RORA_HUMAN
ID RORA_HUMAN Reviewed; 523 AA.
AC P35398; P35397; P35399; P45445; Q495X4; Q96H83;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 2.
DT 03-AUG-2022, entry version 216.
DE RecName: Full=Nuclear receptor ROR-alpha;
DE AltName: Full=Nuclear receptor RZR-alpha;
DE AltName: Full=Nuclear receptor subfamily 1 group F member 1;
DE AltName: Full=RAR-related orphan receptor A;
DE AltName: Full=Retinoid-related orphan receptor-alpha;
GN Name=RORA; Synonyms=NR1F1, RZRA;
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 1; 2 AND 3), FUNCTION AS TRANSCRIPTION
RP ACTIVATOR, DNA-BINDING, AND SUBUNIT.
RC TISSUE=Retina, and Testis;
RX PubMed=7926749; DOI=10.1101/gad.8.5.538;
RA Giguere V., Tini M., Flock G., Ong E., Evans R.M., Otulakowski G.;
RT "Isoform-specific amino-terminal domains dictate DNA-binding properties of
RT ROR alpha, a novel family of orphan hormone nuclear receptors.";
RL Genes Dev. 8:538-553(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND TISSUE SPECIFICITY.
RC TISSUE=Umbilical vein endothelial cell;
RX PubMed=7916608; DOI=10.1006/bbrc.1993.1976;
RA Becker-Andre M., Andre E., Delamarter J.F.;
RT "Identification of nuclear receptor mRNAs by RT-PCR amplification of
RT conserved zinc-finger motif sequences.";
RL Biochem. Biophys. Res. Commun. 194:1371-1379(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RC TISSUE=Kidney;
RA Kaighin V.A., Martin A.L., Aronstam R.S.;
RT "Isolation of cDNA coding for multiple human nuclear receptor clones.";
RL Submitted (DEC-2010) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC TISSUE=Muscle;
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 [7]
RP FUNCTION AS TRANSCRIPTION ACTIVATOR, INTERACTION WITH NCOR1, DNA-BINDING,
RP AND SUBUNIT.
RX PubMed=9328355; DOI=10.1210/mend.11.11.0002;
RA Harding H.P., Atkins G.B., Jaffe A.B., Seo W.J., Lazar M.A.;
RT "Transcriptional activation and repression by RORalpha, an orphan nuclear
RT receptor required for cerebellar development.";
RL Mol. Endocrinol. 11:1737-1746(1997).
RN [8]
RP FUNCTION AS TRANSCRIPTION ACTIVATOR, INTERACTION WITH MED1 AND NCOA2, AND
RP MUTAGENESIS OF VAL-335 AND 510-LEU-PHE-511.
RX PubMed=10478845; DOI=10.1210/mend.13.9.0343;
RA Atkins G.B., Hu X., Guenther M.G., Rachez C., Freedman L.P., Lazar M.A.;
RT "Coactivators for the orphan nuclear receptor RORalpha.";
RL Mol. Endocrinol. 13:1550-1557(1999).
RN [9]
RP FUNCTION IN MYOGENESIS, AND INTERACTION WITH EP300.
RX PubMed=9862959; DOI=10.1093/nar/27.2.411;
RA Lau P., Bailey P., Dowhan D.H., Muscat G.E.;
RT "Exogenous expression of a dominant negative RORalpha1 vector in muscle
RT cells impairs differentiation: RORalpha1 directly interacts with p300 and
RT myoD.";
RL Nucleic Acids Res. 27:411-420(1999).
RN [10]
RP FUNCTION AS TRANSCRIPTION ACTIVATOR, AND DNA-BINDING.
RX PubMed=11554739; DOI=10.1006/bbrc.2001.5602;
RA Sundvold H., Lien S.;
RT "Identification of a novel peroxisome proliferator-activated receptor
RT (PPAR) gamma promoter in man and transactivation by the nuclear receptor
RT RORalpha1.";
RL Biochem. Biophys. Res. Commun. 287:383-390(2001).
RN [11]
RP FUNCTION IN INFLAMMATION.
RX PubMed=11252722; DOI=10.1093/embo-reports/kve007;
RA Delerive P., Monte D., Dubois G., Trottein F., Fruchart-Najib J.,
RA Mariani J., Fruchart J.C., Staels B.;
RT "The orphan nuclear receptor ROR alpha is a negative regulator of the
RT inflammatory response.";
RL EMBO Rep. 2:42-48(2001).
RN [12]
RP FUNCTION IN TRIGLYCERIDE METABOLISM, AND DNA-BINDING.
RX PubMed=11053433; DOI=10.1074/jbc.m004982200;
RA Raspe E., Duez H., Gervois P., Fievet C., Fruchart J.C., Besnard S.,
RA Mariani J., Tedgui A., Staels B.;
RT "Transcriptional regulation of apolipoprotein C-III gene expression by the
RT orphan nuclear receptor RORalpha.";
RL J. Biol. Chem. 276:2865-2871(2001).
RN [13]
RP FUNCTION AS TRANSCRIPTION ACTIVATOR, UBIQUITINATION, AND MUTAGENESIS OF
RP LYS-357; LEU-361; VAL-364 AND GLU-509.
RX PubMed=14570920; DOI=10.1074/jbc.m308152200;
RA Moraitis A.N., Giguere V.;
RT "The co-repressor hairless protects RORalpha orphan nuclear receptor from
RT proteasome-mediated degradation.";
RL J. Biol. Chem. 278:52511-52518(2003).
RN [14]
RP INDUCTION BY HYPOXIA (ISOFORM 4).
RX PubMed=14742449; DOI=10.1074/jbc.m313186200;
RA Miki N., Ikuta M., Matsui T.;
RT "Hypoxia-induced activation of the retinoic acid receptor-related orphan
RT receptor alpha4 gene by an interaction between hypoxia-inducible factor-1
RT and Sp1.";
RL J. Biol. Chem. 279:15025-15031(2004).
RN [15]
RP FUNCTION IN TRIGLYCERIDE METABOLISM, AND DNA-BINDING.
RX PubMed=15790933; DOI=10.1161/01.atv.0000163841.85333.83;
RA Genoux A., Dehondt H., Helleboid-Chapman A., Duhem C., Hum D.W., Martin G.,
RA Pennacchio L.A., Staels B., Fruchart-Najib J., Fruchart J.C.;
RT "Transcriptional regulation of apolipoprotein A5 gene expression by the
RT nuclear receptor RORalpha.";
RL Arterioscler. Thromb. Vasc. Biol. 25:1186-1192(2005).
RN [16]
RP FUNCTION IN TRIGLYCERIDE METABOLISM, AND DNA-BINDING.
RX PubMed=15781255; DOI=10.1016/j.bbrc.2005.02.151;
RA Lind U., Nilsson T., McPheat J., Stroemstedt P.E., Bamberg K.,
RA Balendran C., Kang D.;
RT "Identification of the human ApoAV gene as a novel RORalpha target gene.";
RL Biochem. Biophys. Res. Commun. 330:233-241(2005).
RN [17]
RP FUNCTION IN CELL GROWTH, AND INDUCTION BY CELLULAR STRESS.
RX PubMed=16462772; DOI=10.1038/sj.onc.1209314;
RA Zhu Y., McAvoy S., Kuhn R., Smith D.I.;
RT "RORA, a large common fragile site gene, is involved in cellular stress
RT response.";
RL Oncogene 25:2901-2908(2006).
RN [18]
RP PHOSPHORYLATION AT THR-183, FUNCTION, AND MUTAGENESIS OF THR-183.
RX PubMed=17512500; DOI=10.1016/j.bbrc.2007.05.016;
RA Lechtken A., Hoernig M., Werz O., Corvey N., Zoendorf I., Dingermann T.,
RA Brandes R., Steinhilber D.;
RT "Extracellular signal-regulated kinase-2 phosphorylates RORalpha4 in
RT vitro.";
RL Biochem. Biophys. Res. Commun. 358:890-896(2007).
RN [19]
RP FUNCTION IN HYPOXIA SIGNALING, INTERACTION WITH HIF1A, INDUCTION BY
RP HYPOXIA, AND SUBCELLULAR LOCATION.
RX PubMed=18658046; DOI=10.1161/atvbaha.108.171546;
RA Kim E.J., Yoo Y.G., Yang W.K., Lim Y.S., Na T.Y., Lee I.K., Lee M.O.;
RT "Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia
RT signaling.";
RL Arterioscler. Thromb. Vasc. Biol. 28:1796-1802(2008).
RN [20]
RP FUNCTION, INTERACTION WITH FOXP3, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP AND MUTAGENESIS OF 510-LEU-PHE-511.
RX PubMed=18354202; DOI=10.4049/jimmunol.180.7.4785;
RA Du J., Huang C., Zhou B., Ziegler S.F.;
RT "Isoform-specific inhibition of ROR alpha-mediated transcriptional
RT activation by human FOXP3.";
RL J. Immunol. 180:4785-4792(2008).
RN [21]
RP FUNCTION AS TRANSCRIPTION ACTIVATOR, PHOSPHORYLATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=18005000; DOI=10.1111/j.1471-4159.2007.05074.x;
RA Duplus E., Gras C., Soubeyre V., Vodjdani G., Lemaigre-Dubreuil Y.,
RA Brugg B.;
RT "Phosphorylation and transcriptional activity regulation of retinoid-
RT related orphan receptor alpha 1 by protein kinases C.";
RL J. Neurochem. 104:1321-1332(2008).
RN [22]
RP SUMOYLATION AT LYS-240, AND MUTAGENESIS OF LYS-240 AND LYS-441.
RX PubMed=19041634; DOI=10.1016/j.bbrc.2008.11.072;
RA Hwang E.J., Lee J.M., Jeong J., Park J.H., Yang Y., Lim J.S., Kim J.H.,
RA Baek S.H., Kim K.I.;
RT "SUMOylation of RORalpha potentiates transcriptional activation function.";
RL Biochem. Biophys. Res. Commun. 378:513-517(2009).
RN [23]
RP REVIEW ON FUNCTION.
RX PubMed=19381306; DOI=10.1621/nrs.07003;
RA Jetten A.M.;
RT "Retinoid-related orphan receptors (RORs): critical roles in development,
RT immunity, circadian rhythm, and cellular metabolism.";
RL Nucl. Recept. Signal. 7:3-35(2009).
RN [24]
RP FUNCTION IN GLUCOSE METABOLISM REGULATION, AND IDENTIFICATION OF LIGANDS.
RX PubMed=19965867; DOI=10.1074/jbc.m109.080614;
RA Wang Y., Kumar N., Solt L.A., Richardson T.I., Helvering L.M., Crumbley C.,
RA Garcia-Ordonez R.D., Stayrook K.R., Zhang X., Novick S., Chalmers M.J.,
RA Griffin P.R., Burris T.P.;
RT "Modulation of retinoic acid receptor-related orphan receptor alpha and
RT gamma activity by 7-oxygenated sterol ligands.";
RL J. Biol. Chem. 285:5013-5025(2010).
RN [25]
RP INTERACTION WITH NRIP1.
RX PubMed=21628546; DOI=10.1177/0748730411401579;
RA Poliandri A.H., Gamsby J.J., Christian M., Spinella M.J., Loros J.J.,
RA Dunlap J.C., Parker M.G.;
RT "Modulation of clock gene expression by the transcriptional coregulator
RT receptor interacting protein 140 (RIP140).";
RL J. Biol. Rhythms 26:187-199(2011).
RN [26]
RP FUNCTION IN T(H)17 CELLS DIFFERENTIATION, AND IDENTIFICATION OF LIGANDS.
RX PubMed=21499262; DOI=10.1038/nature10075;
RA Solt L.A., Kumar N., Nuhant P., Wang Y., Lauer J.L., Liu J., Istrate M.A.,
RA Kamenecka T.M., Roush W.R., Vidovic D., Schuerer S.C., Xu J., Wagoner G.,
RA Drew P.D., Griffin P.R., Burris T.P.;
RT "Suppression of TH17 differentiation and autoimmunity by a synthetic ROR
RT ligand.";
RL Nature 472:491-494(2011).
RN [27]
RP INTERACTION WITH CRY1.
RX PubMed=22170608; DOI=10.1038/nature10700;
RA Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., Jonker J.W.,
RA Downes M., Evans R.M.;
RT "Cryptochromes mediate rhythmic repression of the glucocorticoid
RT receptor.";
RL Nature 480:552-556(2011).
RN [28]
RP METHYLATION AT LYS-38.
RX PubMed=23063525; DOI=10.1016/j.molcel.2012.09.004;
RA Lee J.M., Lee J.S., Kim H., Kim K., Park H., Kim J.Y., Lee S.H., Kim I.S.,
RA Kim J., Lee M., Chung C.H., Seo S.B., Yoon J.B., Ko E., Noh D.Y., Kim K.I.,
RA Kim K.K., Baek S.H.;
RT "EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4
RT E3 ubiquitin ligase complex.";
RL Mol. Cell 48:572-586(2012).
RN [29]
RP REVIEW ON FUNCTION AND LIGANDS.
RX PubMed=22789990; DOI=10.1016/j.tem.2012.05.012;
RA Solt L.A., Burris T.P.;
RT "Action of RORs and their ligands in (patho)physiology.";
RL Trends Endocrinol. Metab. 23:619-627(2012).
RN [30]
RP INVOLVEMENT IN IDDECA, VARIANTS IDDECA SER-90; ALA-92; ARG-94; ARG-409;
RP GLN-462 AND 500-ARG--GLY-523 DEL, CHARACTERIZATION OF VARIANTS IDDECA
RP ALA-92; ARG-94 AND GLN-462, FUNCTION, TISSUE SPECIFICITY, VARIANT ALA-476,
RP AND CHARACTERIZATION OF VARIANT ALA-476.
RX PubMed=29656859; DOI=10.1016/j.ajhg.2018.02.021;
RA Guissart C., Latypova X., Rollier P., Khan T.N., Stamberger H.,
RA McWalter K., Cho M.T., Kjaergaard S., Weckhuysen S., Lesca G., Besnard T.,
RA Ounap K., Schema L., Chiocchetti A.G., McDonald M., de Bellescize J.,
RA Vincent M., Van Esch H., Sattler S., Forghani I., Thiffault I.,
RA Freitag C.M., Barbouth D.S., Cadieux-Dion M., Willaert R.,
RA Guillen Sacoto M.J., Safina N.P., Dubourg C., Grote L., Carre W.,
RA Saunders C., Pajusalu S., Farrow E., Boland A., Karlowicz D.H.,
RA Deleuze J.F., Wojcik M.H., Pressman R., Isidor B., Vogels A.,
RA Van Paesschen W., Al-Gazali L., Al Shamsi A.M., Claustres M., Pujol A.,
RA Sanders S.J., Rivier F., Leboucq N., Cogne B., Sasorith S., Sanlaville D.,
RA Retterer K., Odent S., Katsanis N., Bezieau S., Koenig M., Davis E.E.,
RA Pasquier L., Kuery S.;
RT "Dual molecular effects of dominant RORA mutations cause two variants of
RT syndromic intellectual disability with either autism or cerebellar
RT ataxia.";
RL Am. J. Hum. Genet. 102:744-759(2018).
RN [31]
RP VARIANT [LARGE SCALE ANALYSIS] SER-18 (ISOFORM 2).
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS) OF 271-523 IN COMPLEX WITH
RP CHOLESTEROL, FUNCTION AS TRANSCRIPTION ACTIVATOR, IDENTIFICATION OF
RP LIGANDS, MUTAGENESIS OF CYS-323; ALA-330; ALA-371; PHE-399; HIS-484 AND
RP TYR-507, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=12467577; DOI=10.1016/s0969-2126(02)00912-7;
RA Kallen J.A., Schlaeppi J.-M., Bitsch F., Geisse S., Geiser M., Delhon I.,
RA Fournier B.;
RT "X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional
RT data that cholesterol or a cholesterol derivative is the natural ligand of
RT RORalpha.";
RL Structure 10:1697-1707(2002).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 271-523 IN COMPLEX WITH
RP CHOLESTEROL SULFATE, MUTAGENESIS OF CYS-288; CYS-323; ALA-330; LYS-339 AND
RP GLU-509, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=14722075; DOI=10.1074/jbc.m400302200;
RA Kallen J., Schlaeppi J.-M., Bitsch F., Delhon I., Fournier B.;
RT "Crystal structure of the human RORalpha Ligand binding domain in complex
RT with cholesterol sulfate at 2.2 A.";
RL J. Biol. Chem. 279:14033-14038(2004).
CC -!- FUNCTION: Nuclear receptor that binds DNA as a monomer to ROR response
CC elements (RORE) containing a single core motif half-site 5'-AGGTCA-3'
CC preceded by a short A-T-rich sequence. Key regulator of embryonic
CC development, cellular differentiation, immunity, circadian rhythm as
CC well as lipid, steroid, xenobiotics and glucose metabolism. Considered
CC to have intrinsic transcriptional activity, have some natural ligands
CC like oxysterols that act as agonists (25-hydroxycholesterol) or inverse
CC agonists (7-oxygenated sterols), enhancing or repressing the
CC transcriptional activity, respectively. Recruits distinct combinations
CC of cofactors to target genes regulatory regions to modulate their
CC transcriptional expression, depending on the tissue, time and promoter
CC contexts. Regulates genes involved in photoreceptor development
CC including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with
CC MYOD1. Required for proper cerebellum development (PubMed:29656859).
CC Regulates SHH gene expression, among others, to induce granule cells
CC proliferation as well as expression of genes involved in calcium-
CC mediated signal transduction. Regulates the circadian expression of
CC several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1.
CC Competes with NR1D1 for binding to their shared DNA response element on
CC some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting
CC in NR1D1-mediated repression or RORA-mediated activation of clock genes
CC expression, leading to the circadian pattern of clock genes expression.
CC Therefore influences the period length and stability of the clock.
CC Regulates genes involved in lipid metabolism such as apolipoproteins
CC APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant
CC functions with RORC as positive or negative modulator of expression of
CC genes encoding phase I and phase II proteins involved in the metabolism
CC of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1.
CC Induces a rhythmic expression of some of these genes. In addition,
CC interplays functionally with NR1H2 and NR1H3 for the regulation of
CC genes involved in cholesterol metabolism. Also involved in the
CC regulation of hepatic glucose metabolism through the modulation of
CC G6PC1 and PCK1. In adipose tissue, plays a role as negative regulator
CC of adipocyte differentiation, probably acting through dual mechanisms.
CC May suppress CEBPB-dependent adipogenesis through direct interaction
CC and PPARG-dependent adipogenesis through competition for DNA-binding.
CC Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is
CC implicated in the lineage specification of uncommitted CD4(+) T-helper
CC (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program.
CC Probably regulates IL17 and IL17F expression on T(H) by binding to the
CC essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-
CC IL17F locus. Involved in hypoxia signaling by interacting with and
CC activating the transcriptional activity of HIF1A. May inhibit cell
CC growth in response to cellular stress. May exert an anti-inflammatory
CC role by inducing CHUK expression and inhibiting NF-kappa-B signaling.
CC {ECO:0000269|PubMed:10478845, ECO:0000269|PubMed:11053433,
CC ECO:0000269|PubMed:11252722, ECO:0000269|PubMed:11554739,
CC ECO:0000269|PubMed:12467577, ECO:0000269|PubMed:14570920,
CC ECO:0000269|PubMed:15781255, ECO:0000269|PubMed:15790933,
CC ECO:0000269|PubMed:16462772, ECO:0000269|PubMed:17512500,
CC ECO:0000269|PubMed:18005000, ECO:0000269|PubMed:18354202,
CC ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19965867,
CC ECO:0000269|PubMed:21499262, ECO:0000269|PubMed:29656859,
CC ECO:0000269|PubMed:7926749, ECO:0000269|PubMed:9328355,
CC ECO:0000269|PubMed:9862959}.
CC -!- SUBUNIT: Monomer. Interacts (via the DNA-binding domain) with HIF1A;
CC the interaction enhances HIF1A transcription under hypoxia through
CC increasing protein stability. Interacts with CEBPB; the interaction
CC disrupts the interaction CEBPB:EP300. Interacts with the coactivators
CC NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the
CC corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with
CC CRY1 and PER2. Interacts (via AF-2 motif) with PROX1 (By similarity).
CC Interacts with NRIP1. Isoform 4 interacts (via AF-2 motif) with isoform
CC 1 of FOXP3 (via LXXLL motif). {ECO:0000250|UniProtKB:P51448,
CC ECO:0000269|PubMed:10478845, ECO:0000269|PubMed:12467577,
CC ECO:0000269|PubMed:14722075, ECO:0000269|PubMed:18354202,
CC ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:21628546,
CC ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:7926749,
CC ECO:0000269|PubMed:9328355, ECO:0000269|PubMed:9862959}.
CC -!- INTERACTION:
CC P35398; P14136: GFAP; NbExp=3; IntAct=EBI-748689, EBI-744302;
CC P35398; P51843: NR0B1; NbExp=2; IntAct=EBI-748689, EBI-946109;
CC P35398-4; Q9BZS1: FOXP3; NbExp=5; IntAct=EBI-11295807, EBI-983719;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407,
CC ECO:0000269|PubMed:18005000, ECO:0000269|PubMed:18354202,
CC ECO:0000269|PubMed:18658046}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Alpha-1;
CC IsoId=P35398-2; Sequence=Displayed;
CC Name=2; Synonyms=Alpha-2;
CC IsoId=P35398-1; Sequence=VSP_053973;
CC Name=3; Synonyms=Alpha-3;
CC IsoId=P35398-3; Sequence=VSP_053975;
CC Name=4; Synonyms=Alpha-4;
CC IsoId=P35398-4; Sequence=VSP_053974;
CC -!- TISSUE SPECIFICITY: Widely expressed in a number of tissues. Expressed
CC in both regulatory T-cells (Treg) and effector T-cells (Teff)
CC (PubMed:18354202, PubMed:7916608). Isoform 4: Highly expressed in the
CC central nervous system, including in the cerebellum (PubMed:29656859).
CC {ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:29656859,
CC ECO:0000269|PubMed:7916608}.
CC -!- INDUCTION: Induced by oxidative stress and DNA damage. Isoform 4 is
CC induced by hypoxia (through transactivation by HIF1A and SP1), but not
CC isoform 1. {ECO:0000269|PubMed:16462772, ECO:0000269|PubMed:18658046}.
CC -!- DOMAIN: The AF-2 (activation function-2) motif is required for
CC recruiting coregulators containing LXXLL motifs. {ECO:0000250}.
CC -!- PTM: Phosphorylation by conventional PKCs in neurons inhibits
CC transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in
CC vitro. {ECO:0000269|PubMed:17512500, ECO:0000269|PubMed:18005000}.
CC -!- PTM: Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2,
CC PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity.
CC Desumoylated by SENP1. {ECO:0000269|PubMed:19041634}.
CC -!- PTM: Ubiquitinated, leading to its degradation by the proteasome.
CC Proteasomal degradation is required for efficient transcriptional
CC activity and is prevented by HR. {ECO:0000269|PubMed:14570920}.
CC -!- PTM: [Isoform 1]: Monomethylated at Lys-38 by EZH2, this creates a
CC degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin
CC ligase complex. {ECO:0000269|PubMed:14570920}.
CC -!- DISEASE: Intellectual developmental disorder with or without epilepsy
CC or cerebellar ataxia (IDDECA) [MIM:618060]: An autosomal dominant
CC neurodevelopmental disorder that manifests with variable features of
CC mild-to-severe intellectual disability, developmental delay, autism
CC spectrum disorder, cerebellar ataxia and epilepsy.
CC {ECO:0000269|PubMed:29656859}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative promoter usage.
CC Region from 23 to 71 inhibits DNA-binding and transactivation activity.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Produced by alternative promoter usage.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
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DR EMBL; U04897; AAA62658.1; -; mRNA.
DR EMBL; U04898; AAA62659.1; -; mRNA.
DR EMBL; U04899; AAA62660.1; -; mRNA.
DR EMBL; L14611; AAA02963.1; -; mRNA.
DR EMBL; HQ692818; ADZ17329.1; -; mRNA.
DR EMBL; AC009560; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC012404; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022898; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC079068; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087385; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107241; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107905; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471082; EAW77594.1; -; Genomic_DNA.
DR EMBL; BC008831; AAH08831.1; -; mRNA.
DR EMBL; BC100987; AAI00988.1; -; mRNA.
DR EMBL; BC100988; AAI00989.1; -; mRNA.
DR EMBL; BC100989; AAI00990.1; -; mRNA.
DR EMBL; BC100990; AAI00991.1; -; mRNA.
DR CCDS; CCDS10177.1; -. [P35398-2]
DR CCDS; CCDS10179.1; -. [P35398-1]
DR CCDS; CCDS45271.1; -. [P35398-4]
DR PIR; A53196; A53196.
DR PIR; A56856; A56856.
DR PIR; B53196; B53196.
DR PIR; C53196; C53196.
DR RefSeq; NP_002934.1; NM_002943.3.
DR RefSeq; NP_599022.1; NM_134260.2. [P35398-1]
DR RefSeq; NP_599023.1; NM_134261.2. [P35398-2]
DR RefSeq; NP_599024.1; NM_134262.2.
DR PDB; 1N83; X-ray; 1.63 A; A=271-523.
DR PDB; 1S0X; X-ray; 2.20 A; A=271-523.
DR PDB; 4S15; X-ray; 1.90 A; A/B=269-523.
DR PDBsum; 1N83; -.
DR PDBsum; 1S0X; -.
DR PDBsum; 4S15; -.
DR AlphaFoldDB; P35398; -.
DR SMR; P35398; -.
DR BioGRID; 112022; 31.
DR DIP; DIP-29938N; -.
DR IntAct; P35398; 9.
DR STRING; 9606.ENSP00000261523; -.
DR BindingDB; P35398; -.
DR ChEMBL; CHEMBL5868; -.
DR DrugBank; DB04540; Cholesterol.
DR DrugBank; DB01990; Cholesterol sulfate.
DR DrugCentral; P35398; -.
DR GuidetoPHARMACOLOGY; 598; -.
DR iPTMnet; P35398; -.
DR PhosphoSitePlus; P35398; -.
DR BioMuta; RORA; -.
DR DMDM; 548814; -.
DR jPOST; P35398; -.
DR MassIVE; P35398; -.
DR PaxDb; P35398; -.
DR PeptideAtlas; P35398; -.
DR PRIDE; P35398; -.
DR ProteomicsDB; 55055; -. [P35398-2]
DR ProteomicsDB; 55056; -. [P35398-2]
DR ProteomicsDB; 55057; -. [P35398-3]
DR ProteomicsDB; 55058; -. [P35398-4]
DR Antibodypedia; 4080; 583 antibodies from 37 providers.
DR DNASU; 6095; -.
DR Ensembl; ENST00000261523.9; ENSP00000261523.5; ENSG00000069667.16. [P35398-1]
DR Ensembl; ENST00000335670.11; ENSP00000335087.6; ENSG00000069667.16. [P35398-2]
DR GeneID; 6095; -.
DR KEGG; hsa:6095; -.
DR MANE-Select; ENST00000335670.11; ENSP00000335087.6; NM_134261.3; NP_599023.1.
DR UCSC; uc002agt.5; human. [P35398-2]
DR CTD; 6095; -.
DR DisGeNET; 6095; -.
DR GeneCards; RORA; -.
DR HGNC; HGNC:10258; RORA.
DR HPA; ENSG00000069667; Tissue enhanced (skin).
DR MalaCards; RORA; -.
DR MIM; 600825; gene.
DR MIM; 618060; phenotype.
DR neXtProt; NX_P35398; -.
DR OpenTargets; ENSG00000069667; -.
DR PharmGKB; PA34630; -.
DR VEuPathDB; HostDB:ENSG00000069667; -.
DR eggNOG; KOG4216; Eukaryota.
DR GeneTree; ENSGT00940000157387; -.
DR InParanoid; P35398; -.
DR OMA; VRKQTCS; -.
DR OrthoDB; 583704at2759; -.
DR TreeFam; TF319910; -.
DR PathwayCommons; P35398; -.
DR Reactome; R-HSA-1368082; RORA activates gene expression.
DR Reactome; R-HSA-1989781; PPARA activates gene expression.
DR Reactome; R-HSA-383280; Nuclear Receptor transcription pathway.
DR Reactome; R-HSA-400253; Circadian Clock.
DR Reactome; R-HSA-4090294; SUMOylation of intracellular receptors.
DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR Reactome; R-HSA-9707616; Heme signaling.
DR SignaLink; P35398; -.
DR SIGNOR; P35398; -.
DR BioGRID-ORCS; 6095; 8 hits in 1096 CRISPR screens.
DR ChiTaRS; RORA; human.
DR EvolutionaryTrace; P35398; -.
DR GeneWiki; RAR-related_orphan_receptor_alpha; -.
DR GenomeRNAi; 6095; -.
DR Pharos; P35398; Tchem.
DR PRO; PR:P35398; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P35398; protein.
DR Bgee; ENSG00000069667; Expressed in upper leg skin and 197 other tissues.
DR ExpressionAtlas; P35398; baseline and differential.
DR Genevisible; P35398; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0008013; F:beta-catenin binding; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0098531; F:ligand-activated transcription factor activity; IDA:UniProtKB.
DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0008142; F:oxysterol binding; IDA:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:MGI.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0001223; F:transcription coactivator binding; IPI:UniProtKB.
DR GO; GO:0001221; F:transcription coregulator binding; IPI:UniProtKB.
DR GO; GO:0001222; F:transcription corepressor binding; IPI:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0001525; P:angiogenesis; IMP:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; IMP:UniProtKB.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEA:Ensembl.
DR GO; GO:0036315; P:cellular response to sterol; IDA:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0021930; P:cerebellar granule cell precursor proliferation; ISS:UniProtKB.
DR GO; GO:0021702; P:cerebellar Purkinje cell differentiation; IEA:Ensembl.
DR GO; GO:0046068; P:cGMP metabolic process; IEA:Ensembl.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0030522; P:intracellular receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0042692; P:muscle cell differentiation; IMP:UniProtKB.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0006809; P:nitric oxide biosynthetic process; IEA:Ensembl.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IMP:UniProtKB.
DR GO; GO:0010906; P:regulation of glucose metabolic process; ISS:UniProtKB.
DR GO; GO:0043030; P:regulation of macrophage activation; IEA:Ensembl.
DR GO; GO:0008589; P:regulation of smoothened signaling pathway; ISS:UniProtKB.
DR GO; GO:0019218; P:regulation of steroid metabolic process; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0072539; P:T-helper 17 cell differentiation; IEA:Ensembl.
DR GO; GO:0070328; P:triglyceride homeostasis; IMP:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; ISS:UniProtKB.
DR CDD; cd06968; NR_DBD_ROR; 1.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR IDEAL; IID00550; -.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR044101; NR_DBD_ROR.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR003079; ROR_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR01293; RORNUCRECPTR.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative promoter usage; Alternative splicing;
KW Biological rhythms; Developmental protein; Disease variant; DNA-binding;
KW Epilepsy; Intellectual disability; Isopeptide bond; Metal-binding;
KW Methylation; Nucleus; Phosphoprotein; Receptor; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..523
FT /note="Nuclear receptor ROR-alpha"
FT /id="PRO_0000053512"
FT DOMAIN 272..510
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 73..138
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 73..93
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 109..133
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..63
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 154..183
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 506..523
FT /note="AF-2"
FT COMPBIAS 45..63
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 154..169
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 38
FT /note="N6-methyllysine"
FT /evidence="ECO:0000269|PubMed:23063525"
FT MOD_RES 183
FT /note="Phosphothreonine; by MAPK1"
FT /evidence="ECO:0000269|PubMed:17512500"
FT CROSSLNK 240
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000269|PubMed:19041634"
FT VAR_SEQ 1..66
FT /note="MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSS
FT TSRGISVTKKTHTS -> MNEGAPGDSDLETEARVPWSIMGHCLRTGQARMSATPTPAG
FT EGARRDELFGILQILHQCILSSGDAFVLTGVCCSWRQNGKPPYSQKEDKEVQTGYMNA
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:7926749"
FT /id="VSP_053973"
FT VAR_SEQ 1..65
FT /note="MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSS
FT TSRGISVTKKTHT -> MMYFVIAAMK (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:7916608, ECO:0000303|Ref.3"
FT /id="VSP_053974"
FT VAR_SEQ 38..65
FT /note="KSEPPAPVRRQSYSSTSRGISVTKKTHT -> SSSTCSSLSRLFWSQLEHIN
FT WDGATAKNFINLREFFSFLLPALRK (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:7926749"
FT /id="VSP_053975"
FT VARIANT 90
FT /note="C -> S (in IDDECA; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081089"
FT VARIANT 92
FT /note="G -> A (in IDDECA; deleterious effect on embryonic
FT development, when assayed in a heterologous system;
FT dbSNP:rs1555427498)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081090"
FT VARIANT 94
FT /note="K -> R (in IDDECA; deleterious effect on embryonic
FT development, when assayed in a heterologous system;
FT dbSNP:rs1555427497)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081091"
FT VARIANT 409
FT /note="S -> R (in IDDECA)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081092"
FT VARIANT 462
FT /note="R -> Q (in IDDECA; loss of function in cerebellar
FT development, when assayed in a heterologous system;
FT dbSNP:rs1433850094)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081093"
FT VARIANT 476
FT /note="T -> A (no effect on cerebellar development, when
FT assayed in a heterologous system; dbSNP:rs190933482)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081094"
FT VARIANT 500..523
FT /note="Missing (in IDDECA; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29656859"
FT /id="VAR_081095"
FT MUTAGEN 183
FT /note="T->A: Greatly increased transcriptional activity.
FT Decrease in repression by NR1D1."
FT /evidence="ECO:0000269|PubMed:17512500"
FT MUTAGEN 183
FT /note="T->D,E: Some increase in transcriptional activity.
FT No change in repression by NR1D1."
FT /evidence="ECO:0000269|PubMed:17512500"
FT MUTAGEN 183
FT /note="T->R: Attenuates transcriptional activity."
FT /evidence="ECO:0000269|PubMed:17512500"
FT MUTAGEN 183
FT /note="T->V,I: Some increase in transcriptional activity."
FT /evidence="ECO:0000269|PubMed:17512500"
FT MUTAGEN 240
FT /note="K->R: Loss of sumoylation."
FT /evidence="ECO:0000269|PubMed:19041634"
FT MUTAGEN 288
FT /note="C->Q: Less effect on transcriptional activity with
FT cholesterol sulfate as substrate as compared to cholesterol
FT as substrate."
FT /evidence="ECO:0000269|PubMed:14722075"
FT MUTAGEN 323
FT /note="C->L: About 60% loss of transcriptional activity."
FT /evidence="ECO:0000269|PubMed:12467577,
FT ECO:0000269|PubMed:14722075"
FT MUTAGEN 330
FT /note="A->L: About 80% loss of transcriptional activity."
FT /evidence="ECO:0000269|PubMed:12467577,
FT ECO:0000269|PubMed:14722075"
FT MUTAGEN 335
FT /note="V->R: Strongly decreases interaction with NCOA2 and
FT MED1."
FT /evidence="ECO:0000269|PubMed:10478845"
FT MUTAGEN 339
FT /note="K->A: Complete loss of transcriptional activity;
FT when associated with A-507."
FT /evidence="ECO:0000269|PubMed:14722075"
FT MUTAGEN 357
FT /note="K->A: Increased transcriptional activity. No effect
FT on protein degradation."
FT /evidence="ECO:0000269|PubMed:14570920"
FT MUTAGEN 361
FT /note="L->F: Small reduction in transcriptional activity.
FT No protein degradation."
FT /evidence="ECO:0000269|PubMed:14570920"
FT MUTAGEN 364
FT /note="V->G: Greatly reduced transcriptional activity.
FT Protects from protein degradation."
FT /evidence="ECO:0000269|PubMed:14570920"
FT MUTAGEN 371
FT /note="A->Q: Almost total loss of transcriptional
FT activity."
FT /evidence="ECO:0000269|PubMed:12467577"
FT MUTAGEN 399
FT /note="F->W: Slight loss of transcriptional activity."
FT /evidence="ECO:0000269|PubMed:12467577"
FT MUTAGEN 441
FT /note="K->R: No effect on sumoylation."
FT /evidence="ECO:0000269|PubMed:19041634"
FT MUTAGEN 484
FT /note="H->W: Almost total loss of transcriptional
FT activity."
FT /evidence="ECO:0000269|PubMed:12467577"
FT MUTAGEN 507
FT /note="Y->A: Complete loss of transcriptional activity;
FT when associated with A-339."
FT /evidence="ECO:0000269|PubMed:12467577"
FT MUTAGEN 507
FT /note="Y->F: About 40% loss of transcriptional activity."
FT /evidence="ECO:0000269|PubMed:12467577"
FT MUTAGEN 509
FT /note="E->K: Abolishes transcriptional activity. Protects
FT from protein degradation."
FT /evidence="ECO:0000269|PubMed:14570920,
FT ECO:0000269|PubMed:14722075"
FT MUTAGEN 510..511
FT /note="LF->AA: Decreases interaction with NCOA2. Loss of
FT interaction with FOXP3."
FT /evidence="ECO:0000269|PubMed:10478845,
FT ECO:0000269|PubMed:18354202"
FT CONFLICT 368
FT /note="M -> V (in Ref. 2; AAA02963)"
FT /evidence="ECO:0000305"
FT CONFLICT 466
FT /note="I -> M (in Ref. 2; AAA02963)"
FT /evidence="ECO:0000305"
FT HELIX 271..286
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 292..297
FT /evidence="ECO:0007829|PDB:1N83"
FT TURN 298..300
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 305..313
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 316..340
FT /evidence="ECO:0007829|PDB:1N83"
FT TURN 342..346
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 349..367
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 368..371
FT /evidence="ECO:0007829|PDB:1N83"
FT TURN 374..377
FT /evidence="ECO:0007829|PDB:1N83"
FT STRAND 378..381
FT /evidence="ECO:0007829|PDB:1N83"
FT STRAND 384..386
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 388..394
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 397..411
FT /evidence="ECO:0007829|PDB:1N83"
FT TURN 412..414
FT /evidence="ECO:0007829|PDB:4S15"
FT HELIX 417..428
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 439..460
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 466..494
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 496..502
FT /evidence="ECO:0007829|PDB:1N83"
FT HELIX 505..510
FT /evidence="ECO:0007829|PDB:1N83"
FT VARIANT P35398-1:18
FT /note="P -> S (in a colorectal cancer sample, somatic
FT mutation; dbSNP:rs1332895658)"
FT /evidence="ECO:0007744|PubMed:16959974"
FT /id="VAR_082877"
FT CONFLICT P35398-4:7
FT /note="A -> E (in Ref. 2; AAA02963)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 523 AA; 58975 MW; 0FA43BBCE6E28DC7 CRC64;
MESAPAAPDP AASEPGSSGA DAAAGSRETP LNQESARKSE PPAPVRRQSY SSTSRGISVT
KKTHTSQIEI IPCKICGDKS SGIHYGVITC EGCKGFFRRS QQSNATYSCP RQKNCLIDRT
SRNRCQHCRL QKCLAVGMSR DAVKFGRMSK KQRDSLYAEV QKHRMQQQQR DHQQQPGEAE
PLTPTYNISA NGLTELHDDL SNYIDGHTPE GSKADSAVSS FYLDIQPSPD QSGLDINGIK
PEPICDYTPA SGFFPYCSFT NGETSPTVSM AELEHLAQNI SKSHLETCQY LREELQQITW
QTFLQEEIEN YQNKQREVMW QLCAIKITEA IQYVVEFAKR IDGFMELCQN DQIVLLKAGS
LEVVFIRMCR AFDSQNNTVY FDGKYASPDV FKSLGCEDFI SFVFEFGKSL CSMHLTEDEI
ALFSAFVLMS ADRSWLQEKV KIEKLQQKIQ LALQHVLQKN HREDGILTKL ICKVSTLRAL
CGRHTEKLMA FKAIYPDIVR LHFPPLYKEL FTSEFEPAMQ IDG
