ID HNF4A_HUMAN Reviewed; 474 AA. AC P41235; A5JW41; B2RPP8; O00659; O00723; Q14540; Q5QPB8; Q6B4V5; Q6B4V6; AC Q6B4V7; Q92653; Q92654; Q92655; Q99864; Q9NQH0; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 29-MAY-2007, sequence version 3. DT 27-MAR-2024, entry version 250. DE RecName: Full=Hepatocyte nuclear factor 4-alpha; DE Short=HNF-4-alpha; DE AltName: Full=Nuclear receptor subfamily 2 group A member 1; DE AltName: Full=Transcription factor 14; DE Short=TCF-14; DE AltName: Full=Transcription factor HNF-4; GN Name=HNF4A; Synonyms=HNF4, NR2A1, TCF14; 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] (ISOFORMS HNF4-ALPHA-1; HNF4-ALPHA-2 AND RP HNF4-ALPHA-3), AND VARIANT SER-445. RC TISSUE=Liver; RX PubMed=8964514; DOI=10.1016/0378-1119(96)00183-7; RA Kritis A.A., Argyrokastritis A., Moschonas N.K., Power S., Katrakili N., RA Zannis V.I., Cereghini S., Talianidis I.; RT "Isolation and characterization of a third isoform of human hepatocyte RT nuclear factor 4."; RL Gene 173:275-280(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING. RC TISSUE=Kidney; RX PubMed=8622695; DOI=10.1128/mcb.16.3.925; RA Drewes T., Senkel S., Holewa B., Ryffel G.U.; RT "Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and RT differentially expressed genes."; RL Mol. Cell. Biol. 16:925-931(1996). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8945471; DOI=10.1038/384458a0; RA Yamagata K., Furuta H., Oda N., Kaisaki P.J., Menzel S., Cox N.J., RA Fajans S.S., Signorini S., Stoffel M., Bell G.I.; RT "Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset RT diabetes of the young (MODY1)."; RL Nature 384:458-460(1996). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE PROMOTER USAGE (ISOFORMS RP HNF4-ALPHA-7; HNF4-ALPHA-8 AND HNF4-ALPHA-9). RA Tanaka T., Jiang S., Hotta H., Takano K., Iwanari H., Hirayama Y., RA Midorikawa Y., Hippo Y., Watanabe A., Yamashita H., Kumakura J., RA Uchiyama Y., Hasegawa G., Aburatani H., Hamakubo T., Naito M., Sakai J., RA Kodama T.; RT "Variation in P1 and P2 promoter-driven hepatocyte nuclear factor-4a RT (HNF4a) expression in human tissues: implications for carcinogenesis."; RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-139 AND ILE-453. RG SeattleSNPs variation discovery resource; RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM HNF4-ALPHA-3). 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-474, AND ALTERNATIVE SPLICING. RC TISSUE=Liver; RX PubMed=7926813; DOI=10.1016/0378-1119(94)90079-5; RA Chartier F.L., Bossu J.-P., Laudet V., Fruchart J.-C., Laine B.; RT "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear RT factor 4 indicate the presence of two isoforms in human liver."; RL Gene 147:269-272(1994). RN [10] RP PHOSPHORYLATION. RX PubMed=7568236; DOI=10.1073/pnas.92.21.9876; RA Ktistaki E., Ktistakis N.T., Papadogeorgaki E., Talianidis I.; RT "Recruitment of hepatocyte nuclear factor 4 into specific intranuclear RT compartments depends on tyrosine phosphorylation that affects its DNA- RT binding and transactivation potential."; RL Proc. Natl. Acad. Sci. U.S.A. 92:9876-9880(1995). RN [11] RP PHOSPHORYLATION AT SER-313, AND MUTAGENESIS OF SER-313. RX PubMed=12740371; DOI=10.1074/jbc.m304112200; RA Hong Y.H., Varanasi U.S., Yang W., Leff T.; RT "AMP-activated protein kinase regulates HNF4alpha transcriptional activity RT by inhibiting dimer formation and decreasing protein stability."; RL J. Biol. Chem. 278:27495-27501(2003). RN [12] RP PHOSPHORYLATION AT SER-142; THR-166; SER-167; THR-432 AND SER-436, RP UBIQUITINATION AT LYS-234 AND LYS-307, AND ACETYLATION AT LYS-458. RX PubMed=21708125; DOI=10.1016/j.bbrc.2011.06.033; RA Yokoyama A., Katsura S., Ito R., Hashiba W., Sekine H., Fujiki R., Kato S.; RT "Multiple post-translational modifications in hepatocyte nuclear factor RT 4alpha."; RL Biochem. Biophys. Res. Commun. 410:749-753(2011). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-144; THR-429; THR-432 AND RP SER-436, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [14] RP INTERACTION WITH DDX3X AND NR0B2. RX PubMed=28128295; DOI=10.1038/srep41452; RA Tsai T.Y., Wang W.T., Li H.K., Chen W.J., Tsai Y.H., Chao C.H., RA Wu Lee Y.H.; RT "RNA helicase DDX3 maintains lipid homeostasis through upregulation of the RT microsomal triglyceride transfer protein by interacting with HNF4 and RT SHP."; RL Sci. Rep. 7:41452-41452(2017). RN [15] RP 9AATAD MOTIF. RX PubMed=30468856; DOI=10.1016/j.jsbmb.2018.11.008; RA Piskacek M., Havelka M., Jendruchova K., Knight A.; RT "Nuclear hormone receptors: Ancient 9aaTAD and evolutionally gained NCoA RT activation pathways."; RL J. Steroid Biochem. Mol. Biol. 187:118-123(2019). RN [16] RP FUNCTION. RX PubMed=30597922; DOI=10.3390/genes10010021; RA DeLaForest A., Di Furio F., Jing R., Ludwig-Kubinski A., Twaroski K., RA Urick A., Pulakanti K., Rao S., Duncan S.A.; RT "HNF4A regulates the formation of hepatic progenitor cells from human iPSC- RT Derived endoderm by facilitating efficient recruitment of RNA Pol II."; RL Genes (Basel) 10:0-0(2018). RN [17] RP FUNCTION, AND INTERACTION WITH CLOCK; BMAL1; CRY1; CRY2; PER1 AND PER2. RX PubMed=30530698; DOI=10.1073/pnas.1816411115; RA Qu M., Duffy T., Hirota T., Kay S.A.; RT "Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue- RT specific circadian networks."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E12305-E12312(2018). RN [18] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 142-378, FATTY ACID BINDING, AND RP SUBUNIT. RX PubMed=14982928; DOI=10.1074/jbc.m400864200; RA Duda K., Chi Y.-I., Shoelson S.E.; RT "Structural basis for HNF-4alpha activation by ligand and coactivator RT binding."; RL J. Biol. Chem. 279:23311-23316(2004). RN [19] RP VARIANT MODY1 TRP-136. RX PubMed=9313765; DOI=10.2337/diacare.46.10.1652; RA Furuta H., Iwasaki N., Oda N., Hinokio Y., Horikawa Y., Yamagata K., RA Yano N., Sugahiro J., Ogata M., Ohgawara H., Omori Y., Iwamoto Y., RA Bell G.I.; RT "Organization and partial sequence of the hepatocyte nuclear factor-4- RT alpha/MODY1 gene and identification of a missense mutation, R127W, in a RT Japanese family with MODY."; RL Diabetes 46:1652-1657(1997). RN [20] RP VARIANT MODY1 GLN-285. RX PubMed=9243109; DOI=10.1007/s001250050760; RA Bulman M.P., Dronsfield M.J., Frayling T.M., Appleton M., Bain S.C., RA Ellard S., Hattersley A.T.; RT "A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK RT pedigree with maturity-onset diabetes of the young."; RL Diabetologia 40:859-862(1997). RN [21] RP VARIANTS ILE-139 AND MET-264. RX PubMed=9267996; DOI=10.1007/s001250050778; RA Moeller A.M., Urhammer S.A., Dalgaard L.T., Reneland R., Berglund L., RA Hansen T., Clausen J.O., Lithell H., Pedersen O.; RT "Studies of the genetic variability of the coding region of the hepatocyte RT nuclear factor-4alpha in Caucasians with maturity onset NIDDM."; RL Diabetologia 40:980-983(1997). RN [22] RP VARIANT T2D ILE-402. RX PubMed=9449683; DOI=10.1172/jci1403; RA Hani E.H., Suaud L., Boutin P., Chevre J.-C., Durand E., Philippi A., RA Demenais F., Vionnet N., Furuta H., Velho G., Bell G.I., Laine B., RA Froguel P.; RT "A missense mutation in hepatocyte nuclear factor-4-alpha, resulting in a RT reduced transactivation activity, in human late-onset non-insulin-dependent RT diabetes mellitus."; RL J. Clin. Invest. 101:521-526(1998). RN [23] RP CHARACTERIZATION OF VARIANT MET-264, AND CHARACTERIZATION OF VARIANT MODY1 RP GLN-285. RX PubMed=10389854; DOI=10.2337/diabetes.48.7.1459; RA Navas M.A., Munoz-Elias E.J., Kim J., Shih D., Stoffel M.; RT "Functional characterization of the MODY1 gene mutations HNF4(R127W), RT HNF4(V255M), and HNF4(E276Q)."; RL Diabetes 48:1459-1465(1999). RN [24] RP VARIANT MODY1 ARG-373. RX PubMed=17407387; DOI=10.1371/journal.pmed.0040118; RA Pearson E.R., Boj S.F., Steele A.M., Barrett T., Stals K., Shield J.P., RA Ellard S., Ferrer J., Hattersley A.T.; RT "Macrosomia and hyperinsulinaemic hypoglycaemia in patients with RT heterozygous mutations in the HNF4A gene."; RL PLoS Med. 4:E118-E118(2007). RN [25] RP INVOLVEMENT IN FRTS4, AND VARIANT FRTS4 TRP-85. RX PubMed=22802087; DOI=10.1210/jc.2012-1356; RA Stanescu D.E., Hughes N., Kaplan B., Stanley C.A., De Leon D.D.; RT "Novel presentations of congenital hyperinsulinism due to mutations in the RT MODY genes: HNF1A and HNF4A."; RL J. Clin. Endocrinol. Metab. 97:E2026-2030(2012). RN [26] RP VARIANT FRTS4 TRP-85. RX PubMed=24285859; DOI=10.1136/jmedgenet-2013-102066; RA Hamilton A.J., Bingham C., McDonald T.J., Cook P.R., Caswell R.C., RA Weedon M.N., Oram R.A., Shields B.M., Shepherd M., Inward C.D., RA Hamilton-Shield J.P., Kohlhase J., Ellard S., Hattersley A.T.; RT "The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in RT addition to a beta cell phenotype."; RL J. Med. Genet. 51:165-169(2014). CC -!- FUNCTION: Transcriptional regulator which controls the expression of CC hepatic genes during the transition of endodermal cells to hepatic CC progenitor cells, facilitating the recruitment of RNA pol II to the CC promoters of target genes (PubMed:30597922). Activates the CC transcription of CYP2C38 (By similarity). Represses the CLOCK-BMAL1 CC transcriptional activity and is essential for circadian rhythm CC maintenance and period regulation in the liver and colon cells CC (PubMed:30530698). {ECO:0000250|UniProtKB:P49698, CC ECO:0000269|PubMed:30530698, ECO:0000269|PubMed:30597922}. CC -!- SUBUNIT: Homodimerization is required for HNF4-alpha to bind to its CC recognition site (PubMed:14982928). Interacts with CLOCK, BMAL1, CRY1, CC CRY2, PER1 and PER2 (PubMed:30530698). Interacts with NR0B2/SHP; the CC resulting heterodimer is transcriptionally inactive (PubMed:28128295). CC Interacts with DDX3X; this interaction disrupts the interaction between CC HNF4 and NR0B2 that forms inactive heterodimers and enhances the CC formation of active HNF4 homodimers (PubMed:28128295). CC {ECO:0000269|PubMed:14982928, ECO:0000269|PubMed:28128295, CC ECO:0000269|PubMed:30530698}. CC -!- INTERACTION: CC P41235; Q99967: CITED2; NbExp=3; IntAct=EBI-1049011, EBI-937732; CC P41235; A8MYZ6: FOXO6; NbExp=2; IntAct=EBI-1049011, EBI-8531039; CC P41235; P04150: NR3C1; NbExp=2; IntAct=EBI-1049011, EBI-493507; CC P41235; Q9UBK2: PPARGC1A; NbExp=4; IntAct=EBI-1049011, EBI-765486; CC P41235; Q92786: PROX1; NbExp=3; IntAct=EBI-1049011, EBI-3912635; CC P41235; P23246: SFPQ; NbExp=2; IntAct=EBI-1049011, EBI-355453; CC P41235; Q12772: SREBF2; NbExp=2; IntAct=EBI-1049011, EBI-465059; CC P41235-3; P11532: DMD; NbExp=3; IntAct=EBI-12690684, EBI-295827; CC P41235-3; O14602: EIF1AY; NbExp=3; IntAct=EBI-12690684, EBI-286439; CC P41235-3; O43688: PLPP2; NbExp=3; IntAct=EBI-12690684, EBI-722017; CC -!- SUBCELLULAR LOCATION: Nucleus. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=7; CC Comment=Additional isoforms seem to exist.; CC Name=HNF4-Alpha-1; Synonyms=HNF-4B; CC IsoId=P41235-1; Sequence=Displayed; CC Name=HNF4-Alpha-2; Synonyms=HNF4-A; CC IsoId=P41235-2; Sequence=VSP_003674; CC Name=HNF4-Alpha-3; Synonyms=HNF4-C; CC IsoId=P41235-3; Sequence=VSP_003675; CC Name=HNF4-Alpha-4; CC IsoId=P41235-4; Sequence=VSP_003673; CC Name=HNF4-Alpha-7; CC IsoId=P41235-5; Sequence=VSP_026030; CC Name=HNF4-Alpha-8; CC IsoId=P41235-6; Sequence=VSP_026030, VSP_003674; CC Name=HNF4-Alpha-9; CC IsoId=P41235-7; Sequence=VSP_026030, VSP_003675; CC -!- DOMAIN: The 9aaTAD motif is a transactivation domain present in a large CC number of yeast and animal transcription factors. CC {ECO:0000305|PubMed:30468856}. CC -!- PTM: Phosphorylated on tyrosine residue(s); phosphorylation is CC important for its DNA-binding activity. Phosphorylation may directly or CC indirectly play a regulatory role in the subnuclear distribution. CC Phosphorylation at Ser-313 by AMPK reduces the ability to form CC homodimers and bind DNA. {ECO:0000269|PubMed:12740371, CC ECO:0000269|PubMed:21708125, ECO:0000269|PubMed:7568236}. CC -!- PTM: Acetylation at Lys-458 lowers transcriptional activation by about CC two-fold. {ECO:0000269|PubMed:21708125}. CC -!- DISEASE: Maturity-onset diabetes of the young 1 (MODY1) [MIM:125850]: A CC form of diabetes that is characterized by an autosomal dominant mode of CC inheritance, onset in childhood or early adulthood (usually before 25 CC years of age), a primary defect in insulin secretion and frequent CC insulin-independence at the beginning of the disease. CC {ECO:0000269|PubMed:10389854, ECO:0000269|PubMed:17407387, CC ECO:0000269|PubMed:9243109, ECO:0000269|PubMed:9313765}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Type 2 diabetes mellitus (T2D) [MIM:125853]: A multifactorial CC disorder of glucose homeostasis caused by a lack of sensitivity to the CC body's own insulin. Affected individuals usually have an obese body CC habitus and manifestations of a metabolic syndrome characterized by CC diabetes, insulin resistance, hypertension and hypertriglyceridemia. CC The disease results in long-term complications that affect the eyes, CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:9449683}. CC Note=Disease susceptibility may be associated with variants affecting CC the gene represented in this entry. CC -!- DISEASE: Fanconi renotubular syndrome 4 with maturity-onset diabetes of CC the young (FRTS4) [MIM:616026]: An autosomal dominant disease CC characterized by Fanconi syndrome associated with a beta cell phenotype CC of neonatal hyperinsulinism with macrosomia and young onset diabetes. CC Fanconi syndrome is a proximal tubulopathy resulting in generalized CC aminoaciduria, low molecular weight proteinuria, glycosuria, CC hyperphosphaturia and hypouricemia. Some FRTS4 patients have CC nephrocalcinosis, renal impairment, hypercalciuria with relative CC hypocalcemia, and hypermagnesemia. {ECO:0000269|PubMed:22802087, CC ECO:0000269|PubMed:24285859}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Binds fatty acids. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-1]: Produced by alternative promoter CC usage. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-2]: Produced by alternative splicing CC of isoform HNF4-Alpha-1. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-3]: Produced by alternative splicing CC of isoform HNF4-Alpha-1. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-4]: Produced by alternative splicing CC of isoform HNF4-Alpha-1. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-7]: Produced by alternative promoter CC usage. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-8]: Produced by alternative splicing CC of isoform HNF4-Alpha-7. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform HNF4-Alpha-9]: Produced by alternative splicing CC of isoform HNF4-Alpha-7. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR2 CC subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB48082.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC Sequence=CAA54248.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAA61133.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=CAA61134.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=CAA61135.1; Type=Frameshift; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hepatocyte nuclear factors entry; CC URL="https://en.wikipedia.org/wiki/Hepatocyte_nuclear_factors"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/hnf4a/"; 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; X87870; CAA61133.1; ALT_FRAME; mRNA. DR EMBL; X87871; CAA61134.1; ALT_FRAME; mRNA. DR EMBL; X87872; CAA61135.1; ALT_FRAME; mRNA. DR EMBL; Z49825; CAA89989.1; -; mRNA. DR EMBL; AY680696; AAT91237.1; -; mRNA. DR EMBL; AY680697; AAT91238.1; -; mRNA. DR EMBL; AY680698; AAT91239.1; -; mRNA. DR EMBL; U72969; AAB48082.1; ALT_SEQ; Genomic_DNA. DR EMBL; U72959; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72961; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72962; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72963; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72964; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72965; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72966; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72967; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72968; AAB48082.1; JOINED; Genomic_DNA. DR EMBL; U72967; AAB48083.1; -; Genomic_DNA. DR EMBL; U72959; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; U72961; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; U72962; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; U72963; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; U72964; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; U72965; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; U72966; AAB48083.1; JOINED; Genomic_DNA. DR EMBL; EF591040; ABQ52204.1; -; Genomic_DNA. DR EMBL; AL132772; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471077; EAW75924.1; -; Genomic_DNA. DR EMBL; CH471077; EAW75925.1; -; Genomic_DNA. DR EMBL; BC137539; AAI37540.1; -; mRNA. DR EMBL; BC137540; AAI37541.1; -; mRNA. DR EMBL; X76930; CAA54248.1; ALT_INIT; mRNA. DR CCDS; CCDS13330.1; -. [P41235-1] DR CCDS; CCDS13331.1; -. [P41235-3] DR CCDS; CCDS42876.1; -. [P41235-5] DR CCDS; CCDS46604.1; -. [P41235-6] DR CCDS; CCDS46605.1; -. [P41235-2] DR CCDS; CCDS68131.1; -. [P41235-7] DR PIR; JC4937; JC4937. DR PIR; JC4938; JC4938. DR PIR; JC6096; JC6096. DR RefSeq; NP_000448.3; NM_000457.4. [P41235-1] DR RefSeq; NP_001025174.1; NM_001030003.2. [P41235-6] DR RefSeq; NP_001025175.1; NM_001030004.2. [P41235-7] DR RefSeq; NP_001245284.1; NM_001258355.1. DR RefSeq; NP_001274111.1; NM_001287182.1. DR RefSeq; NP_001274112.1; NM_001287183.1. DR RefSeq; NP_001274113.1; NM_001287184.1. DR RefSeq; NP_787110.2; NM_175914.4. [P41235-5] DR RefSeq; NP_849181.1; NM_178850.2. [P41235-3] DR PDB; 1PZL; X-ray; 2.10 A; A=142-378. DR PDB; 3CBB; X-ray; 2.00 A; A/B=58-135. DR PDB; 3FS1; X-ray; 2.20 A; A=148-377. DR PDB; 4B7W; X-ray; 4.00 A; A/B/C/D=142-377. DR PDB; 4IQR; X-ray; 2.90 A; A/B/E/F=55-377. DR PDB; 6CHT; X-ray; 3.17 A; A/B/D/E/G/H/J/K/M/N/P/Q/S/T/V/W=148-391. DR PDBsum; 1PZL; -. DR PDBsum; 3CBB; -. DR PDBsum; 3FS1; -. DR PDBsum; 4B7W; -. DR PDBsum; 4IQR; -. DR PDBsum; 6CHT; -. DR AlphaFoldDB; P41235; -. DR SMR; P41235; -. DR BioGRID; 109414; 271. DR CORUM; P41235; -. DR DIP; DIP-499N; -. DR IntAct; P41235; 214. DR MINT; P41235; -. DR STRING; 9606.ENSP00000312987; -. DR BindingDB; P41235; -. DR ChEMBL; CHEMBL5398; -. DR DrugBank; DB05447; AVI-4557. DR DrugBank; DB03017; Lauric acid. DR DrugBank; DB08231; Myristic acid. DR GlyGen; P41235; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P41235; -. DR PhosphoSitePlus; P41235; -. DR BioMuta; HNF4A; -. DR DMDM; 148886624; -. DR jPOST; P41235; -. DR MassIVE; P41235; -. DR MaxQB; P41235; -. DR PaxDb; 9606-ENSP00000312987; -. DR PeptideAtlas; P41235; -. DR ProteomicsDB; 55441; -. [P41235-1] DR ProteomicsDB; 55442; -. [P41235-2] DR ProteomicsDB; 55443; -. [P41235-3] DR ProteomicsDB; 55444; -. [P41235-4] DR ProteomicsDB; 55445; -. [P41235-5] DR ProteomicsDB; 55446; -. [P41235-6] DR ProteomicsDB; 55447; -. [P41235-7] DR ABCD; P41235; 1 sequenced antibody. DR Antibodypedia; 1326; 1156 antibodies from 43 providers. DR DNASU; 3172; -. DR Ensembl; ENST00000316099.10; ENSP00000312987.3; ENSG00000101076.20. [P41235-1] DR Ensembl; ENST00000316673.9; ENSP00000315180.4; ENSG00000101076.20. [P41235-5] DR Ensembl; ENST00000415691.2; ENSP00000412111.1; ENSG00000101076.20. [P41235-2] DR Ensembl; ENST00000443598.6; ENSP00000410911.2; ENSG00000101076.20. [P41235-3] DR Ensembl; ENST00000457232.5; ENSP00000396216.1; ENSG00000101076.20. [P41235-6] DR Ensembl; ENST00000609795.5; ENSP00000476609.1; ENSG00000101076.20. [P41235-7] DR GeneID; 3172; -. DR KEGG; hsa:3172; -. DR MANE-Select; ENST00000316673.9; ENSP00000315180.4; NM_175914.5; NP_787110.2. [P41235-5] DR UCSC; uc002xlt.4; human. [P41235-1] DR AGR; HGNC:5024; -. DR CTD; 3172; -. DR DisGeNET; 3172; -. DR GeneCards; HNF4A; -. DR GeneReviews; HNF4A; -. DR HGNC; HGNC:5024; HNF4A. DR HPA; ENSG00000101076; Group enriched (intestine, kidney, liver). DR MalaCards; HNF4A; -. DR MIM; 125850; phenotype. DR MIM; 125853; phenotype. DR MIM; 600281; gene. DR MIM; 606391; phenotype. DR MIM; 616026; phenotype. DR neXtProt; NX_P41235; -. DR OpenTargets; ENSG00000101076; -. DR Orphanet; 544628; Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome. DR Orphanet; 263455; Congenital hyperinsulinism due to HNF4A deficiency. DR Orphanet; 552; MODY. DR PharmGKB; PA29349; -. DR VEuPathDB; HostDB:ENSG00000101076; -. DR eggNOG; KOG4215; Eukaryota. DR GeneTree; ENSGT00940000157965; -. DR HOGENOM; CLU_007368_5_2_1; -. DR InParanoid; P41235; -. DR OMA; IVFFDPY; -. DR OrthoDB; 5400963at2759; -. DR PhylomeDB; P41235; -. DR TreeFam; TF352097; -. DR PathwayCommons; P41235; -. DR Reactome; R-HSA-210745; Regulation of gene expression in beta cells. DR Reactome; R-HSA-383280; Nuclear Receptor transcription pathway. DR SignaLink; P41235; -. DR SIGNOR; P41235; -. DR BioGRID-ORCS; 3172; 49 hits in 1184 CRISPR screens. DR ChiTaRS; HNF4A; human. DR EvolutionaryTrace; P41235; -. DR GeneWiki; Hepatocyte_nuclear_factor_4_alpha; -. DR GenomeRNAi; 3172; -. DR Pharos; P41235; Tchem. DR PRO; PR:P41235; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; P41235; Protein. DR Bgee; ENSG00000101076; Expressed in right lobe of liver and 93 other cell types or tissues. DR ExpressionAtlas; P41235; baseline and differential. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL. DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl. DR GO; GO:0003677; F:DNA binding; IDA:BHF-UCL. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:BHF-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:BHF-UCL. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO:0005504; F:fatty acid binding; IDA:BHF-UCL. DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central. DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:BHF-UCL. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0005102; F:signaling receptor binding; IDA:BHF-UCL. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:BHF-UCL. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0048856; P:anatomical structure development; IBA:GO_Central. DR GO; GO:0007596; P:blood coagulation; IDA:BHF-UCL. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0042632; P:cholesterol homeostasis; ISS:BHF-UCL. DR GO; GO:0042593; P:glucose homeostasis; ISS:BHF-UCL. DR GO; GO:0055088; P:lipid homeostasis; IMP:BHF-UCL. DR GO; GO:0006629; P:lipid metabolic process; IEA:Ensembl. DR GO; GO:0030308; P:negative regulation of cell growth; IMP:BHF-UCL. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:BHF-UCL. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0006591; P:ornithine metabolic process; IMP:BHF-UCL. DR GO; GO:0055091; P:phospholipid homeostasis; ISS:BHF-UCL. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:0010470; P:regulation of gastrulation; IEA:Ensembl. DR GO; GO:0060398; P:regulation of growth hormone receptor signaling pathway; NAS:BHF-UCL. DR GO; GO:0050796; P:regulation of insulin secretion; ISS:BHF-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; IDA:BHF-UCL. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0009749; P:response to glucose; ISS:BHF-UCL. DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW. DR GO; GO:0007548; P:sex differentiation; IEA:Ensembl. DR GO; GO:0023019; P:signal transduction involved in regulation of gene expression; IEA:Ensembl. DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0070328; P:triglyceride homeostasis; ISS:BHF-UCL. DR GO; GO:0006805; P:xenobiotic metabolic process; IMP:BHF-UCL. DR CDD; cd06960; NR_DBD_HNF4A; 1. DR CDD; cd06931; NR_LBD_HNF4_like; 1. DR Gene3D; 3.30.50.10; Erythroid Transcription Factor GATA-1, subunit A; 1. DR Gene3D; 1.10.565.10; Retinoid X Receptor; 1. DR IDEAL; IID00045; -. DR InterPro; IPR049636; HNF4-like_DBD. DR InterPro; IPR049635; HNF4_LBD. DR InterPro; IPR035500; NHR-like_dom_sf. DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd. DR InterPro; IPR001723; Nuclear_hrmn_rcpt. DR InterPro; IPR001628; Znf_hrmn_rcpt. DR InterPro; IPR013088; Znf_NHR/GATA. DR PANTHER; PTHR24083:SF41; HEPATOCYTE NUCLEAR FACTOR 4-ALPHA; 1. DR PANTHER; PTHR24083; NUCLEAR HORMONE RECEPTOR; 1. DR Pfam; PF00104; Hormone_recep; 1. DR Pfam; PF00105; zf-C4; 1. DR PRINTS; PR01282; COUPTNFACTOR. DR PRINTS; PR00398; STRDHORMONER. DR PRINTS; PR00047; STROIDFINGER. DR SMART; SM00430; HOLI; 1. DR SMART; SM00399; ZnF_C4; 1. DR SUPFAM; SSF57716; Glucocorticoid receptor-like (DNA-binding domain); 1. DR SUPFAM; SSF48508; Nuclear receptor ligand-binding domain; 1. DR PROSITE; PS51843; NR_LBD; 1. DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1. DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1. DR Genevisible; P41235; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activator; Alternative promoter usage; KW Alternative splicing; Biological rhythms; Diabetes mellitus; KW Disease variant; DNA-binding; Isopeptide bond; Metal-binding; Nucleus; KW Phosphoprotein; Receptor; Reference proteome; Repressor; Transcription; KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger. FT CHAIN 1..474 FT /note="Hepatocyte nuclear factor 4-alpha" FT /id="PRO_0000053558" FT DOMAIN 147..377 FT /note="NR LBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189" FT DNA_BIND 57..132 FT /note="Nuclear receptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT ZN_FING 60..80 FT /note="NR C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT ZN_FING 96..120 FT /note="NR C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT REGION 419..447 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 368..376 FT /note="9aaTAD" FT /evidence="ECO:0000269|PubMed:30468856" FT MOD_RES 142 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:21708125" FT MOD_RES 143 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P22449" FT MOD_RES 144 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 166 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:21708125" FT MOD_RES 167 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:21708125" FT MOD_RES 313 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:12740371" FT MOD_RES 429 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 432 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:21708125, FT ECO:0007744|PubMed:24275569" FT MOD_RES 436 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:21708125, FT ECO:0007744|PubMed:24275569" FT MOD_RES 458 FT /note="N6-acetyllysine" FT /evidence="ECO:0000269|PubMed:21708125" FT CROSSLNK 234 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:21708125" FT CROSSLNK 307 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:21708125" FT VAR_SEQ 1..38 FT /note="MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGN -> MVSVNAPLGA FT PVESSY (in isoform HNF4-Alpha-7, isoform HNF4-Alpha-8 and FT isoform HNF4-Alpha-9)" FT /evidence="ECO:0000305" FT /id="VSP_026030" FT VAR_SEQ 38 FT /note="N -> NDLLPLRLARLRHPLRHHWSISGGVDSSPQG (in isoform FT HNF4-Alpha-4)" FT /evidence="ECO:0000305" FT /id="VSP_003673" FT VAR_SEQ 378..474 FT /note="SPSDAPHAHHPLHPHLMQEHMGTNVIVANTMPTHLSNGQMCEWPRPRGQAAT FT PETPQPSPPGGSGSEPYKLLPGAVATIVKPLSAIPQPTITKQEVI -> PCQAQEGRGW FT SGDSPGDRPHTVSSPLSSLASPLCRFGQVA (in isoform HNF4-Alpha-3 and FT isoform HNF4-Alpha-9)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:8964514" FT /id="VSP_003675" FT VAR_SEQ 418..428 FT /note="CEWPRPRGQAA -> S (in isoform HNF4-Alpha-2 and FT isoform HNF4-Alpha-8)" FT /evidence="ECO:0000303|PubMed:8964514" FT /id="VSP_003674" FT VARIANT 85 FT /note="R -> W (in FRTS4; dbSNP:rs587777732)" FT /evidence="ECO:0000269|PubMed:22802087, FT ECO:0000269|PubMed:24285859" FT /id="VAR_071951" FT VARIANT 136 FT /note="R -> W (in MODY1; dbSNP:rs137853336)" FT /evidence="ECO:0000269|PubMed:9313765" FT /id="VAR_004668" FT VARIANT 139 FT /note="T -> I (in dbSNP:rs1800961)" FT /evidence="ECO:0000269|PubMed:9267996, ECO:0000269|Ref.5" FT /id="VAR_004669" FT VARIANT 264 FT /note="V -> M (found in a patient with FT non-insulin-dependent diabetes mellitus; does not affect FT activity; dbSNP:rs139779712)" FT /evidence="ECO:0000269|PubMed:10389854, FT ECO:0000269|PubMed:9267996" FT /id="VAR_010600" FT VARIANT 285 FT /note="E -> Q (in MODY1; results in loss of function)" FT /evidence="ECO:0000269|PubMed:10389854, FT ECO:0000269|PubMed:9243109" FT /id="VAR_010601" FT VARIANT 373 FT /note="M -> R (in MODY1; dbSNP:rs137853338)" FT /evidence="ECO:0000269|PubMed:17407387" FT /id="VAR_071952" FT VARIANT 402 FT /note="V -> I (in T2D; reduced transactivation activity; FT dbSNP:rs137853337)" FT /evidence="ECO:0000269|PubMed:9449683" FT /id="VAR_004670" FT VARIANT 445 FT /note="P -> S (in dbSNP:rs1063239)" FT /evidence="ECO:0000269|PubMed:8964514" FT /id="VAR_011785" FT VARIANT 453 FT /note="V -> I (in dbSNP:rs776824742)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_062267" FT MUTAGEN 313 FT /note="S->A: Abolishes AMPK-mediated phosphorylation." FT /evidence="ECO:0000269|PubMed:12740371" FT MUTAGEN 313 FT /note="S->D: Phosphomimetic mutant that leads to reduced FT ability to bind DNA." FT /evidence="ECO:0000269|PubMed:12740371" FT CONFLICT 440 FT /note="G -> A (in Ref. 9; CAA54248)" FT /evidence="ECO:0000305" FT TURN 61..63 FT /evidence="ECO:0007829|PDB:3CBB" FT STRAND 64..66 FT /evidence="ECO:0007829|PDB:3CBB" FT STRAND 69..71 FT /evidence="ECO:0007829|PDB:3CBB" FT HELIX 78..89 FT /evidence="ECO:0007829|PDB:3CBB" FT STRAND 97..100 FT /evidence="ECO:0007829|PDB:4IQR" FT TURN 106..111 FT /evidence="ECO:0007829|PDB:3CBB" FT HELIX 113..123 FT /evidence="ECO:0007829|PDB:3CBB" FT HELIX 127..129 FT /evidence="ECO:0007829|PDB:3CBB" FT HELIX 149..153 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 155..163 FT /evidence="ECO:0007829|PDB:1PZL" FT TURN 176..178 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 184..202 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 206..209 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 213..222 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 224..236 FT /evidence="ECO:0007829|PDB:1PZL" FT STRAND 239..244 FT /evidence="ECO:0007829|PDB:1PZL" FT STRAND 250..254 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 256..261 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 262..271 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 273..279 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 283..294 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 305..324 FT /evidence="ECO:0007829|PDB:1PZL" FT STRAND 325..328 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 333..338 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 340..360 FT /evidence="ECO:0007829|PDB:1PZL" FT HELIX 368..374 FT /evidence="ECO:0007829|PDB:1PZL" SQ SEQUENCE 474 AA; 52785 MW; 5F1309B89D95DCAF CRC64; MRLSKTLVDM DMADYSAALD PAYTTLEFEN VQVLTMGNDT SPSEGTNLNA PNSLGVSALC AICGDRATGK HYGASSCDGC KGFFRRSVRK NHMYSCRFSR QCVVDKDKRN QCRYCRLKKC FRAGMKKEAV QNERDRISTR RSSYEDSSLP SINALLQAEV LSRQITSPVS GINGDIRAKK IASIADVCES MKEQLLVLVE WAKYIPAFCE LPLDDQVALL RAHAGEHLLL GATKRSMVFK DVLLLGNDYI VPRHCPELAE MSRVSIRILD ELVLPFQELQ IDDNEYAYLK AIIFFDPDAK GLSDPGKIKR LRSQVQVSLE DYINDRQYDS RGRFGELLLL LPTLQSITWQ MIEQIQFIKL FGMAKIDNLL QEMLLGGSPS DAPHAHHPLH PHLMQEHMGT NVIVANTMPT HLSNGQMCEW PRPRGQAATP ETPQPSPPGG SGSEPYKLLP GAVATIVKPL SAIPQPTITK QEVI //