ID RARA_HUMAN Reviewed; 462 AA. AC P10276; B8Y636; P78456; Q13440; Q13441; Q96S41; Q9NQS0; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1989, sequence version 2. DT 11-NOV-2015, entry version 202. DE RecName: Full=Retinoic acid receptor alpha; DE Short=RAR-alpha; DE AltName: Full=Nuclear receptor subfamily 1 group B member 1; GN Name=RARA; Synonyms=NR1B1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-1). RX PubMed=2825036; DOI=10.1038/330624a0; RA Giguere V., Ong E.S., Segui P., Evans R.M.; RT "Identification of a receptor for the morphogen retinoic acid."; RL Nature 330:624-629(1987). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-1), AND CHROMOSOMAL RP TRANSLOCATION WITH PML. RX PubMed=8302850; DOI=10.1073/pnas.91.3.1178; RA Chen Z., Guidez F., Rousselot P., Agadir A., Chen S.-J., Wang Z.-Y., RA Degos L., Zelent A., Waxman S., Chomienne C.; RT "PLZF-RAR alpha fusion proteins generated from the variant RT t(11;17)(q23;q21) translocation in acute promyelocytic leukemia RT inhibit ligand-dependent transactivation of wild-type retinoic acid RT receptors."; RL Proc. Natl. Acad. Sci. U.S.A. 91:1178-1182(1994). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM ALPHA-1). RX PubMed=10337631; DOI=10.1007/s003359901036; RA Hjalt T.A.H., Murray J.C.; RT "Genomic structure of the human retinoic acid receptor-alpha1 gene."; RL Mamm. Genome 10:528-529(1999). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-1-DELTABC). RX PubMed=11812818; DOI=10.1093/nar/29.24.4901; RA Parrado A., Despouy G., Kraiba R., Le Pogam C., Dupas S., RA Choquette M., Robledo M., Larghero J., Bui H., Le Gall I., RA Rochette-Egly C., Chomienne C., Padua R.A.; RT "Retinoic acid receptor alpha1 variants, RARalpha1DeltaB and RT RARalpha1DeltaBC, define a new class of nuclear receptor isoforms."; RL Nucleic Acids Res. 29:4901-4908(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in RT the human lineage."; RL Nature 440:1045-1049(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS ALPHA-1 AND ALPHA-2). RC TISSUE=Blood, and Brain; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-80 (ISOFORM ALPHA-1). RX PubMed=2175878; DOI=10.1093/nar/18.23.6799; RA Brand N.J., Petkovich M., Chambon P.; RT "Characterization of a functional promoter for the human retinoic acid RT receptor-alpha (hRAR-alpha)."; RL Nucleic Acids Res. 18:6799-6806(1990). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 31-462. RX PubMed=2825025; DOI=10.1038/330444a0; RA Petkovich M., Brand N.J., Krust A., Chambon P.; RT "A human retinoic acid receptor which belongs to the family of nuclear RT receptors."; RL Nature 330:444-450(1987). RN [9] RP SEQUENCE REVISION. RA Chambon P.; RL Submitted (DEC-1988) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-462, AND CHROMOSOMAL TRANSLOCATION RP WITH NPM. RC TISSUE=Bone marrow; RX PubMed=8562957; RA Redner R.L., Rush E.A., Faas S., Rudert W.A., Corey S.J.; RT "The t(5;17) variant of acute promyelocytic leukemia expresses a RT nucleophosmin-retinoic acid receptor fusion."; RL Blood 87:882-886(1996). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-54 (ISOFORM ALPHA-2). RA Chen A., Petrie K., Waxman S., Zelent A.; RT "Homo sapiens retinoic acid receptor alpha (RAR-alpha) gene, promoter RT and 5' region of RAR-alpha 2 isoform."; RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-68, AND CHROMOSOMAL TRANSLOCATION RP WITH PML. RX PubMed=12691149; RA Fujita K., Oba R., Harada H., Mori H., Niikura H., Isoyama K., RA Omine M.; RT "Cytogenetics, FISH and RT-PCR analysis of acute promyelocytic RT leukemia: structure of the fusion point in a case lacking classic RT t(15;17) translocation."; RL Leuk. Lymphoma 44:111-115(2003). RN [13] RP INTERACTION WITH NCOA3. RX PubMed=9267036; DOI=10.1016/S0092-8674(00)80516-4; RA Chen H., Lin R.J., Schiltz R.L., Chakravarti D., Nash A., Nagy L., RA Privalsky M.L., Nakatani Y., Evans R.M.; RT "Nuclear receptor coactivator ACTR is a novel histone RT acetyltransferase and forms a multimeric activation complex with P/CAF RT and CBP/p300."; RL Cell 90:569-580(1997). RN [14] RP INTERACTION WITH NCOA6. RX PubMed=10567404; DOI=10.1074/jbc.274.48.34283; RA Lee S.-K., Anzick S.L., Choi J.-E., Bubendorf L., Guan X.-Y., RA Jung Y.-K., Kallioniemi O.-P., Kononen J., Trent J.M., Azorsa D., RA Jhun B.-H., Cheong J.H., Lee Y.C., Meltzer P.S., Lee J.W.; RT "A nuclear factor ASC-2, as a cancer-amplified transcriptional RT coactivator essential for ligand-dependent transactivation by nuclear RT receptors in vivo."; RL J. Biol. Chem. 274:34283-34293(1999). RN [15] RP INTERACTION WITH PRMT2. RX PubMed=12039952; DOI=10.1074/jbc.M201053200; RA Qi C., Chang J., Zhu Y., Yeldandi A.V., Rao S.M., Zhu Y.-J.; RT "Identification of protein arginine methyltransferase 2 as a RT coactivator for estrogen receptor alpha."; RL J. Biol. Chem. 277:28624-28630(2002). RN [16] RP INTERACTION WITH NCOA7. RX PubMed=11971969; DOI=10.1128/MCB.22.10.3358-3372.2002; RA Shao W., Halachmi S., Brown M.; RT "ERAP140, a conserved tissue-specific nuclear receptor coactivator."; RL Mol. Cell. Biol. 22:3358-3372(2002). RN [17] RP INTERACTION OF THE PML-RARALPHA ONCOPROTEIN WITH UBE2I, SUMOYLATION, RP AND SUBCELLULAR LOCATION. RX PubMed=15809060; DOI=10.1016/j.bbrc.2005.03.052; RA Kim Y.E., Kim D.Y., Lee J.M., Kim S.T., Han T.H., Ahn J.H.; RT "Requirement of the coiled-coil domain of PML-RARalpha oncoprotein for RT localization, sumoylation, and inhibition of monocyte RT differentiation."; RL Biochem. Biophys. Res. Commun. 330:746-754(2005). RN [18] RP INTERACTION WITH PRAME. RX PubMed=16179254; DOI=10.1016/j.cell.2005.07.003; RA Epping M.T., Wang L., Edel M.J., Carlee L., Hernandez M., Bernards R.; RT "The human tumor antigen PRAME is a dominant repressor of retinoic RT acid receptor signaling."; RL Cell 122:835-847(2005). RN [19] RP PHOSPHORYLATION AT SER-96, FUNCTION, INTERACTION WITH AKT1, AND RP MUTAGENESIS OF SER-95; SER-96; SER-154 AND SER-157. RX PubMed=16417524; DOI=10.1042/BJ20051794; RA Srinivas H., Xia D., Moore N.L., Uray I.P., Kim H., Ma L., RA Weigel N.L., Brown P.H., Kurie J.M.; RT "Akt phosphorylates and suppresses the transactivation of retinoic RT acid receptor alpha."; RL Biochem. J. 395:653-662(2006). RN [20] RP INTERACTION WITH ASXL1 AND NCOA1, AND MUTAGENESIS OF 409-ILE-LEU-410; RP GLU-412; 413-MET-LEU-414 AND GLU-415. RX PubMed=16606617; DOI=10.1074/jbc.M512616200; RA Cho Y.S., Kim E.J., Park U.H., Sin H.S., Um S.J.; RT "Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts RT as a ligand-dependent coactivator for retinoic acid receptor."; RL J. Biol. Chem. 281:17588-17598(2006). RN [21] RP INTERACTION WITH LRIF1. RX PubMed=17455211; DOI=10.1002/jcb.21340; RA Li H.J., Haque Z.K., Chen A., Mendelsohn M.; RT "RIF-1, a novel nuclear receptor corepressor that associates with the RT nuclear matrix."; RL J. Cell. Biochem. 102:1021-1035(2007). RN [22] RP SUMOYLATION AT LYS-166; LYS-171 AND LYS-399, FUNCTION, SUBCELLULAR RP LOCATION, AND MUTAGENESIS OF LYS-147; LYS-166; LYS-171 AND LYS-399. RX PubMed=19850744; DOI=10.1210/en.2009-0868; RA Zhu L., Santos N.C., Kim K.H.; RT "Small ubiquitin-like modifier-2 modification of retinoic acid RT receptor-alpha regulates its subcellular localization and RT transcriptional activity."; RL Endocrinology 150:5586-5595(2009). RN [23] RP FUNCTION, AND INTERACTION WITH KMT2E. RX PubMed=19377461; DOI=10.1038/nature07954; RA Fujiki R., Chikanishi T., Hashiba W., Ito H., Takada I., Roeder R.G., RA Kitagawa H., Kato S.; RT "GlcNAcylation of a histone methyltransferase in retinoic-acid-induced RT granulopoiesis."; RL Nature 459:455-459(2009). RN [24] RP PHOSPHORYLATION AT SER-219 AND SER-369, INTERACTION WITH RXRA AND RP PRKAR1A, FUNCTION, AND MUTAGENESIS OF SER-219 AND SER-369. RX PubMed=20215566; DOI=10.1210/en.2009-1338; RA Santos N.C., Kim K.H.; RT "Activity of retinoic acid receptor-alpha is directly regulated at its RT protein kinase A sites in response to follicle-stimulating hormone RT signaling."; RL Endocrinology 151:2361-2372(2010). RN [25] RP INTERACTION WITH ACTN4. RX PubMed=22351778; DOI=10.1074/jbc.M112.345421; RA Khurana S., Chakraborty S., Lam M., Liu Y., Su Y.T., Zhao X., RA Saleem M.A., Mathieson P.W., Bruggeman L.A., Kao H.Y.; RT "Familial focal segmental glomerulosclerosis (FSGS)-linked alpha- RT actinin 4 (ACTN4) protein mutants lose ability to activate RT transcription by nuclear hormone receptors."; RL J. Biol. Chem. 287:12027-12035(2012). RN [26] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 82-167 IN COMPLEX WITH RXRA RP AND DNA. RX PubMed=10698945; DOI=10.1093/emboj/19.5.1045; RA Rastinejad F., Wagner T., Zhao Q., Khorasanizadeh S.; RT "Structure of the RXR-RAR DNA-binding complex on the retinoic acid RT response element DR1."; RL EMBO J. 19:1045-1054(2000). RN [27] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 182-416 IN COMPLEX WITH RP M.MUSCULUS RXRA. RX PubMed=10882070; DOI=10.1016/S1097-2765(00)80424-4; RA Bourguet W., Vivat V., Wurtz J.M., Chambon P., Gronemeyer H., RA Moras D.; RT "Crystal structure of a heterodimeric complex of RAR and RXR ligand- RT binding domains."; RL Mol. Cell 5:289-298(2000). RN [28] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 176-421 IN COMPLEXES WITH RP AGONIST AM580 AND NCOA1 AND WITH INVERSE AGONIST BMS493 AND NCOR1, RP INTERACTION WITH NCOR1 AND NCOR2, AND MUTAGENESIS OF ILE-396. RX PubMed=20543827; DOI=10.1038/nsmb.1855; RA le Maire A., Teyssier C., Erb C., Grimaldi M., Alvarez S., RA de Lera A.R., Balaguer P., Gronemeyer H., Royer C.A., Germain P., RA Bourguet W.; RT "A unique secondary-structure switch controls constitutive gene RT repression by retinoic acid receptor."; RL Nat. Struct. Mol. Biol. 17:801-807(2010). CC -!- FUNCTION: Receptor for retinoic acid. Retinoic acid receptors bind CC as heterodimers to their target response elements in response to CC their ligands, all-trans or 9-cis retinoic acid, and regulate gene CC expression in various biological processes. The RXR/RAR CC heterodimers bind to the retinoic acid response elements (RARE) CC composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the CC absence of ligand, the RXR-RAR heterodimers associate with a CC multiprotein complex containing transcription corepressors that CC induce histone acetylation, chromatin condensation and CC transcriptional suppression. On ligand binding, the corepressors CC dissociate from the receptors and associate with the coactivators CC leading to transcriptional activation. RARA plays an essential CC role in the regulation of retinoic acid-induced germ cell CC development during spermatogenesis. Has a role in the survival of CC early spermatocytes at the beginning prophase of meiosis. In CC Sertoli cells, may promote the survival and development of early CC meiotic prophase spermatocytes. In concert with RARG, required for CC skeletal growth, matrix homeostasis and growth plate function (By CC similarity). Regulates expression of target genes in a ligand- CC dependent manner by recruiting chromatin complexes containing CC KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis. CC {ECO:0000250, ECO:0000269|PubMed:16417524, CC ECO:0000269|PubMed:19377461, ECO:0000269|PubMed:19850744, CC ECO:0000269|PubMed:20215566}. CC -!- SUBUNIT: Heterodimer; with RXRA. Binds DNA preferentially as a CC heterodimer. Interacts with CDK7 (By similarity). Interacts with CC coactivators NCOA3 and NCOA6. Interacts with NCOA7; the CC interaction requires ligand-binding. Interacts with KMT2E/MLL5. CC Interacts (via the ligand-binding domain) with PRAME; the CC interaction is ligand (retinoic acid)-dependent. Interacts with CC AKT1; the interaction phosphorylates RARA and represses CC transactivation. Interacts with PRKAR1A; the interaction CC negatively regulates RARA transcriptional activity. Interacts with CC NCOR1 and NCOR2. Interacts with PRMT2. Interacts with LRIF1. CC Interacts with ASXL1 and NCOA1. Interacts with ACTN4. CC {ECO:0000250|UniProtKB:P11416, ECO:0000269|PubMed:10567404, CC ECO:0000269|PubMed:10698945, ECO:0000269|PubMed:10882070, CC ECO:0000269|PubMed:11971969, ECO:0000269|PubMed:12039952, CC ECO:0000269|PubMed:15809060, ECO:0000269|PubMed:16179254, CC ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:16606617, CC ECO:0000269|PubMed:17455211, ECO:0000269|PubMed:19377461, CC ECO:0000269|PubMed:20215566, ECO:0000269|PubMed:20543827, CC ECO:0000269|PubMed:22351778, ECO:0000269|PubMed:9267036}. CC -!- INTERACTION: CC P59598:Asxl1 (xeno); NbExp=4; IntAct=EBI-413374, EBI-5743705; CC Q15910:EZH2; NbExp=2; IntAct=EBI-413374, EBI-530054; CC P50148:GNAQ; NbExp=4; IntAct=EBI-413374, EBI-3909604; CC Q9UKP3:ITGB1BP2; NbExp=2; IntAct=EBI-413374, EBI-5659717; CC Q15648:MED1; NbExp=3; IntAct=EBI-413374, EBI-394459; CC Q71SY5:MED25; NbExp=10; IntAct=EBI-413374, EBI-394558; CC Q15788:NCOA1; NbExp=3; IntAct=EBI-413374, EBI-455189; CC Q9Y6Q9:NCOA3; NbExp=2; IntAct=EBI-413374, EBI-81196; CC O75376:NCOR1; NbExp=3; IntAct=EBI-413374, EBI-347233; CC P48552:NRIP1; NbExp=4; IntAct=EBI-413374, EBI-746484; CC Q9UPP1-2:PHF8; NbExp=2; IntAct=EBI-413374, EBI-6601215; CC P78527:PRKDC; NbExp=3; IntAct=EBI-413374, EBI-352053; CC P19793:RXRA; NbExp=6; IntAct=EBI-413374, EBI-78598; CC P28702:RXRB; NbExp=4; IntAct=EBI-413374, EBI-748576; CC P48443:RXRG; NbExp=10; IntAct=EBI-413374, EBI-712405; CC Q96EB6:SIRT1; NbExp=3; IntAct=EBI-413374, EBI-1802965; CC P63165:SUMO1; NbExp=5; IntAct=EBI-413374, EBI-80140; CC Q8WW24:TEKT4; NbExp=3; IntAct=EBI-10197061, EBI-750487; CC Q2M1K9:ZNF423; NbExp=2; IntAct=EBI-413374, EBI-950016; CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Nuclear CC localization depends on ligand binding, phosphorylation and CC sumoylation. Transloaction to the nucleus in the absence of ligand CC is dependent on activation of PKC and the downstream MAPK CC phosphorylation. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=Alpha-1; CC IsoId=P10276-1; Sequence=Displayed; CC Name=Alpha-2; CC IsoId=P10276-2; Sequence=VSP_003629; CC Name=Alpha-1-deltaBC; CC IsoId=P10276-3; Sequence=VSP_043143; CC Note=Does not bind nor transactivate RARE on its own but may do CC so as a heterodimer with Alpha-1.; CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain, CC a DNA-binding domain and a C-terminal ligand-binding domain. CC -!- PTM: Phosphorylated on serine and threonine residues. CC Phosphorylation does not change during cell cycle. Phosphorylation CC on Ser-77 is crucial for transcriptional activity (By similarity). CC Phosphorylation by AKT1 is required for the repressor activity but CC has no effect on DNA binding, protein stability nor subcellular CC localization. Phosphorylated by PKA in vitro. This phosphorylation CC on Ser-219 and Ser-369 is critical for ligand binding, nuclear CC localization and transcriptional activity in response to FSH CC signaling. {ECO:0000250, ECO:0000269|PubMed:16417524, CC ECO:0000269|PubMed:20215566}. CC -!- PTM: Sumoylated with SUMO2, mainly on Lys-399 which is also CC required for SENP6 binding. On all-trans retinoic acid (ATRA) CC binding, a confromational change may occur that allows sumoylation CC on two additional site, Lys-166 and Lys-171. Probably desumoylated CC by SENP6. Sumoylation levels determine nuclear localization and CC regulate ATRA-mediated transcriptional activity. CC {ECO:0000269|PubMed:15809060, ECO:0000269|PubMed:19850744}. CC -!- PTM: Trimethylation enhances heterodimerization with RXRA and CC positively modulates the transcriptional activation. CC -!- PTM: Ubiquitinated. CC -!- DISEASE: Note=Chromosomal aberrations involving RARA are commonly CC found in acute promyelocytic leukemia. Translocation CC t(11;17)(q32;q21) with ZBTB16/PLZF; translocation CC t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with CC NPM. The PML-RARA oncoprotein requires both the PML ring structure CC and coiled-coil domain for both interaction with UBE2I, nuclear CC microspeckle location and sumoylation. In addition, the coiled- CC coil domain functions in blocking RA-mediated transactivation and CC cell differentiation. CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1 CC subfamily. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 nuclear receptor DNA-binding domain. CC {ECO:0000255|PROSITE-ProRule:PRU00407}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB00112.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=AAB00113.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=BAB62809.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/RARAID46.html"; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Retinoic acid receptor entry; CC URL="https://en.wikipedia.org/wiki/Retinoic_acid_receptor"; 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; X06614; CAA29829.1; -; mRNA. DR EMBL; X06538; CAA29787.1; -; mRNA. DR EMBL; AF088895; AAD05222.1; -; Genomic_DNA. DR EMBL; AF088889; AAD05222.1; JOINED; Genomic_DNA. DR EMBL; AF088890; AAD05222.1; JOINED; Genomic_DNA. DR EMBL; AF088891; AAD05222.1; JOINED; Genomic_DNA. DR EMBL; AF088892; AAD05222.1; JOINED; Genomic_DNA. DR EMBL; AF088893; AAD05222.1; JOINED; Genomic_DNA. DR EMBL; AF088894; AAD05222.1; JOINED; Genomic_DNA. DR EMBL; FJ487576; ACK86665.1; -; mRNA. DR EMBL; AC080112; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC008727; AAH08727.1; -; mRNA. DR EMBL; BC071733; AAH71733.1; -; mRNA. DR EMBL; X56058; CAA39533.1; -; Genomic_DNA. DR EMBL; X58685; CAA39533.1; JOINED; mRNA. DR EMBL; X58685; CAA41532.1; -; mRNA. DR EMBL; U41742; AAB00112.1; ALT_INIT; mRNA. DR EMBL; U41743; AAB00113.1; ALT_INIT; mRNA. DR EMBL; AF283809; AAF87249.1; -; Genomic_DNA. DR EMBL; AB067754; BAB62809.1; ALT_INIT; mRNA. DR CCDS; CCDS11366.1; -. [P10276-1] DR CCDS; CCDS42317.1; -. [P10276-2] DR CCDS; CCDS45671.1; -. [P10276-3] DR PIR; A29491; A29491. DR RefSeq; NP_000955.1; NM_000964.3. [P10276-1] DR RefSeq; NP_001019980.1; NM_001024809.3. [P10276-2] DR RefSeq; NP_001138773.1; NM_001145301.2. DR RefSeq; NP_001138774.1; NM_001145302.2. [P10276-3] DR RefSeq; XP_005257610.1; XM_005257553.1. [P10276-1] DR RefSeq; XP_005257611.1; XM_005257554.1. [P10276-1] DR RefSeq; XP_011523397.1; XM_011525095.1. [P10276-1] DR UniGene; Hs.654583; -. DR PDB; 1DKF; X-ray; 2.50 A; B=182-416. DR PDB; 1DSZ; X-ray; 1.70 A; A=82-167. DR PDB; 3A9E; X-ray; 2.75 A; B=153-421. DR PDB; 3KMR; X-ray; 1.80 A; A=176-421. DR PDB; 3KMZ; X-ray; 2.10 A; A/B=176-421. DR PDB; 4DQM; X-ray; 2.75 A; A/C=182-415. DR PDBsum; 1DKF; -. DR PDBsum; 1DSZ; -. DR PDBsum; 3A9E; -. DR PDBsum; 3KMR; -. DR PDBsum; 3KMZ; -. DR PDBsum; 4DQM; -. DR ProteinModelPortal; P10276; -. DR SMR; P10276; 87-415. DR BioGrid; 111849; 123. DR DIP; DIP-34N; -. DR IntAct; P10276; 52. DR MINT; MINT-123081; -. DR STRING; 9606.ENSP00000254066; -. DR BindingDB; P10276; -. DR ChEMBL; CHEMBL2363072; -. DR DrugBank; DB00459; Acitretin. DR DrugBank; DB00210; Adapalene. DR DrugBank; DB00523; Alitretinoin. DR DrugBank; DB00982; Isotretinoin. DR DrugBank; DB04942; Tamibarotene. DR DrugBank; DB00799; Tazarotene. DR GuidetoPHARMACOLOGY; 590; -. DR PhosphoSite; P10276; -. DR BioMuta; RARA; -. DR DMDM; 133483; -. DR MaxQB; P10276; -. DR PaxDb; P10276; -. DR PRIDE; P10276; -. DR DNASU; 5914; -. DR Ensembl; ENST00000254066; ENSP00000254066; ENSG00000131759. [P10276-1] DR Ensembl; ENST00000394081; ENSP00000377643; ENSG00000131759. [P10276-2] DR Ensembl; ENST00000394089; ENSP00000377649; ENSG00000131759. [P10276-1] DR Ensembl; ENST00000425707; ENSP00000389993; ENSG00000131759. [P10276-3] DR GeneID; 5914; -. DR KEGG; hsa:5914; -. DR UCSC; uc002huk.2; human. [P10276-1] DR UCSC; uc010wfe.2; human. [P10276-3] DR CTD; 5914; -. DR GeneCards; RARA; -. DR HGNC; HGNC:9864; RARA. DR MIM; 180240; gene. DR MIM; 612376; phenotype. DR neXtProt; NX_P10276; -. DR Orphanet; 520; Acute promyelocytic leukemia. DR PharmGKB; PA34225; -. DR eggNOG; KOG3575; Eukaryota. DR eggNOG; ENOG410XRZC; LUCA. DR GeneTree; ENSGT00810000125350; -. DR HOGENOM; HOG000010312; -. DR HOVERGEN; HBG005606; -. DR InParanoid; P10276; -. DR KO; K08527; -. DR OMA; NNSSDQR; -. DR PhylomeDB; P10276; -. DR TreeFam; TF328382; -. DR Reactome; R-HSA-383280; Nuclear Receptor transcription pathway. DR Reactome; R-HSA-5362517; Signaling by Retinoic Acid. DR SignaLink; P10276; -. DR ChiTaRS; RARA; human. DR EvolutionaryTrace; P10276; -. DR GeneWiki; Retinoic_acid_receptor_alpha; -. DR GenomeRNAi; 5914; -. DR NextBio; 23018; -. DR PRO; PR:P10276; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; P10276; -. DR CleanEx; HS_RARA; -. DR ExpressionAtlas; P10276; baseline and differential. DR Genevisible; P10276; HS. DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA. DR GO; GO:0009986; C:cell surface; IC:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0000790; C:nuclear chromatin; IDA:BHF-UCL. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0051393; F:alpha-actinin binding; IPI:UniProtKB. DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB. DR GO; GO:0051018; F:protein kinase A binding; IDA:UniProtKB. DR GO; GO:0043422; F:protein kinase B binding; IPI:UniProtKB. DR GO; GO:0005102; F:receptor binding; IDA:UniProtKB. DR GO; GO:0001972; F:retinoic acid binding; IDA:BHF-UCL. DR GO; GO:0003708; F:retinoic acid receptor activity; IDA:BHF-UCL. DR GO; GO:0044323; F:retinoic acid-responsive element binding; IDA:UniProtKB. DR GO; GO:0000977; F:RNA polymerase II regulatory region sequence-specific DNA binding; IEA:Ensembl. DR GO; GO:0003707; F:steroid hormone receptor activity; IEA:InterPro. DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB. DR GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB. DR GO; GO:0003700; F:transcription factor activity, sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0043277; P:apoptotic cell clearance; IMP:UniProtKB. DR GO; GO:0071391; P:cellular response to estrogen stimulus; IDA:UniProtKB. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0071300; P:cellular response to retinoic acid; IDA:UniProtKB. DR GO; GO:0060591; P:chondroblast differentiation; IEA:Ensembl. DR GO; GO:0031076; P:embryonic camera-type eye development; IEA:Ensembl. DR GO; GO:0060324; P:face development; IEA:Ensembl. DR GO; GO:0010467; P:gene expression; TAS:Reactome. DR GO; GO:0007281; P:germ cell development; IEA:Ensembl. DR GO; GO:0002068; P:glandular epithelial cell development; IEA:Ensembl. DR GO; GO:0003417; P:growth plate cartilage development; IEA:Ensembl. DR GO; GO:0060173; P:limb development; IEA:Ensembl. DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0061037; P:negative regulation of cartilage development; IEA:Ensembl. DR GO; GO:0030853; P:negative regulation of granulocyte differentiation; IDA:UniProtKB. DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IDA:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl. DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:0045947; P:negative regulation of translational initiation; IEA:Ensembl. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IDA:BHF-UCL. DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl. DR GO; GO:0003148; P:outflow tract septum morphogenesis; IEA:Ensembl. DR GO; GO:0051099; P:positive regulation of binding; IMP:UniProtKB. DR GO; GO:0045787; P:positive regulation of cell cycle; IMP:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:UniProtKB. DR GO; GO:0032736; P:positive regulation of interleukin-13 production; IDA:BHF-UCL. DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IDA:BHF-UCL. DR GO; GO:0032754; P:positive regulation of interleukin-5 production; IDA:BHF-UCL. DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IMP:UniProtKB. DR GO; GO:0032526; P:response to retinoic acid; IMP:BHF-UCL. DR GO; GO:0048384; P:retinoic acid receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0060010; P:Sertoli cell fate commitment; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IDA:BHF-UCL. DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl. DR GO; GO:0060534; P:trachea cartilage development; IEA:Ensembl. DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome. DR GO; GO:0001657; P:ureteric bud development; IEA:Ensembl. DR GO; GO:0055012; P:ventricular cardiac muscle cell differentiation; IEA:Ensembl. DR Gene3D; 1.10.565.10; -; 1. DR Gene3D; 3.30.50.10; -; 1. DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd. DR InterPro; IPR001723; Nuclear_hrmn_rcpt. DR InterPro; IPR003078; Retinoic_acid_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; PR01292; RETNOICACIDR. 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; PS00031; NUCLEAR_REC_DBD_1; 1. DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Chromosomal rearrangement; KW Complete proteome; Cytoplasm; DNA-binding; Isopeptide bond; KW Metal-binding; Nucleus; Phosphoprotein; Proto-oncogene; Receptor; KW Reference proteome; Transcription; Transcription regulation; KW Ubl conjugation; Zinc; Zinc-finger. FT CHAIN 1 462 Retinoic acid receptor alpha. FT /FTId=PRO_0000053461. FT DNA_BIND 88 153 Nuclear receptor. {ECO:0000255|PROSITE- FT ProRule:PRU00407}. FT ZN_FING 88 108 NR C4-type. {ECO:0000255|PROSITE- FT ProRule:PRU00407}. FT ZN_FING 124 148 NR C4-type. {ECO:0000255|PROSITE- FT ProRule:PRU00407}. FT REGION 1 87 Modulating. FT REGION 154 199 Hinge. FT REGION 200 419 Ligand-binding. FT REGION 404 419 Required for binding corepressor NCOR1. FT SITE 60 61 Breakpoint for translocation to form FT PLZF-RAR-alpha, RAR-alpha1-PLZF and PML- FT RAR-alpha oncogenes. FT MOD_RES 77 77 Phosphoserine; by CDK7. {ECO:0000250}. FT MOD_RES 96 96 Phosphoserine; by PKB/AKT1. FT {ECO:0000269|PubMed:16417524}. FT MOD_RES 219 219 Phosphoserine; by PKA. FT {ECO:0000269|PubMed:20215566}. FT MOD_RES 369 369 Phosphoserine; by PKA. FT {ECO:0000269|PubMed:20215566}. FT CROSSLNK 166 166 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO). FT CROSSLNK 171 171 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO). FT CROSSLNK 399 399 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO). FT VAR_SEQ 1 60 MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGAL FT TTLQHQLPVSGYSTPSPAT -> MYESVEVGGPTPNPFLVV FT DFYNQNRACLLPEKGLPAPGPYSTPLRTPLWNGSNHS (in FT isoform Alpha-2). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_003629. FT VAR_SEQ 61 157 Missing (in isoform Alpha-1-deltaBC). FT {ECO:0000303|PubMed:11812818}. FT /FTId=VSP_043143. FT MUTAGEN 95 95 S->A: No effect on PKB/AKT1-mediated FT phosphorylation. Repressed FT transactivation. FT {ECO:0000269|PubMed:16417524}. FT MUTAGEN 96 96 S->A: Abolishes PKB/AKT1-mediated FT phosphorylation. Repressed FT transactivation. FT {ECO:0000269|PubMed:16417524}. FT MUTAGEN 147 147 K->R: Abrogates sumoylation in the FT presence or absence of ATRA and primarily FT nuclear localization and enhanced ATRA- FT mediated transcriptional activity; when FT associated with R-166; R-171 and R-399. FT {ECO:0000269|PubMed:19850744}. FT MUTAGEN 154 154 S->A: No effect on PKB/AKT1-mediated FT phosphorylation. No repression of FT transactivation. FT {ECO:0000269|PubMed:16417524}. FT MUTAGEN 157 157 S->A: No effect on PKB/AKT1-mediated FT phosphorylation. Repressed FT transactivation. FT {ECO:0000269|PubMed:16417524}. FT MUTAGEN 166 166 K->R: Cytoplasmic in the absence of ATRA FT and reduced transcriptional activity in FT the presence of ATRA. Low sumoylation FT levels in the presence of ATRA; when FT associated with R-399. Nuclear FT localization and enhanced transcriptional FT activity; when associated with R-171 and FT R-399. Primarily nuclear localization and FT enhanced ATRA-mediated transcriptional FT activity; when associated with R-147; R- FT 171 and R-399. FT {ECO:0000269|PubMed:19850744}. FT MUTAGEN 171 171 K->R: Cytoplasmic in the absence of ATRA FT and reduced transcriptional activity in FT the presence of ATRA. Low sumoylation FT levels in the presence of ATRA; when FT associated with R-399. Nuclear FT localization and enhanced transcriptional FT activity; when associated with R-166 and FT R-399. Primarily nuclear localization and FT enhanced ATRA-mediated transcriptional FT activity; when associated with R-147; R- FT 166 and R-399. FT {ECO:0000269|PubMed:19850744}. FT MUTAGEN 219 219 S->A: No effect on heterodimerization FT with RARA. On ATRA treatment, localizes FT to the nucleus, and increased protein FT levels; when associated with A-369. FT {ECO:0000269|PubMed:20215566}. FT MUTAGEN 219 219 S->E: No effect on heterodimerization FT with RARA. On ATRA treatment, localizes FT to both nucleus and cytoplasm, no FT increase in protein levels, and decrease FT in RARA-mediated transcriptional FT activity; when associated with E-369. FT {ECO:0000269|PubMed:20215566}. FT MUTAGEN 369 369 S->A: No effect on heterodimerization FT with RARA. On ATRA treatment, localizes FT to the nucleus, and increased protein FT levels; when associated with A-219. FT {ECO:0000269|PubMed:20215566}. FT MUTAGEN 369 369 S->E: Some inhibition of FT heterodimerization with RARA. On ATRA FT treatment, localizes to both nucleus and FT cytoplasm, increase in protein levels, FT and decrease in RARA-mediated FT transcriptional activity; when associated FT with E-219. FT {ECO:0000269|PubMed:20215566}. FT MUTAGEN 396 396 I->E: Abrogates interaction with NCOR1 or FT NCOR2. Increased affinity for NCOR1 and FT NCOR2 in the presence of BMS493. FT Increased transcriptional activity in the FT presence of agonist and decreased FT activity in the presence of neutral FT antagonist. FT {ECO:0000269|PubMed:20543827}. FT MUTAGEN 399 399 K->R: In the absence of ATRA, abolishes FT sumoylation and is mainly nuclear. In the FT presence of ATRA, some sumoylation, FT cytoplasmic location, reduced FT transcriptional activity and no SENP6 FT binding. Low sumoylation levels in the FT presence of ATRA and nuclear location in FT the absence of ATRA; when associated with FT R-166 or with R-171. Primarily nuclear FT localization and enhanced ATRA-mediated FT transcriptional activity; when associated FT with R-147; R-166 and R-171. FT {ECO:0000269|PubMed:19850744}. FT MUTAGEN 409 410 LI->AA: Abolishes interaction with ASXL1 FT and NCOA1. {ECO:0000269|PubMed:16606617}. FT MUTAGEN 412 412 E->Q: Impairs interaction with ASXL1 and FT NCOA1; when associated with Q-415. FT {ECO:0000269|PubMed:16606617}. FT MUTAGEN 413 414 ML->AA: Abolishes interaction with ASXL1 FT and NCOA1. {ECO:0000269|PubMed:16606617}. FT MUTAGEN 415 415 E->Q: Impairs interaction with ASXL1 and FT NCOA1; when associated with Q-412. FT {ECO:0000269|PubMed:16606617}. FT CONFLICT 241 241 E -> D (in Ref. 3; AAD05222). FT {ECO:0000305}. FT TURN 89 91 {ECO:0000244|PDB:1DSZ}. FT STRAND 97 99 {ECO:0000244|PDB:1DSZ}. FT HELIX 106 117 {ECO:0000244|PDB:1DSZ}. FT TURN 134 136 {ECO:0000244|PDB:1DSZ}. FT HELIX 137 139 {ECO:0000244|PDB:1DSZ}. FT HELIX 141 150 {ECO:0000244|PDB:1DSZ}. FT HELIX 155 157 {ECO:0000244|PDB:1DSZ}. FT HELIX 183 196 {ECO:0000244|PDB:3KMR}. FT HELIX 202 204 {ECO:0000244|PDB:3KMR}. FT STRAND 214 216 {ECO:0000244|PDB:4DQM}. FT HELIX 222 244 {ECO:0000244|PDB:3KMR}. FT HELIX 249 251 {ECO:0000244|PDB:3KMR}. FT HELIX 254 275 {ECO:0000244|PDB:3KMR}. FT TURN 279 282 {ECO:0000244|PDB:3KMR}. FT STRAND 283 285 {ECO:0000244|PDB:3KMR}. FT STRAND 289 293 {ECO:0000244|PDB:3KMR}. FT HELIX 294 300 {ECO:0000244|PDB:3KMR}. FT HELIX 303 305 {ECO:0000244|PDB:3KMR}. FT HELIX 306 316 {ECO:0000244|PDB:3KMR}. FT HELIX 317 319 {ECO:0000244|PDB:3KMR}. FT HELIX 323 334 {ECO:0000244|PDB:3KMR}. FT HELIX 345 366 {ECO:0000244|PDB:3KMR}. FT HELIX 373 401 {ECO:0000244|PDB:3KMR}. FT STRAND 402 404 {ECO:0000244|PDB:3KMR}. FT HELIX 408 414 {ECO:0000244|PDB:3KMR}. SQ SEQUENCE 462 AA; 50771 MW; E8D1CF9A1E57CB99 CRC64; MASNSSSCPT PGGGHLNGYP VPPYAFFFPP MLGGLSPPGA LTTLQHQLPV SGYSTPSPAT IETQSSSSEE IVPSPPSPPP LPRIYKPCFV CQDKSSGYHY GVSACEGCKG FFRRSIQKNM VYTCHRDKNC IINKVTRNRC QYCRLQKCFE VGMSKESVRN DRNKKKKEVP KPECSESYTL TPEVGELIEK VRKAHQETFP ALCQLGKYTT NNSSEQRVSL DIDLWDKFSE LSTKCIIKTV EFAKQLPGFT TLTIADQITL LKAACLDILI LRICTRYTPE QDTMTFSDGL TLNRTQMHNA GFGPLTDLVF AFANQLLPLE MDDAETGLLS AICLICGDRQ DLEQPDRVDM LQEPLLEALK VYVRKRRPSR PHMFPKMLMK ITDLRSISAK GAERVITLKM EIPGSMPPLI QEMLENSEGL DTLSGQPGGG GRDGGGLAPP PGSCSPSLSP SSNRSSPATH SP //