IKKE_HUMAN
ID IKKE_HUMAN Reviewed; 716 AA.
AC Q14164; D3DT78; Q3B754; Q3KR43; Q5JTS6;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Inhibitor of nuclear factor kappa-B kinase subunit epsilon;
DE Short=I-kappa-B kinase epsilon;
DE Short=IKK-E;
DE Short=IKK-epsilon;
DE Short=IkBKE;
DE EC=2.7.11.10;
DE AltName: Full=Inducible I kappa-B kinase;
DE Short=IKK-i;
GN Name=IKBKE; Synonyms=IKKE, IKKI, KIAA0151;
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] (ISOFORM 1), AND MUTAGENESIS OF LYS-38; GLU-168
RP AND SER-172.
RX PubMed=10421793; DOI=10.1093/intimm/11.8.1357;
RA Shimada T., Kawai T., Takeda K., Matsumoto M., Inoue J., Tatsumi Y.,
RA Kanamaru A., Akira S.;
RT "IKK-i, a novel lipopolysaccharide-inducible kinase that is related to
RT IkappaB kinases.";
RL Int. Immunol. 11:1357-1362(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Leukocyte;
RX PubMed=10882136; DOI=10.1016/s1097-2765(00)80445-1;
RA Peters R.T., Liao S.-M., Maniatis T.;
RT "IKK epsilon is part of a novel PMA-inducible IkappaB kinase complex.";
RL Mol. Cell 5:513-522(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV. The
RT coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-128; THR-371; ASP-515;
RP MET-543; VAL-602 AND LEU-713.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH AZI2.
RX PubMed=14560022; DOI=10.1128/mcb.23.21.7780-7793.2003;
RA Fujita F., Taniguchi Y., Kato T., Narita Y., Furuya A., Ogawa T.,
RA Sakurai H., Joh T., Itoh M., Delhase M., Karin M., Nakanishi M.;
RT "Identification of NAP1, a regulatory subunit of IkappaB kinase-related
RT kinases that potentiates NF-kappaB signaling.";
RL Mol. Cell. Biol. 23:7780-7793(2003).
RN [9]
RP INTERACTION WITH TICAM1.
RX PubMed=14739303; DOI=10.1074/jbc.m311629200;
RA Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B.;
RT "Mechanisms of the TRIF-induced interferon-stimulated response element and
RT NF-kappaB activation and apoptosis pathways.";
RL J. Biol. Chem. 279:15652-15661(2004).
RN [10]
RP INTERACTION WITH SIKE1; IRF3; TICAM1 AND DDX58.
RX PubMed=16281057; DOI=10.1038/sj.emboj.7600863;
RA Huang J., Liu T., Xu L.-G., Chen D., Zhai Z., Shu H.-B.;
RT "SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-
RT triggered IRF-3 activation pathways.";
RL EMBO J. 24:4018-4028(2005).
RN [11]
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 [12]
RP FUNCTION, AND INTERACTION WITH AZI2; TANK AND TBKBP1.
RX PubMed=17568778; DOI=10.1038/sj.emboj.7601743;
RA Ryzhakov G., Randow F.;
RT "SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-
RT binding domain with NAP1 and TANK.";
RL EMBO J. 26:3180-3190(2007).
RN [13]
RP INTERACTION WITH IFIH1.
RX PubMed=17600090; DOI=10.1073/pnas.0700544104;
RA Diao F., Li S., Tian Y., Zhang M., Xu L.G., Zhang Y., Wang R.P., Chen D.,
RA Zhai Z., Zhong B., Tien P., Shu H.B.;
RT "Negative regulation of MDA5- but not RIG-I-mediated innate antiviral
RT signaling by the dihydroxyacetone kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:11706-11711(2007).
RN [14]
RP FUNCTION IN PHOSPHORYLATION OF DDX3X.
RX PubMed=18583960; DOI=10.1038/emboj.2008.126;
RA Soulat D., Burckstummer T., Westermayer S., Goncalves A., Bauch A.,
RA Stefanovic A., Hantschel O., Bennett K.L., Decker T., Superti-Furga G.;
RT "The DEAD-box helicase DDX3X is a critical component of the TANK-binding
RT kinase 1-dependent innate immune response.";
RL EMBO J. 27:2135-2146(2008).
RN [15]
RP INTERACTION WITH DDX3X.
RX PubMed=18636090; DOI=10.1038/emboj.2008.143;
RA Schroder M., Baran M., Bowie A.G.;
RT "Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-
RT mediated IRF activation.";
RL EMBO J. 27:2147-2157(2008).
RN [16]
RP INTERACTION WITH CYLD.
RX PubMed=18636086; DOI=10.1038/embor.2008.136;
RA Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A., Cardenas W.B.,
RA Yount J.S., Moran T.M., Basler C.F., Komuro A., Horvath C.M., Xavier R.,
RA Ting A.T.;
RT "The tumour suppressor CYLD is a negative regulator of RIG-I-mediated
RT antiviral response.";
RL EMBO Rep. 9:930-936(2008).
RN [17]
RP FUNCTION IN IRF3 PHOSPHORYLATION, INTERACTION WITH EBOLAVIRUS PROTEIN VP35
RP (MICROBIAL INFECTION), AND AUTOPHOSPHORYLATION.
RX PubMed=19153231; DOI=10.1128/jvi.01875-08;
RA Prins K.C., Cardenas W.B., Basler C.F.;
RT "Ebola virus protein VP35 impairs the function of interferon regulatory
RT factor-activating kinases IKKepsilon and TBK-1.";
RL J. Virol. 83:3069-3077(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-664, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [19]
RP FUNCTION, INTERACTION WITH TOPORS, SUMOYLATION AT LYS-231 BY TOPORS,
RP DESUMOYLATION BY SENP1, MUTAGENESIS OF LYS-231, AND SUBCELLULAR LOCATION.
RX PubMed=20188669; DOI=10.1016/j.molcel.2010.01.018;
RA Renner F., Moreno R., Schmitz M.L.;
RT "SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is
RT essential for protection against DNA-damage-triggered cell death.";
RL Mol. Cell 37:503-515(2010).
RN [20]
RP INTERACTION WITH DDX3X.
RX PubMed=20657822; DOI=10.1371/journal.ppat.1000986;
RA Wang H., Ryu W.S.;
RT "Hepatitis B virus polymerase blocks pattern recognition receptor signaling
RT via interaction with DDX3: implications for immune evasion.";
RL PLoS Pathog. 6:E1000986-E1000986(2010).
RN [21]
RP FUNCTION, AND PHOSPHORYLATION BY IKBKB/IKKB.
RX PubMed=21138416; DOI=10.1042/bj20101701;
RA Clark K., Peggie M., Plater L., Sorcek R.J., Young E.R., Madwed J.B.,
RA Hough J., McIver E.G., Cohen P.;
RT "Novel cross-talk within the IKK family controls innate immunity.";
RL Biochem. J. 434:93-104(2011).
RN [22]
RP FUNCTION IN AKT PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=21464307; DOI=10.1073/pnas.1016132108;
RA Xie X., Zhang D., Zhao B., Lu M.K., You M., Condorelli G., Wang C.Y.,
RA Guan K.L.;
RT "IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct
RT phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:6474-6479(2011).
RN [23]
RP FUNCTION, AND INTERACTION WITH ARENAVIRUS PROTEIN N (MICROBIAL INFECTION).
RX PubMed=22532683; DOI=10.1128/jvi.00187-12;
RA Pythoud C., Rodrigo W.W., Pasqual G., Rothenberger S., Martinez-Sobrido L.,
RA de la Torre J.C., Kunz S.;
RT "Arenavirus nucleoprotein targets interferon regulatory factor-activating
RT kinase IKKepsilon.";
RL J. Virol. 86:7728-7738(2012).
RN [24]
RP FUNCTION, HOMODIMER, INTERACTION WITH IKBKB; IKBKG AND MYD88, INDUCTION BY
RP LPS, UBIQUITINATION AT LYS-30 AND LYS-401, AND MUTAGENESIS OF LYS-30;
RP LYS-401 AND LYS-416.
RX PubMed=23453969; DOI=10.1016/j.celrep.2013.01.031;
RA Zhou A.Y., Shen R.R., Kim E., Lock Y.J., Xu M., Chen Z.J., Hahn W.C.;
RT "IKKepsilon-mediated tumorigenesis requires K63-linked polyubiquitination
RT by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.";
RL Cell Rep. 3:724-733(2013).
RN [25]
RP FUNCTION IN DDX3X AND IRF3 PHOSPHORYLATION, INTERACTION WITH DDX3X AND
RP IRF3, AND PHOSPHORYLATION AT SER-172.
RX PubMed=23478265; DOI=10.1128/mcb.01603-12;
RA Gu L., Fullam A., Brennan R., Schroder M.;
RT "Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon
RT regulatory factor 3 activation.";
RL Mol. Cell. Biol. 33:2004-2015(2013).
RN [26]
RP INTERACTION WITH TRIM6 AND POLYUBIQUITIN, SUBCELLULAR LOCATION, AND
RP PHOSPHORYLATION AT THR-501.
RX PubMed=24882218; DOI=10.1016/j.immuni.2014.04.018;
RA Rajsbaum R., Versteeg G.A., Schmid S., Maestre A.M., Belicha-Villanueva A.,
RA Martinez-Romero C., Patel J.R., Morrison J., Pisanelli G., Miorin L.,
RA Laurent-Rolle M., Moulton H.M., Stein D.A., Fernandez-Sesma A.,
RA tenOever B.R., Garcia-Sastre A.;
RT "Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase
RT TRIM6 stimulates the interferon-IKKepsilon kinase-mediated antiviral
RT response.";
RL Immunity 40:880-895(2014).
RN [27]
RP INTERACTION WITH SFTSV NSS (MICROBIAL INFECTION).
RX PubMed=24706939; DOI=10.1093/jmcb/mju015;
RA Ning Y.J., Wang M., Deng M., Shen S., Liu W., Cao W.C., Deng F., Wang Y.Y.,
RA Hu Z., Wang H.;
RT "Viral suppression of innate immunity via spatial isolation of
RT TBK1/IKKepsilon from mitochondrial antiviral platform.";
RL J. Mol. Cell Biol. 6:324-337(2014).
RN [28]
RP INTERACTION WITH FKBP5.
RX PubMed=26101251; DOI=10.1093/nar/gkv615;
RA Romano S., Xiao Y., Nakaya M., D'Angelillo A., Chang M., Jin J., Hausch F.,
RA Masullo M., Feng X., Romano M.F., Sun S.C.;
RT "FKBP51 employs both scaffold and isomerase functions to promote NF-kappaB
RT activation in melanoma.";
RL Nucleic Acids Res. 43:6983-6993(2015).
RN [29]
RP INTERACTION WITH DDX3X AND MAVS.
RX PubMed=27980081; DOI=10.1042/bcj20160956;
RA Gu L., Fullam A., McCormack N., Hoehn Y., Schroeder M.;
RT "DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co-
RT ordinate assembly of signalling complexes downstream from MAVS.";
RL Biochem. J. 474:571-587(2017).
RN [30]
RP INTERACTION WITH TTLL12 AND MAVS.
RX PubMed=28011935; DOI=10.4049/jimmunol.1601194;
RA Ju L.G., Zhu Y., Lei P.J., Yan D., Zhu K., Wang X., Li Q.L., Li X.J.,
RA Chen J.W., Li L.Y., Wu M.;
RT "TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through
RT Interaction with VISA/MAVS.";
RL J. Immunol. 198:1274-1284(2017).
RN [31]
RP INTERACTION WITH HUMAN T-CELL LEUKEMIA VIRUS 1/HTLV-1 PROTEIN HBZ.
RX PubMed=28768861; DOI=10.1128/jvi.00853-17;
RA Narulla M.S., Alasiri A., Charmier L., Noonan S., Conroy D., Hall W.W.,
RA Sheehy N.;
RT "Positive and Negative Regulation of Type I Interferons by the Human T Cell
RT Leukemia Virus Antisense Protein HBZ.";
RL J. Virol. 91:0-0(2017).
RN [32]
RP INTERACTION WITH TBK1.
RX PubMed=29251827; DOI=10.1002/pmic.201700403;
RA Shang J., Xia T., Han Q.Q., Zhao X., Hu M.M., Shu H.B., Guo L.;
RT "Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a
RT Positive Regulator of SeV-Induced Innate Immunity.";
RL Proteomics 18:0-0(2018).
RN [33]
RP INTERACTION WITH FKBP5.
RX PubMed=31434731; DOI=10.1128/jvi.01159-19;
RA DeDiego M.L., Martinez-Sobrido L., Topham D.J.;
RT "Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral
RT Responses.";
RL J. Virol. 93:0-0(2019).
RN [34]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-371; MET-483; VAL-602; GLU-660 AND
RP LEU-713.
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).
CC -!- FUNCTION: Serine/threonine kinase that plays an essential role in
CC regulating inflammatory responses to viral infection, through the
CC activation of the type I IFN, NF-kappa-B and STAT signaling. Also
CC involved in TNFA and inflammatory cytokines, like Interleukin-1,
CC signaling. Following activation of viral RNA sensors, such as RIG-I-
CC like receptors, associates with DDX3X and phosphorylates interferon
CC regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This
CC activity allows subsequent homodimerization and nuclear translocation
CC of the IRF3 leading to transcriptional activation of pro-inflammatory
CC and antiviral genes including IFNB. In order to establish such an
CC antiviral state, IKBKE forms several different complexes whose
CC composition depends on the type of cell and cellular stimuli. Thus,
CC several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or
CC TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes.
CC Activated by polyubiquitination in response to TNFA and interleukin-1,
CC regulates the NF-kappa-B signaling pathway through, at least, the
CC phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus
CC leading to the dissociation of the inhibitor/NF-kappa-B complex and
CC ultimately the degradation of the inhibitor. In addition, is also
CC required for the induction of a subset of ISGs which displays antiviral
CC activity, may be through the phosphorylation of STAT1 at 'Ser-708'.
CC Phosphorylation of STAT1 at 'Ser-708' seems also to promote the
CC assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared
CC to GAF (STAT1:STAT1) complexes, in this way regulating the balance
CC between type I and type II IFN responses. Protects cells against DNA
CC damage-induced cell death. Also plays an important role in energy
CC balance regulation by sustaining a state of chronic, low-grade
CC inflammation in obesity, wich leads to a negative impact on insulin
CC sensitivity. Phosphorylates AKT1. {ECO:0000269|PubMed:17568778,
CC ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:19153231,
CC ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:21138416,
CC ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:22532683,
CC ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23478265}.
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 -!- SUBUNIT: Homodimer. Interacts with MAVS/IPS1 (PubMed:16177806,
CC PubMed:28011935, PubMed:27980081). Interacts (via protein kinase
CC domain) with TTLL12 (via N-terminus); the interaction prevents MAVS
CC binding to IKBKE (PubMed:28011935). Interacts with the adapter proteins
CC AZI2/NAP1, TANK and TBKBP1/SINTBAD (PubMed:17568778). Interacts with
CC SIKE1 (PubMed:16281057, PubMed:14560022). Interacts with TICAM1/TRIF,
CC IRF3 and DDX58/RIG-I; interactions are disrupted by the interaction
CC between IKBKE and SIKE1 (PubMed:14739303, PubMed:16281057,
CC PubMed:23478265). Interacts with TOPORS; induced by DNA damage
CC (PubMed:20188669). Interacts with CYLD (PubMed:18636086). Interacts
CC (when polyubiquitinated) with IKBKB, IKBKG and MYD88 (PubMed:23453969).
CC Interacts with IFIH1 (PubMed:17600090). Interacts with DDX3X; the
CC interaction may be induced upon virus infection (PubMed:18636090,
CC PubMed:20657822, PubMed:23478265, PubMed:27980081). Interacts with
CC TRIM6 (via SPRY box) (PubMed:24882218). Interacts with unanchored K48-
CC linked polyubiquitin chains; this leads to IKBKE activation
CC (PubMed:24882218). Interacts with TBK1 (PubMed:29251827). Interacts
CC with FKBP5 (PubMed:26101251, PubMed:31434731).
CC {ECO:0000269|PubMed:14560022, ECO:0000269|PubMed:14739303,
CC ECO:0000269|PubMed:16177806, ECO:0000269|PubMed:16281057,
CC ECO:0000269|PubMed:17568778, ECO:0000269|PubMed:17600090,
CC ECO:0000269|PubMed:18636086, ECO:0000269|PubMed:18636090,
CC ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:20657822,
CC ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23478265,
CC ECO:0000269|PubMed:24882218, ECO:0000269|PubMed:26101251,
CC ECO:0000269|PubMed:27980081, ECO:0000269|PubMed:28011935,
CC ECO:0000269|PubMed:29251827, ECO:0000269|PubMed:31434731}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via Protein kinase domain)
CC with arenavirus protein N; the interaction inhibits IKBKE kinase
CC function. {ECO:0000269|PubMed:22532683}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Ebola virus protein VP35;
CC the interaction leads to inhibition of cellular antiviral response by
CC blocking necessary interactions between the IKBKE and MAVS/IPS as well
CC as its substrates IRF3 and IRF7. {ECO:0000269|PubMed:19153231}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Severe fever with
CC thrombocytopenia virus (SFTSV) NSs; this interaction this interaction
CC sequesters IKBKE in NSs-induced cytoplasmic inclusion bodies thereby
CC inhibiting the IFN responses. {ECO:0000269|PubMed:24706939}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human T-cell leukemia
CC virus 1/HTLV-1 protein HBZ. {ECO:0000269|PubMed:28768861}.
CC -!- INTERACTION:
CC Q14164; Q92624: APPBP2; NbExp=4; IntAct=EBI-307369, EBI-743771;
CC Q14164; Q16543: CDC37; NbExp=3; IntAct=EBI-307369, EBI-295634;
CC Q14164; O00571: DDX3X; NbExp=4; IntAct=EBI-307369, EBI-353779;
CC Q14164; P08238: HSP90AB1; NbExp=2; IntAct=EBI-307369, EBI-352572;
CC Q14164; Q9BYX4: IFIH1; NbExp=2; IntAct=EBI-307369, EBI-6115771;
CC Q14164; Q14653: IRF3; NbExp=2; IntAct=EBI-307369, EBI-2650369;
CC Q14164; Q7Z434: MAVS; NbExp=4; IntAct=EBI-307369, EBI-995373;
CC Q14164; Q92844: TANK; NbExp=4; IntAct=EBI-307369, EBI-356349;
CC Q14164; Q9UHD2: TBK1; NbExp=5; IntAct=EBI-307369, EBI-356402;
CC Q14164; A7MCY6: TBKBP1; NbExp=4; IntAct=EBI-307369, EBI-359969;
CC Q14164; P09936: UCHL1; NbExp=3; IntAct=EBI-307369, EBI-714860;
CC Q14164; Q05127: VP35; Xeno; NbExp=3; IntAct=EBI-307369, EBI-6148294;
CC Q14164; K7Y1A2; Xeno; NbExp=2; IntAct=EBI-307369, EBI-8788634;
CC Q14164; PRO_0000037572 [P27958]; Xeno; NbExp=2; IntAct=EBI-307369, EBI-6919131;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24882218}. Nucleus.
CC Nucleus, PML body {ECO:0000269|PubMed:20188669}. Note=Targeting to PML
CC nuclear bodies upon DNA damage is TOPORS-dependent (PubMed:20188669).
CC Located diffusely throughout the cytoplasm but locates to punctate
CC cytoplasmic bodies when coexpressed with TRIM6 (PubMed:24882218).
CC {ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:24882218}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q14164-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q14164-2; Sequence=VSP_044305;
CC -!- TISSUE SPECIFICITY: Highly expressed in spleen followed by thymus,
CC peripheral blood leukocytes, pancreas, placenta. Weakly expressed in
CC lung, kidney, prostate, ovary and colon.
CC -!- INDUCTION: Induced by lipopolysaccharide (LPS) and TNFA.
CC {ECO:0000269|PubMed:23453969}.
CC -!- PTM: Autophosphorylated and phosphorylated by IKBKB/IKKB.
CC Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X.
CC Phosphorylated at Thr-501 upon IFN activation.
CC {ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:23478265}.
CC -!- PTM: Sumoylation by TOPORS upon DNA damage is required for protection
CC of cells against DNA damage-induced cell death. Desumoylated by SENP1.
CC {ECO:0000269|PubMed:20188669}.
CC -!- PTM: 'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by
CC TRAF2:BIRC2 and TRAF2:BIRC3 complexes. Ubiquitination is induced by
CC LPS, TNFA and interleukin-1 and required for full kinase activity and
CC KF-kappa-B pathway activation. {ECO:0000269|PubMed:23453969}.
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 -!- SEQUENCE CAUTION:
CC Sequence=BAA09772.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ikbke/";
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DR EMBL; D63485; BAA09772.2; ALT_INIT; mRNA.
DR EMBL; AB016590; BAA85155.1; -; mRNA.
DR EMBL; AF241789; AAF45307.1; -; mRNA.
DR EMBL; DQ667176; ABG25921.1; -; Genomic_DNA.
DR EMBL; AL354681; CAI15250.1; -; Genomic_DNA.
DR EMBL; CH471100; EAW93549.1; -; Genomic_DNA.
DR EMBL; BC105923; AAI05924.1; -; mRNA.
DR EMBL; BC105924; AAI05925.1; -; mRNA.
DR EMBL; BC107812; AAI07813.1; -; mRNA.
DR CCDS; CCDS30996.1; -. [Q14164-1]
DR CCDS; CCDS53464.1; -. [Q14164-2]
DR RefSeq; NP_001180250.1; NM_001193321.1. [Q14164-2]
DR RefSeq; NP_001180251.1; NM_001193322.1.
DR RefSeq; NP_054721.1; NM_014002.3. [Q14164-1]
DR RefSeq; XP_005273413.1; XM_005273356.2. [Q14164-1]
DR AlphaFoldDB; Q14164; -.
DR SMR; Q14164; -.
DR BioGRID; 115000; 93.
DR ComplexPortal; CPX-6038; TBK1-IKKepsilon-NAP1 complex.
DR ComplexPortal; CPX-6089; TBK1-IKKepsilon-TANK complex.
DR ComplexPortal; CPX-6090; TBK1-IKKepsilon-SINTBAD complex.
DR CORUM; Q14164; -.
DR DIP; DIP-27530N; -.
DR IntAct; Q14164; 51.
DR MINT; Q14164; -.
DR STRING; 9606.ENSP00000464030; -.
DR BindingDB; Q14164; -.
DR ChEMBL; CHEMBL3529; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q14164; -.
DR GuidetoPHARMACOLOGY; 2040; -.
DR iPTMnet; Q14164; -.
DR PhosphoSitePlus; Q14164; -.
DR BioMuta; IKBKE; -.
DR DMDM; 14548079; -.
DR EPD; Q14164; -.
DR jPOST; Q14164; -.
DR MassIVE; Q14164; -.
DR MaxQB; Q14164; -.
DR PaxDb; Q14164; -.
DR PeptideAtlas; Q14164; -.
DR PRIDE; Q14164; -.
DR ProteomicsDB; 59892; -. [Q14164-1]
DR ProteomicsDB; 61647; -.
DR Antibodypedia; 73513; 623 antibodies from 45 providers.
DR DNASU; 9641; -.
DR Ensembl; ENST00000581977.7; ENSP00000464030.1; ENSG00000263528.8. [Q14164-1]
DR Ensembl; ENST00000584998.5; ENSP00000462396.1; ENSG00000263528.8. [Q14164-2]
DR GeneID; 9641; -.
DR KEGG; hsa:9641; -.
DR MANE-Select; ENST00000581977.7; ENSP00000464030.1; NM_014002.4; NP_054721.1.
DR UCSC; uc001hdz.3; human. [Q14164-1]
DR CTD; 9641; -.
DR DisGeNET; 9641; -.
DR GeneCards; IKBKE; -.
DR HGNC; HGNC:14552; IKBKE.
DR HPA; ENSG00000263528; Tissue enhanced (lymphoid).
DR MIM; 605048; gene.
DR neXtProt; NX_Q14164; -.
DR OpenTargets; ENSG00000263528; -.
DR PharmGKB; PA134962294; -.
DR VEuPathDB; HostDB:ENSG00000263528; -.
DR eggNOG; KOG4250; Eukaryota.
DR GeneTree; ENSGT00950000182937; -.
DR InParanoid; Q14164; -.
DR OMA; ELQCNNG; -.
DR OrthoDB; 563981at2759; -.
DR PhylomeDB; Q14164; -.
DR TreeFam; TF324269; -.
DR BRENDA; 2.7.11.10; 2681.
DR PathwayCommons; Q14164; -.
DR Reactome; R-HSA-4755510; SUMOylation of immune response proteins.
DR Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR Reactome; R-HSA-918233; TRAF3-dependent IRF activation pathway.
DR Reactome; R-HSA-933541; TRAF6 mediated IRF7 activation.
DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR Reactome; R-HSA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR SABIO-RK; Q14164; -.
DR SignaLink; Q14164; -.
DR SIGNOR; Q14164; -.
DR BioGRID-ORCS; 9641; 17 hits in 1109 CRISPR screens.
DR ChiTaRS; IKBKE; human.
DR GeneWiki; IKBKE; -.
DR GenomeRNAi; 9641; -.
DR Pharos; Q14164; Tchem.
DR PRO; PR:Q14164; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q14164; protein.
DR Bgee; ENSG00000263528; Expressed in colonic epithelium and 122 other tissues.
DR ExpressionAtlas; Q14164; baseline and differential.
DR Genevisible; Q14164; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031966; C:mitochondrial membrane; IMP:AgBase.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR GO; GO:1902554; C:serine/threonine protein kinase complex; IC:ComplexPortal.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0008384; F:IkappaB kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0036435; F:K48-linked polyubiquitin modification-dependent protein binding; IMP:UniProtKB.
DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; IDA:UniProtKB.
DR GO; GO:0019903; F:protein phosphatase binding; ISS:ARUK-UCL.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; IEA:Ensembl.
DR GO; GO:0051607; P:defense response to virus; IC:ComplexPortal.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; NAS:UniProtKB.
DR GO; GO:0097400; P:interleukin-17-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:UniProtKB.
DR GO; GO:0048255; P:mRNA stabilization; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEP:UniProtKB.
DR GO; GO:0010884; P:positive regulation of lipid storage; ISS:BHF-UCL.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IEA:Ensembl.
DR GO; GO:0035456; P:response to interferon-beta; IMP:UniProtKB.
DR GO; GO:0060337; P:type I interferon signaling pathway; IC:ComplexPortal.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR041309; TBK1_CCD1.
DR InterPro; IPR041087; TBK1_ULD.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF18394; TBK1_CCD1; 1.
DR Pfam; PF18396; TBK1_ULD; 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.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cytoplasm; DNA damage;
KW Host-virus interaction; Isopeptide bond; Kinase; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..716
FT /note="Inhibitor of nuclear factor kappa-B kinase subunit
FT epsilon"
FT /id="PRO_0000086017"
FT DOMAIN 9..315
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 383..647
FT /note="Interaction with DDX3X"
FT REGION 436..457
FT /note="Leucine-zipper"
FT ACT_SITE 135
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 15..23
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 38
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT MOD_RES 172
FT /note="Phosphoserine; by autocatalysis and IKKB"
FT /evidence="ECO:0000269|PubMed:23478265"
FT MOD_RES 501
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:24882218"
FT MOD_RES 664
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT CROSSLNK 30
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23453969"
FT CROSSLNK 231
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:20188669"
FT CROSSLNK 401
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23453969"
FT VAR_SEQ 1..85
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044305"
FT VARIANT 128
FT /note="E -> K (in dbSNP:rs41296028)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_038816"
FT VARIANT 371
FT /note="A -> T (in dbSNP:rs17021877)"
FT /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.4"
FT /id="VAR_038817"
FT VARIANT 483
FT /note="T -> M (in dbSNP:rs52817862)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040571"
FT VARIANT 515
FT /note="E -> D (in dbSNP:rs41299015)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_038818"
FT VARIANT 543
FT /note="I -> M (in dbSNP:rs41299037)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_038819"
FT VARIANT 602
FT /note="A -> V (in dbSNP:rs12059562)"
FT /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.4"
FT /id="VAR_038820"
FT VARIANT 660
FT /note="G -> E (in dbSNP:rs55822317)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040572"
FT VARIANT 713
FT /note="P -> L (in dbSNP:rs3748022)"
FT /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.4"
FT /id="VAR_019989"
FT MUTAGEN 30
FT /note="K->A: Loss of ubiquitination and decreased kinase
FT activity. No effect on homodimerization."
FT /evidence="ECO:0000269|PubMed:23453969"
FT MUTAGEN 30
FT /note="K->R: Loss of ubiquitination and decreased kinase
FT activity. Decreases interaction with IKBKB, IKBKG and
FT MYD88. No effect on homodimerization."
FT /evidence="ECO:0000269|PubMed:23453969"
FT MUTAGEN 38
FT /note="K->A: Loss of kinase activity and loss of nuclear
FT import."
FT /evidence="ECO:0000269|PubMed:10421793"
FT MUTAGEN 168
FT /note="E->A: Slight decrease of kinase activity."
FT /evidence="ECO:0000269|PubMed:10421793"
FT MUTAGEN 172
FT /note="S->A: Loss of autophosphorylation and of kinase
FT activity."
FT /evidence="ECO:0000269|PubMed:10421793"
FT MUTAGEN 172
FT /note="S->E: Decrease in kinase activity."
FT /evidence="ECO:0000269|PubMed:10421793"
FT MUTAGEN 231
FT /note="K->R: Loss of sumoylation and loss of targeting to
FT nuclear bodies."
FT /evidence="ECO:0000269|PubMed:20188669"
FT MUTAGEN 401
FT /note="K->A: Loss of ubiquitination and decreased kinase
FT activity. No effect on homodimerization."
FT /evidence="ECO:0000269|PubMed:23453969"
FT MUTAGEN 401
FT /note="K->R: Loss of ubiquitination and decreased kinase
FT activity. Decreases interaction with IKBKB, IKBKG and
FT MYD88. No effect on homodimerization."
FT /evidence="ECO:0000269|PubMed:23453969"
FT MUTAGEN 416
FT /note="K->A: No effect on ubiquitination."
FT /evidence="ECO:0000269|PubMed:23453969"
FT MUTAGEN 416
FT /note="K->R: No effect on ubiquitination."
FT /evidence="ECO:0000269|PubMed:23453969"
FT CONFLICT 187
FT /note="R -> Q (in Ref. 7; AAI05925)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 716 AA; 80462 MW; 3E5FBE5840734D81 CRC64;
MQSTANYLWH TDDLLGQGAT ASVYKARNKK SGELVAVKVF NTTSYLRPRE VQVREFEVLR
KLNHQNIVKL FAVEETGGSR QKVLVMEYCS SGSLLSVLES PENAFGLPED EFLVVLRCVV
AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLTDFGA ARELDDDEKF VSVYGTEEYL
HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE
KPAGAIAGAQ RRENGPLEWS YTLPITCQLS LGLQSQLVPI LANILEVEQA KCWGFDQFFA
ETSDILQRVV VHVFSLSQAV LHHIYIHAHN TIAIFQEAVH KQTSVAPRHQ EYLFEGHLCV
LEPSVSAQHI AHTTASSPLT LFSTAIPKGL AFRDPALDVP KFVPKVDLQA DYNTAKGVLG
AGYQALRLAR ALLDGQELMF RGLHWVMEVL QATCRRTLEV ARTSLLYLSS SLGTERFSSV
AGTPEIQELK AAAELRSRLR TLAEVLSRCS QNITETQESL SSLNRELVKS RDQVHEDRSI
QQIQCCLDKM NFIYKQFKKS RMRPGLGYNE EQIHKLDKVN FSHLAKRLLQ VFQEECVQKY
QASLVTHGKR MRVVHETRNH LRLVGCSVAA CNTEAQGVQE SLSKLLEELS HQLLQDRAKG
AQASPPPIAP YPSPTRKDLL LHMQELCEGM KLLASDLLDN NRIIERLNRV PAPPDV