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Details on Person UniProt:P35398 RORA

Class:Id	ReferenceGeneProduct:63463
_chainChangeLog	chain:1-523 added on Sat February 7 2015
_displayName	UniProt:P35398 RORA
_timestamp	2024-11-03 19:48:19
chain	chain:1-523
checksum	0FA43BBCE6E28DC7
comment	FUNCTION 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 (PubMed:29656859). Regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as 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 G6PC1 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.SUBUNIT 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. Interacts (via AF-2 motif) with PROX1 (By similarity). Interacts with NRIP1. Isoform 4 interacts (via AF-2 motif) with isoform 1 of FOXP3 (via LXXLL motif).INTERACTION Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff) (PubMed:18354202, PubMed:7916608). Isoform 4: Highly expressed in the central nervous system, including in the cerebellum (PubMed:29656859).INDUCTION Induced by oxidative stress and DNA damage. Isoform 4 is induced by hypoxia (through transactivation by HIF1A and SP1), but not isoform 1.DOMAIN The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs.PTM Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro.PTM Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1.PTM Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR.PTM Monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS Produced by alternative promoter usage. Region from 23 to 71 inhibits DNA-binding and transactivation activity.MISCELLANEOUS Produced by alternative splicing.MISCELLANEOUS Produced by alternative promoter usage.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily.
description	recommendedName: Nuclear receptor ROR-alpha alternativeName: Nuclear receptor RZR-alpha alternativeName: Nuclear receptor subfamily 1 group F member 1 alternativeName: RAR-related orphan receptor A alternativeName: Retinoid-related orphan receptor-alpha
geneName	RORA NR1F1 RZRA
identifier	P35398
isSequenceChanged	FALSE
keyword	3D-structure Activator Alternative promoter usage Alternative splicing Biological rhythms Developmental protein Disease variant DNA-binding Epilepsy Intellectual disability Isopeptide bond Metal-binding Methylation Nucleus Phosphoprotein Proteomics identification Receptor Reference proteome Transcription Transcription regulation Ubl conjugation Zinc Zinc-finger
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03
name	RORA
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:5640198] ENSEMBL:ENSG00000069667 RORA [Homo sapiens]
secondaryIdentifier	RORA_HUMAN P35397 P35399 P45445 Q495X4 Q96H83
sequenceLength	523
species	[Species:48887] Homo sapiens
(isoformParent)	[ReferenceIsoform:153216] UniProt:P35398-2 RORA [Homo sapiens] [ReferenceIsoform:153217] UniProt:P35398-3 RORA [Homo sapiens] [ReferenceIsoform:153218] UniProt:P35398-4 RORA [Homo sapiens] [ReferenceIsoform:403812] UniProt:P35398-1 RORA [Homo sapiens]
(referenceEntity)	[EntityWithAccessionedSequence:400325] RORA [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:4719422] monoSUMO1-K240-RORA [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:4719425] polySUMO2-K240-RORA [nucleoplasm] [Homo sapiens]
(referenceSequence)	[GroupModifiedResidue:4719403] sumoylated lysine (polySUMO2 [nucleoplasm]) at 240 [GroupModifiedResidue:4719405] sumoylated lysine (monoSUMO1 [nucleoplasm]) at 240
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