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Target not currently curated in GtoImmuPdb
Target id: 598
Nomenclature: RAR-related orphan receptor-α
Systematic Nomenclature: NR1F1
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 523 | 15q22.2 | RORA | RAR related orphan receptor A | 9 |
| Mouse | 523 | 9 37.45 cM | Rora | RAR-related orphan receptor alpha | 18-19 |
| Rat | 309 | 8q24 | Rora | RAR-related orphan receptor A | |
| Previous and Unofficial Names |
| ROR1 | ROR2 | ROR3 | RORα | RZRα | nuclear receptor ROR-alpha | RAR-related orphan receptor A |
| Database Links |
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| Alphafold | P35398 (Hs), P51448 (Mm) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL5868 (Hs), CHEMBL3217403 (Mm) |
| Ensembl Gene | ENSG00000069667 (Hs), ENSMUSG00000032238 (Mm), ENSRNOG00000027145 (Rn) |
| Entrez Gene | 6095 (Hs), 19883 (Mm), 300807 (Rn) |
| Human Protein Atlas | ENSG00000069667 (Hs) |
| KEGG Gene | hsa:6095 (Hs), mmu:19883 (Mm), rno:300807 (Rn) |
| OMIM | 600825 (Hs) |
| Pharos | P35398 (Hs) |
| RefSeq Nucleotide | NM_134260 (Hs), NM_013646 (Mm) |
| RefSeq Protein | NP_599024 (Hs), NP_002934 (Hs), NP_599022 (Hs), NP_599023 (Hs), NP_038674 (Mm) |
| SynPHARM |
6398 (in complex with cholesterol) 6399 (in complex with cholesterol sulphate) |
| UniProtKB | P35398 (Hs), P51448 (Mm) |
| Wikipedia | RORA (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| cholesterol |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| A recent study identified cholesterol as the lipid bound to purified RORα LBD expressed in insect cells. The same study demonstated that RORα transcriptional activity is modulated by lovastatin, a cholesterol lowering drug, in an in vitro reporter assay, thereby suggesting a cholesterol sensor role for RORα. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immuno Process Associations | ||
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| DNA Binding |
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| DNA Binding Comments | |||||||
| RORs bind to DNA as monomers on monomeric half-site elements with an 5’ A/T rich extension which is identical to the response elements of the Rev-erbs orphan receptors (T/A A/T T/A C A/T A/GGGTCA). RORα may also bind as a homodimer to Rev-DR2 sites (composed of one classical RevRE followed in 3’ by an AGGTCA motif; these two motifs are separated by two bases that are always a C and a T). It is now clear that these dimers are not energetically favoured and there is no evidence that homodimer binding is favoured over monomer binding in vitro. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Nm23-1 | Physical | 15 | |
| Nm23-2 | Physical | 15 | |
| MYOD1 | Physical, Functional | 20 | |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| EP300 | Co-activator | No | No | Yes | 20 | |
| NCOA2 | Co-activator | No | No | Yes | 3 | |
| MED1 | Co-activator | No | No | Yes | 3 | |
| HR | None | No | Yes | Yes | Mutagenesis of conserved amino acids in the ligand binding domain indicates that RORa activity is ligand-dependent, suggesting that corepressor activity is maintained in the presence of ligand. Despite similar recognition helices shared with coactivators, Hr does not compete for the same molecular determinants at the surface of the RORa ligand binding domain, indicating that Hr-mediated repression is not simply through displacement of coactivators. Remarkably, the specificity of Hr corepressor action can be transferred to a retinoic acid receptor by exchanging the activation function 2 (AF-2) helix. Repression of the chimeric receptor is observed in the presence of retinoic acid, demonstrating that in this context, Hr is indeed a ligand-oblivious nuclear receptor corepressor. These results suggest a novel molecular mechanism for corepressor action and demonstrate that the AF-2 helix can play a dynamic role in controlling corepressor as well as coactivator interactions. | 11 |
| NCOR1 | Co-repressor | No | No | No | A repression domain was mapped in RORα and it was shown that this repression domain is more active in some cell types | 2 |
| NCOR2 | Co-repressor | No | No | No | A repression domain was mapped in RORα and it was shown that this repression domain is more active in some cell types | 2 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| LAMB1 | Human | Activated | Transient transfection, EMSA, Other | 17 | |
| NDRG1 | Human | Activated | Transient transfection, EMSA, Other | NDRG1 (N-Myc) is regulated by RORs (activation) and Rev Erbs (inhibition) via the same RORE present in its promoter | 7 |
| APOA5 | Human | Activated | Transient transfection, EMSA, Other | Consistent with role in liver metabolism, ROR alpha regulates ApoA5 expression. | 8 |
| FGB | Human | Activated | ChIP, Transient transfection, EMSA | 5 | |
| NR1D1 | Human | Activated | EMSA, ChIP | 6,25 | |
| Arntl | Mouse | Activated | Transient transfection, EMSA, Other | ROR alpha as well as ROR beta and gamma, is involved in the molecular mechanism supporting the circadian pacemaker. It have been shown that the bHLH PAS protein Bmal1 expression is directly regulated by RORs and Rev erbs which compete for the same response element. | 23,26 |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| RORα was found to be expressed as a series of mRNA transcripts. The predominant species is a ~15 kb mRNA present in many organs (lung, muscle, brain, heart, peripheral blood leucocytes, spleen, liver, ovary, etc.) but smaller bands are also visible at 2.3 kb with a narrower distribution (leucocytes, testis, lung and liver). Other bands at 7.5, 5.5 and 2.0 kb are also visible but with a weaker intensity. These may corresponds to the four different isoforms described. RORα was found to be expressed in murine lens. RORα is also expressed in rat intestinal epithelium. By detection of the β-gal activity in a heterozygous mice strain containing one allele in which part of RORα gene was replaced by the β-gal enzyme, an expression in various area of the brain including retinal ganglion cells, cerebellum, some nucleus in the thalamus and the suprachiasmatic nucleus, testis and skin was detected. RORβ is up-regulated during the differentiation of 3T3-L1 cells into adipocytes as well as during osteogenic differentiation. Recently, it was shown that RORα is expressed in cartilage. The same expression patterns are seen in human, mice and rats. | ||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||||
| The four RORα isoforms differ in their N-Terminal domains and exhibit differential DNA binding preferences. |
1. André E, Conquet F, Steinmayr M, Stratton SC, Porciatti V, Becker-André M. (1998) Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J, 17 (14): 3867-77. [PMID:9670004]
2. Atkins GB, Hu X, Guenther MG, Rachez C, Freedman LP, Lazar MA. (1999) Coactivators for the orphan nuclear receptor RORalpha. Mol Endocrinol, 13 (9): 1550-7. [PMID:10478845]
3. Bitsch F, Aichholz R, Kallen J, Geisse S, Fournier B, Schlaeppi JM. (2003) Identification of natural ligands of retinoic acid receptor-related orphan receptor alpha ligand-binding domain expressed in Sf9 cells--a mass spectrometry approach. Anal Biochem, 323 (1): 139-49. [PMID:14622968]
4. Bordji K, Grillasca JP, Gouze JN, Magdalou J, Schohn H, Keller JM, Bianchi A, Dauça M, Netter P, Terlain B. (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes. J Biol Chem, 275 (16): 12243-50. [PMID:10766862]
5. Chauvet C, Bois-Joyeux B, Fontaine C, Gervois P, Bernard MA, Staels B, Danan JL. (2005) The gene encoding fibrinogen-beta is a target for retinoic acid receptor-related orphan receptor alpha. Mol Endocrinol, 19 (10): 2517-26. [PMID:15941850]
6. Delerive P, Chin WW, Suen CS. (2002) Identification of Reverb(alpha) as a novel ROR(alpha) target gene. J Biol Chem, 277 (38): 35013-8. [PMID:12114512]
7. Dussault I, Giguère V. (1997) Differential regulation of the N-myc proto-oncogene by ROR alpha and RVR, two orphan members of the superfamily of nuclear hormone receptors. Mol Cell Biol, 17 (4): 1860-7. [PMID:9121434]
8. Genoux A, Dehondt H, Helleboid-Chapman A, Duhem C, Hum DW, Martin G, Pennacchio LA, Staels B, Fruchart-Najib J, Fruchart JC. (2005) Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha. Arterioscler Thromb Vasc Biol, 25 (6): 1186-92. [PMID:15790933]
9. Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G. (1994) Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev, 8 (5): 538-53. [PMID:7926749]
10. Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, Kruglyak L, Lander ES. (1996) Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature, 379 (6567): 736-9. [PMID:8602221]
11. Harding HP, Atkins GB, Jaffe AB, Seo WJ, Lazar MA. (1997) Transcriptional activation and repression by RORalpha, an orphan nuclear receptor required for cerebellar development. Mol Endocrinol, 11 (11): 1737-46. [PMID:9328355]
12. Kallen J, Schlaeppi JM, Bitsch F, Delhon I, Fournier B. (2004) Crystal structure of the human RORalpha Ligand binding domain in complex with cholesterol sulfate at 2.2 A. J Biol Chem, 279 (14): 14033-8. [PMID:14722075]
13. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. (2002) X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure, 10 (12): 1697-707. [PMID:12467577]
14. Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA, Busby SA, Garcia-Ordonez RD, Burris TP, Griffin PR. (2010) The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist. Mol Pharmacol, 77 (2): 228-36. [PMID:19887649]
15. Lau P, Bailey P, Dowhan DH, Muscat GE. (1999) Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD. Nucleic Acids Res, 27 (2): 411-20. [PMID:9862959]
16. Lee JM, Kim IS, Kim H, Lee JS, Kim K, Yim HY, Jeong J, Kim JH, Kim JY, Lee H, Seo SB, Kim H, Rosenfeld MG, Kim KI, Baek SH. (2010) RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer. Mol Cell, 37 (2): 183-95. [PMID:20122401]
17. Matsui T. (1996) Differential activation of the murine laminin B1 gene promoter by RAR alpha, ROR alpha, and AP-1. Biochem Biophys Res Commun, 220 (2): 405-10. [PMID:8645318]
18. Matysiak-Scholze U, Nehls M. (1997) The structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4. Genomics, 43 (1): 78-84. [PMID:9226375]
19. McBroom LD, Flock G, Giguère V. (1995) The nonconserved hinge region and distinct amino-terminal domains of the ROR alpha orphan nuclear receptor isoforms are required for proper DNA bending and ROR alpha-DNA interactions. Mol Cell Biol, 15 (2): 796-808. [PMID:7823947]
20. Medvedev A, Yan ZH, Hirose T, Giguère V, Jetten AM. (1996) Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene, 181 (1-2): 199-206. [PMID:8973331]
21. Meyer T, Kneissel M, Mariani J, Fournier B. (2000) In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism. Proc Natl Acad Sci USA, 97 (16): 9197-202. [PMID:10900268]
22. Moraitis AN, Giguère V, Thompson CC. (2002) Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol Cell Biol, 22 (19): 6831-41. [PMID:12215540]
23. Nakajima Y, Ikeda M, Kimura T, Honma S, Ohmiya Y, Honma K. (2004) Bidirectional role of orphan nuclear receptor RORalpha in clock gene transcriptions demonstrated by a novel reporter assay system. FEBS Lett, 565 (1-3): 122-6. [PMID:15135064]
24. Paravicini G, Steinmayr M, André E, Becker-André M. (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem Biophys Res Commun, 227 (1): 82-7. [PMID:8858107]
25. Raspè E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, Staels B. (2002) Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha. J Biol Chem, 277 (51): 49275-81. [PMID:12377782]
26. Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB. (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron, 43 (4): 527-37. [PMID:15312651]
27. Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidović D et al.. (2011) Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature, 472 (7344): 491-4. [PMID:21499262]
28. Steinmayr M, André E, Conquet F, Rondi-Reig L, Delhaye-Bouchaud N, Auclair N, Daniel H, Crépel F, Mariani J, Sotelo C, Becker-André M. (1998) staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice. Proc Natl Acad Sci USA, 95 (7): 3960-5. [PMID:9520475]
29. Tini M, Fraser RA, Giguère V. (1995) Functional interactions between retinoic acid receptor-related orphan nuclear receptor (ROR alpha) and the retinoic acid receptors in the regulation of the gamma F-crystallin promoter. J Biol Chem, 270 (34): 20156-61. [PMID:7650034]
30. Zhao X, Graves C, Ames SJ, Fisher DE, Spanjaard RA. (2009) Mechanism of regulation and suppression of melanoma invasiveness by novel retinoic acid receptor-gamma target gene carbohydrate sulfotransferase 10. Cancer Res, 69 (12): 5218-25. [PMID:19470764]
