbs, which are bound to the trunk and encased
CC under the skin. {ECO:0000269|PubMed:20961246}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Bartsocas-Papas syndrome 2 (BPS2) [MIM:619339]: An autosomal
CC recessive, severe form of popliteal pterygium syndrome. Popliteal
CC pterygia syndromes have considerable variability in severity and in the
CC associated phenotypic features but they are all characterized by
CC cutaneous webbing across one or more major joints, cleft lip and/or
CC palate, syndactyly, and genital malformations.
CC {ECO:0000269|PubMed:25691407}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. I-kappa-B kinase subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/chuk/";
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DR EMBL; AF012890; AAC51662.1; -; mRNA.
DR EMBL; AF009225; AAC51671.1; -; mRNA.
DR EMBL; AF080157; AAD08996.1; -; mRNA.
DR EMBL; AY652653; AAT49098.1; -; Genomic_DNA.
DR EMBL; AL138921; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U22512; AAC50713.1; -; mRNA.
DR CCDS; CCDS7488.1; -.
DR RefSeq; NP_001269.3; NM_001278.4.
DR PDB; 3BRT; X-ray; 2.25 A; A/C=732-745.
DR PDB; 5EBZ; X-ray; 4.50 A; A/B/C/D/E/F/G/H/I/J/K/L=10-660.
DR PDB; 5TQW; EM; 5.60 A; A/B=10-660.
DR PDB; 5TQX; EM; 5.40 A; A/B=10-660.
DR PDB; 5TQY; EM; 5.20 A; A/B=10-660.
DR PDBsum; 3BRT; -.
DR PDBsum; 5EBZ; -.
DR PDBsum; 5TQW; -.
DR PDBsum; 5TQX; -.
DR PDBsum; 5TQY; -.
DR AlphaFoldDB; O15111; -.
DR SMR; O15111; -.
DR BioGRID; 107569; 204.
DR ComplexPortal; CPX-3269; IkappaB kinase complex.
DR CORUM; O15111; -.
DR DIP; DIP-27526N; -.
DR ELM; O15111; -.
DR IntAct; O15111; 84.
DR MINT; O15111; -.
DR STRING; 9606.ENSP00000359424; -.
DR BindingDB; O15111; -.
DR ChEMBL; CHEMBL3476; -.
DR DrugBank; DB06151; Acetylcysteine.
DR DrugBank; DB00233; Aminosalicylic acid.
DR DrugBank; DB00244; Mesalazine.
DR DrugBank; DB00795; Sulfasalazine.
DR DrugCentral; O15111; -.
DR GuidetoPHARMACOLOGY; 1989; -.
DR GlyGen; O15111; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O15111; -.
DR PhosphoSitePlus; O15111; -.
DR BioMuta; CHUK; -.
DR CPTAC; CPTAC-1220; -.
DR CPTAC; CPTAC-1221; -.
DR EPD; O15111; -.
DR jPOST; O15111; -.
DR MassIVE; O15111; -.
DR MaxQB; O15111; -.
DR PaxDb; O15111; -.
DR PeptideAtlas; O15111; -.
DR PRIDE; O15111; -.
DR ProteomicsDB; 48449; -.
DR Antibodypedia; 801; 1502 antibodies from 52 providers.
DR DNASU; 1147; -.
DR Ensembl; ENST00000370397.8; ENSP00000359424.6; ENSG00000213341.11.
DR GeneID; 1147; -.
DR KEGG; hsa:1147; -.
DR MANE-Select; ENST00000370397.8; ENSP00000359424.6; NM_001278.5; NP_001269.3.
DR UCSC; uc001kqp.4; human.
DR CTD; 1147; -.
DR DisGeNET; 1147; -.
DR GeneCards; CHUK; -.
DR HGNC; HGNC:1974; CHUK.
DR HPA; ENSG00000213341; Low tissue specificity.
DR MalaCards; CHUK; -.
DR MIM; 600664; gene.
DR MIM; 613630; phenotype.
DR MIM; 619339; phenotype.
DR neXtProt; NX_O15111; -.
DR OpenTargets; ENSG00000213341; -.
DR Orphanet; 465824; Fetal encasement syndrome.
DR PharmGKB; PA26510; -.
DR VEuPathDB; HostDB:ENSG00000213341; -.
DR eggNOG; KOG4250; Eukaryota.
DR GeneTree; ENSGT00950000182937; -.
DR HOGENOM; CLU_000288_101_2_1; -.
DR InParanoid; O15111; -.
DR OMA; RMMNLDW; -.
DR OrthoDB; 1013139at2759; -.
DR PhylomeDB; O15111; -.
DR TreeFam; TF324269; -.
DR BRENDA; 2.7.11.10; 2681.
DR PathwayCommons; O15111; -.
DR Reactome; R-HSA-1169091; Activation of NF-kappaB in B cells.
DR Reactome; R-HSA-1236974; ER-Phagosome pathway.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-168927; TICAM1, RIP1-mediated IKK complex recruitment.
DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1.
DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-HSA-202424; Downstream TCR signaling.
DR Reactome; R-HSA-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-HSA-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-HSA-5602636; IKBKB deficiency causes SCID.
DR Reactome; R-HSA-5603027; IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR).
DR Reactome; R-HSA-5603029; IkBA variant leads to EDA-ID.
DR Reactome; R-HSA-5607761; Dectin-1 mediated noncanonical NF-kB signaling.
DR Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR Reactome; R-HSA-5676590; NIK-->noncanonical NF-kB signaling.
DR Reactome; R-HSA-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR Reactome; R-HSA-933542; TRAF6 mediated NF-kB activation.
DR Reactome; R-HSA-933543; NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
DR Reactome; R-HSA-937039; IRAK1 recruits IKK complex.
DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR Reactome; R-HSA-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR SABIO-RK; O15111; -.
DR SignaLink; O15111; -.
DR SIGNOR; O15111; -.
DR BioGRID-ORCS; 1147; 39 hits in 1117 CRISPR screens.
DR ChiTaRS; CHUK; human.
DR EvolutionaryTrace; O15111; -.
DR GeneWiki; CHUK; -.
DR GenomeRNAi; 1147; -.
DR Pharos; O15111; Tchem.
DR PRO; PR:O15111; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; O15111; protein.
DR Bgee; ENSG00000213341; Expressed in secondary oocyte and 195 other tissues.
DR Genevisible; O15111; HS.
DR GO; GO:0035631; C:CD40 receptor complex; ISS:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0008385; C:IkappaB kinase complex; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008384; F:IkappaB kinase activity; TAS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0097110; F:scaffold protein binding; IDA:MGI.
DR GO; GO:1990459; F:transferrin receptor binding; IPI:ARUK-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0071276; P:cellular response to cadmium ion; IMP:CAFA.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; IMP:CAFA.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; IMP:CAFA.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IMP:CAFA.
DR GO; GO:0007252; P:I-kappaB phosphorylation; TAS:ProtInc.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0006954; P:inflammatory response; TAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; TAS:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0038061; P:NIK/NF-kappaB signaling; IMP:CAFA.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:ARUK-UCL.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IMP:CAFA.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IBA:GO_Central.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:CAFA.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0009615; P:response to virus; TAS:UniProtKB.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IBA:GO_Central.
DR Gene3D; 1.20.1270.250; -; 1.
DR IDEAL; IID00526; -.
DR InterPro; IPR041185; IKBKB_SDD.
DR InterPro; IPR046375; IKBKB_SDD_sf.
DR InterPro; IPR022007; IKKbetaNEMObind.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF18397; IKBKB_SDD; 1.
DR Pfam; PF12179; IKKbetaNEMObind; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM01239; IKKbetaNEMObind; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Cytoplasm;
KW Direct protein sequencing; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1..745
FT /note="Inhibitor of nuclear factor kappa-B kinase subunit
FT alpha"
FT /id="PRO_0000086011"
FT DOMAIN 15..302
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 455..476
FT /note="Leucine-zipper"
FT REGION 738..743
FT /note="NEMO-binding"
FT ACT_SITE 144
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 21..29
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 44
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 23
FT /note="Phosphothreonine; by PKB/AKT1 and SGK1"
FT /evidence="ECO:0000269|PubMed:10485710,
FT ECO:0000269|PubMed:19088076"
FT MOD_RES 176
FT /note="Phosphoserine; by MAP3K14"
FT /evidence="ECO:0000269|PubMed:9520446"
FT MOD_RES 179
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:17116858"
FT MOD_RES 180
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000269|PubMed:19088076"
FT VARIANT 126
FT /note="S -> C (in dbSNP:rs34427437)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040565"
FT VARIANT 155
FT /note="V -> A (in dbSNP:rs2230803)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040566"
FT VARIANT 268
FT /note="V -> I (in dbSNP:rs2230804)"
FT /evidence="ECO:0000269|PubMed:15164054,
FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:8777433,
FT ECO:0000269|PubMed:9244310, ECO:0000269|PubMed:9252186,
FT ECO:0000269|PubMed:9813230"
FT /id="VAR_021359"
FT MUTAGEN 23
FT /note="T->A: Loss of phosphorylation and decrease of kinase
FT activity."
FT /evidence="ECO:0000269|PubMed:10485710"
FT MUTAGEN 44
FT /note="K->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:9244310,
FT ECO:0000269|PubMed:9346484"
FT MUTAGEN 44
FT /note="K->M: Loss of autophosphorylation."
FT /evidence="ECO:0000269|PubMed:9244310,
FT ECO:0000269|PubMed:9346484"
FT MUTAGEN 176
FT /note="S->A: Loss of phosphorylation and of activity."
FT /evidence="ECO:0000269|PubMed:9346484,
FT ECO:0000269|PubMed:9520446"
FT MUTAGEN 176
FT /note="S->E: Full activation."
FT /evidence="ECO:0000269|PubMed:9346484,
FT ECO:0000269|PubMed:9520446"
FT MUTAGEN 179
FT /note="T->A: No change in phosphorylation."
FT /evidence="ECO:0000269|PubMed:9520446"
FT MUTAGEN 180
FT /note="S->A: No change in phosphorylation."
FT /evidence="ECO:0000269|PubMed:9520446"
FT CONFLICT 543
FT /note="E -> G (in Ref. 2; AAC51671)"
FT /evidence="ECO:0000305"
FT CONFLICT 604
FT /note="L -> R (in Ref. 7; AAC50713)"
FT /evidence="ECO:0000305"
FT CONFLICT 679..680
FT /note="TS -> AY (in Ref. 7; AAC50713)"
FT /evidence="ECO:0000305"
FT CONFLICT 684
FT /note="P -> A (in Ref. 3; no nucleotide entry and 7;
FT AAC50713)"
FT /evidence="ECO:0000305"
FT CONFLICT 686..687
FT /note="TS -> DL (in Ref. 7; AAC50713)"
FT /evidence="ECO:0000305"
FT HELIX 735..737
FT /evidence="ECO:0007829|PDB:3BRT"
FT HELIX 741..743
FT /evidence="ECO:0007829|PDB:3BRT"
SQ SEQUENCE 745 AA; 84640 MW; 4EA55C6FFC66FA16 CRC64;
MERPPGLRPG AGGPWEMRER LGTGGFGNVC LYQHRELDLK IAIKSCRLEL STKNRERWCH
EIQIMKKLNH ANVVKACDVP EELNILIHDV PLLAMEYCSG GDLRKLLNKP ENCCGLKESQ
ILSLLSDIGS GIRYLHENKI IHRDLKPENI VLQDVGGKII HKIIDLGYAK DVDQGSLCTS
FVGTLQYLAP ELFENKPYTA TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK
CIFACEEMSG EVRFSSHLPQ PNSLCSLVVE PMENWLQLML NWDPQQRGGP VDLTLKQPRC
FVLMDHILNL KIVHILNMTS AKIISFLLPP DESLHSLQSR IERETGINTG SQELLSETGI
SLDPRKPASQ CVLDGVRGCD SYMVYLFDKS KTVYEGPFAS RSLSDCVNYI VQDSKIQLPI
IQLRKVWAEA VHYVSGLKED YSRLFQGQRA AMLSLLRYNA NLTKMKNTLI SASQQLKAKL
EFFHKSIQLD LERYSEQMTY GISSEKMLKA WKEMEEKAIH YAEVGVIGYL EDQIMSLHAE
IMELQKSPYG RRQGDLMESL EQRAIDLYKQ LKHRPSDHSY SDSTEMVKII VHTVQSQDRV
LKELFGHLSK LLGCKQKIID LLPKVEVALS NIKEADNTVM FMQGKRQKEI WHLLKIACTQ
SSARSLVGSS LEGAVTPQTS AWLPPTSAEH DHSLSCVVTP QDGETSAQMI EENLNCLGHL
STIIHEANEE QGNSMMNLDW SWLTE
