P51448 (RORA_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 142. History...
Names and origin
|Protein names||Recommended name:|
Nuclear receptor ROR-alpha
Nuclear receptor RZR-alpha
Nuclear receptor subfamily 1 group F member 1
RAR-related orphan receptor A
Retinoid-related orphan receptor-alpha
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||523 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4+ T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling. Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.17 Ref.18 Ref.22 Ref.23 Ref.25 Ref.27
Monomer. Interacts (via the DNA-binding domain) with HIF1A; the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interacts with CEBPB; the interaction disrupts the interaction CEBPB:EP300. Interacts with the coactivators NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with CRY1 and PER2. Ref.8 Ref.10 Ref.16 Ref.18 Ref.20 Ref.21 Ref.23 Ref.24
In cerebellum, expression begins at E12.5. In the developing retina, first expressed at E17 in the ganglion cell layer. At P3, expressed in the inner border of the neuroblasitic border (presumptive amacrine cells). By P6, levels increase in developing cones. Expression found in the presumptive bipolar cells by P9. During adipocyte differentiation, expression gradually increases. Ref.8 Ref.17 Ref.18
In T(H) cells, induced upon antigen receptor ligation in the presence of IL6 and TGB1 (via STAT3). Oscillates diurnally in central nervous system. In liver, Isoform 1 oscillates diurnally but not isoform 4. Ref.14 Ref.23 Ref.25 Ref.27
The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs By similarity.
Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro By similarity.
Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1 By similarity.
Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR By similarity.
Isoform 1:monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex By similarity.
|Involvement in disease|
Defects in Rora are the cause of the staggerer (SG) mutant phenotype which is characterized by disturbance of Purkinje cell development and immune system functioning. This phenotype exhibits lower body weight, reduced adiposity, decreased plasma cholesterol, triglyceride and apolipoprotein CIII levels, and is resistant to diet-induced obesity. Also has abnormal circadian rhythms. Ref.3 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.15 Ref.17
Contains 1 nuclear receptor DNA-binding domain.
The sequence AAH03757.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
The sequence CAA69930.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
|This entry describes 4 isoforms produced by alternative promoter usage. [Align] [Select]|
|Isoform 1 (identifier: P51448-1) |
Also known as: Alpha-1;
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: P51448-3) |
Also known as: Alpha-2;
The sequence of this isoform is not available.
|Isoform 3 (identifier: P51448-4) |
Also known as: Alpha-3;
The sequence of this isoform is not available.
|Isoform 4 (identifier: P51448-2) |
Also known as: Alpha-4;
The sequence of this isoform differs from the canonical sequence as follows:
1-66: MESAPAAPDP...ISVTKKTHTS → MYFVIAAMKA
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 523||523||Nuclear receptor ROR-alpha||PRO_0000053513|
|DNA binding||73 – 138||66||Nuclear receptor Ref.7 Ref.12 Ref.25|
|Zinc finger||73 – 93||21||NR C4-type|
|Zinc finger||109 – 133||25||NR C4-type|
|Region||139 – 271||133||Hinge|
|Region||272 – 523||252||Ligand-binding|
|Motif||506 – 511||6||AF-2|
|Compositional bias||101 – 175||75||Gln-rich|
Amino acid modifications
|Modified residue||38||1||N6-methyllysine By similarity|
|Modified residue||183||1||Phosphothreonine; by MAPK1 By similarity|
|Cross-link||240||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity|
|Alternative sequence||1 – 66||66||MESAP…KTHTS → MYFVIAAMKA in isoform 4.||VSP_003658|
|Natural variant||275 – 314||40||Missing in SG; disturbance of Purkinje cell and muscle development, lipid metabolism, circadian behavior and immune system functioning. |
|Sequence conflict||163||1||H → R in CAA69930. Ref.2|
|Sequence conflict||180 – 181||2||EP → T in CAA69930. Ref.2|
|Sequence conflict||182||1||L → I in AAB46801. Ref.4|
|Sequence conflict||182||1||L → I in BAA22970. Ref.4|
|Sequence conflict||193 – 194||2||LT → SA in CAA69930. Ref.2|
|Sequence conflict||304||1||L → W in CAA69930. Ref.2|
|Sequence conflict||315||1||Missing in AAB46801. Ref.4|
|Sequence conflict||315||1||Missing in BAA22970. Ref.4|
|Sequence conflict||362||1||E → G in CAA69930. Ref.2|
|Sequence conflict||433||1||R → P in CAA69930. Ref.2|
|Sequence conflict||450 – 451||2||QL → HM in CAA69930. Ref.2|
|Sequence conflict||487||1||K → N in AAB46801. Ref.4|
|Sequence conflict||487||1||K → N in BAA22970. Ref.4|
|||"Disruption of the nuclear hormone receptor RORalpha in staggerer mice."|
Hamilton B.A., Frankel W.N., Kerrebrock A.W., Hawkins T.L., Fitzhugh W., Kusumi K., Russell L.B., Mueller K.L., Vanberkel V., Birren B.W., Kruglyak L., Lander E.S.
Nature 379:736-739(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
|||"RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers."|
Carlberg C., Hooft van Huijsduijnen R., Staple J.K., Delamarter J.F., Becker-Andre M.
Mol. Endocrinol. 8:757-770(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
|||"The structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4."|
Matysiak-Scholze U., Nehls M.C.
Genomics 43:78-84(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), VARIANT SG 275-HIS--LYS-314 DEL.
|||"An orphan nuclear receptor, mROR alpha, and its spatial expression in adult mouse brain."|
Matsui T., Sashihara S., Oh Y., Waxman S.G.
Brain Res. Mol. Brain Res. 33:217-226(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
Tissue: Mammary gland.
|||Lubec G., Kang S.U.|
Submitted (APR-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 39-61, IDENTIFICATION BY MASS SPECTROMETRY.
|||"Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha."|
Raspe E., Duez H., Gervois P., Fievet C., Fruchart J.C., Besnard S., Mariani J., Tedgui A., Staels B.
J. Biol. Chem. 276:2865-2871(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TRIGLYCERIDE METABOLISM, DNA-BINDING, CHARACTERIZATION OF VARIANT SG PHENOTYPE.
|||"RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways."|
Gold D.A., Baek S.H., Schork N.J., Rose D.W., Larsen D.D., Sachs B.D., Rosenfeld M.G., Hamilton B.A.
Neuron 40:1119-1131(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CEREBELLAR DEVELOPMENT, DEVELOPMENTAL STAGE, INTERACTION WITH CTNNB1, CHARACTERIZATION OF VARIANT SG PHENOTYPE.
|||"The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1."|
Akashi M., Takumi T.
Nat. Struct. Mol. Biol. 12:441-448(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CIRCADIAN RHYTHMS, CHARACTERIZATION OF VARIANT SG PHENOTYPE.
|||"Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism."|
Liu C., Li S., Liu T., Borjigin J., Lin J.D.
Nature 447:477-481(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPARGC1A.
|||"Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism."|
Kang H.S., Angers M., Beak J.Y., Wu X., Gimble J.M., Wada T., Xie W., Collins J.B., Grissom S.F., Jetten A.M.
Physiol. Genomics 31:281-294(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN METABOLISM REGULATION, CHARACTERIZATION OF VARIANT SG PHENOTYPE, TISSUE SPECIFICITY.
|||"Identification of oxysterol 7alpha-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor alpha (RORalpha) (NR1F1) target gene and a functional cross-talk between RORalpha and liver X receptor (NR1H3)."|
Wada T., Kang H.S., Angers M., Gong H., Bhatia S., Khadem S., Ren S., Ellis E., Strom S.C., Jetten A.M., Xie W.
Mol. Pharmacol. 73:891-899(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN METABOLISM REGULATION, CHARACTERIZATION OF VARIANT SG PHENOTYPE, DNA-BINDING.
|||"The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation."|
Wada T., Kang H.S., Jetten A.M., Xie W.
Exp. Biol. Med. 233:1191-1201(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW OF FUNCTION IN METABOLISM REGULATION.
|||"T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma."|
Yang X.O., Pappu B.P., Nurieva R., Akimzhanov A., Kang H.S., Chung Y., Ma L., Shah B., Panopoulos A.D., Schluns K.S., Watowich S.S., Tian Q., Jetten A.M., Dong C.
Immunity 28:29-39(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN T(H)17 CELLS DIFFERENTIATION, INDUCTION BY IL6 AND TGFB1, TISSUE SPECIFICITY.
|||"The orphan nuclear receptor, RORalpha, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity."|
Lau P., Fitzsimmons R.L., Raichur S., Wang S.C., Lechtken A., Muscat G.E.
J. Biol. Chem. 283:18411-18421(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN LIPID METABOLISM REGULATION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANT SG PHENOTYPE.
|||"Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease."|
Chopra A.R., Louet J.F., Saha P., An J., Demayo F., Xu J., York B., Karpen S., Finegold M., Moore D., Chan L., Newgard C.B., O'Malley B.W.
Science 322:1395-1399(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NCOA2.
|||"Retinoic acid receptor-related orphan receptor alpha regulates a subset of cone genes during mouse retinal development."|
Fujieda H., Bremner R., Mears A.J., Sasaki H.
J. Neurochem. 108:91-101(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DEVELOPMENTAL STAGE, CHARACTERIZATION OF VARIANT SG.
|||"The orphan nuclear receptor RORalpha restrains adipocyte differentiation through a reduction of C/EBPbeta activity and perilipin gene expression."|
Ohoka N., Kato S., Takahashi Y., Hayashi H., Sato R.
Mol. Endocrinol. 23:759-771(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ADIPOGENESIS, INTERACTION WITH CEBPB, DEVELOPMENTAL STAGE.
|||"Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism."|
Nucl. Recept. Signal. 7:3-35(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"Interaction of MAGED1 with nuclear receptors affects circadian clock function."|
Wang X., Tang J., Xing L., Shi G., Ruan H., Gu X., Liu Z., Wu X., Gao X., Xu Y.
EMBO J. 29:1389-1400(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MAGED1.
|||"The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors."|
Schmutz I., Ripperger J.A., Baeriswyl-Aebischer S., Albrecht U.
Genes Dev. 24:345-357(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PER2.
|||"Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands."|
Wang Y., Kumar N., Solt L.A., Richardson T.I., Helvering L.M., Crumbley C., Garcia-Ordonez R.D., Stayrook K.R., Zhang X., Novick S., Chalmers M.J., Griffin P.R., Burris T.P.
J. Biol. Chem. 285:5013-5025(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN GLUCOSE METABOLISM REGULATION, IDENTIFICTION OF LIGANDS.
|||"Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand."|
Solt L.A., Kumar N., Nuhant P., Wang Y., Lauer J.L., Liu J., Istrate M.A., Kamenecka T.M., Roush W.R., Vidovic D., Schuerer S.C., Xu J., Wagoner G., Drew P.D., Griffin P.R., Burris T.P.
Nature 472:491-494(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN T(H)17 CELLS DIFFERENTIATION, INDUCTION BY IL6 AND TGFB1, INTERACTION WITH NCOR1 AND NCOA2, IDENTIFICATION OF LIGANDS.
|||"Cryptochromes mediate rhythmic repression of the glucocorticoid receptor."|
Lamia K.A., Papp S.J., Yu R.T., Barish G.D., Uhlenhaut N.H., Jonker J.W., Downes M., Evans R.M.
Nature 480:552-556(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CRY1.
|||"RORgamma directly regulates the circadian expression of clock genes and downstream targets in vivo."|
Takeda Y., Jothi R., Birault V., Jetten A.M.
Nucleic Acids Res. 40:8519-8535(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CIRCADIAN RHYTHMS, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, DNA-BINDING, INDUCTION.
|||"Action of RORs and their ligands in (patho)physiology."|
Solt L.A., Burris T.P.
Trends Endocrinol. Metab. 23:619-627(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION AND LIGANDS.
|||"Pivotal role of Rho-associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility."|
Saito T., Hirano M., Ide T., Ichiki T., Koibuchi N., Sunagawa K., Hirano K.
Circulation 127:104-114(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
|+||Additional computationally mapped references.|
|U53228 mRNA. Translation: AAC52513.1.|
Y08640 mRNA. Translation: CAA69930.1. Different initiation.
Z82994 mRNA. Translation: CAB05396.1.
S82720 mRNA. Translation: AAB46801.2.
D45910 mRNA. Translation: BAA22970.1.
BC003757 mRNA. Translation: AAH03757.2. Different initiation.
|RefSeq||NP_001276845.1. NM_001289916.1. [P51448-2]|
NP_038674.1. NM_013646.2. [P51448-1]
3D structure databases
|SMR||P51448. Positions 70-513. |
Protein-protein interaction databases
|BioGrid||202956. 1 interaction.|
|IntAct||P51448. 2 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000034766; ENSMUSP00000034766; ENSMUSG00000032238. [P51448-1]|
ENSMUST00000113624; ENSMUSP00000109254; ENSMUSG00000032238. [P51448-2]
|UCSC||uc009qmx.1. mouse. [P51448-1]|
|MGI||MGI:104661. Rora. |
Enzyme and pathway databases
|Reactome||REACT_200794. Mus musculus biological processes. |
Gene expression databases
Family and domain databases
|Gene3D||1.10.565.10. 2 hits. |
188.8.131.52. 1 hit.
|InterPro||IPR008946. Nucl_hormone_rcpt_ligand-bd. |
|Pfam||PF00104. Hormone_recep. 1 hit. |
PF00105. zf-C4. 1 hit.
|PRINTS||PR01293. RORNUCRECPTR. |
|SMART||SM00430. HOLI. 1 hit. |
SM00399. ZnF_C4. 1 hit.
|SUPFAM||SSF48508. SSF48508. 1 hit. |
|PROSITE||PS00031. NUCLEAR_REC_DBD_1. 1 hit. |
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
|ChiTaRS||RORA. mouse. |
|Accession||Primary (citable) accession number: P51448|
Secondary accession number(s): P70283 Q923G1
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|