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 27-MAR-2024, entry version 220. 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 RIGI. 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 INTERACTION WITH EPSTEIN-BARR VIRUS PROTEIN NEC2/BFRF1 (MICROBIAL RP INFECTION). RX PubMed=33391252; DOI=10.3389/fimmu.2020.513383; RA Wang P., Deng Y., Guo Y., Xu Z., Li Y., Ou X., Xie L., Lu M., Zhong J., RA Li B., Hu L., Deng S., Peng T., Cai M., Li M.; RT "Epstein-Barr Virus Early Protein BFRF1 Suppresses IFN-beta Activity by RT Inhibiting the Activation of IRF3."; RL Front. Immunol. 11:513383-513383(2020). RN [35] 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 RIGI; interactions are disrupted by the interaction between CC IKBKE and SIKE1 (PubMed:14739303, PubMed:16281057, PubMed:23478265). CC Interacts with TOPORS; induced by DNA damage (PubMed:20188669). CC Interacts with CYLD (PubMed:18636086). Interacts (when CC 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 -!- SUBUNIT: (Microbial infection) Interacts with Epstein-Barr virus (EBV) CC protein NEC2/BFRF1; this interaction inhibits IKBKE kinase activity and CC IRF3 nuclear translocation. {ECO:0000269|PubMed:33391252}. 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; P62258: YWHAE; NbExp=2; IntAct=EBI-307369, EBI-356498; 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/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 103. 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; 53. 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 CPTAC; CPTAC-2829; -. DR CPTAC; CPTAC-2885; -. DR EPD; Q14164; -. DR jPOST; Q14164; -. DR MassIVE; Q14164; -. DR MaxQB; Q14164; -. DR PaxDb; 9606-ENSP00000464030; -. DR PeptideAtlas; Q14164; -. DR ProteomicsDB; 59892; -. [Q14164-1] DR ProteomicsDB; 61647; -. DR Antibodypedia; 73513; 714 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 AGR; HGNC:14552; -. 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; AEQAKCW; -. DR OrthoDB; 2957757at2759; -. 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-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. 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, IKBKE. DR Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses. 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; 22 hits in 1196 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 123 other cell types or tissues. DR ExpressionAtlas; Q14164; baseline and differential. 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; NAS: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:0019903; F:protein phosphatase binding; ISS:ARUK-UCL. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. 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; NAS: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:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:GO_Central. DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IMP:BHF-UCL. DR GO; GO:0010884; P:positive regulation of lipid storage; ISS:BHF-UCL. DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProt. DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IDA:UniProt. 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-mediated signaling pathway; NAS:ComplexPortal. DR CDD; cd17128; Ubl_IKKE; 1. DR Gene3D; 1.20.1270.420; -; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR22969; IKB KINASE; 1. DR PANTHER; PTHR22969:SF10; INHIBITOR OF NUCLEAR FACTOR KAPPA-B KINASE SUBUNIT EPSILON; 1. 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; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; Q14164; HS. 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 //