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P51449 (RORG_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 133. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Nuclear receptor ROR-gamma
Alternative name(s):
Nuclear receptor RZR-gamma
Nuclear receptor subfamily 1 group F member 3
RAR-related orphan receptor C
Retinoid-related orphan receptor-gamma
Gene names
Name:RORC
Synonyms:NR1F3, RORG, RZRG
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length518 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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 cellular differentiation, immunity, peripheral 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 gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. 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 RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA 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 SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1. Ref.7 Ref.9 Ref.12

Isoform 2:Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches. Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for 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. May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus. Ref.7 Ref.9 Ref.12

Subunit structure

Interacts (via AF-2 motif) with the coactivators NCOA1, NCOA2 and PPARGC1A (via LXXLL motif). Interacts with the corepressor NCOR1. Interacts with CRY1. Ref.6 Ref.10

Subcellular location

Nucleus Probable.

Tissue specificity

Isoform 1 is widely expressed in many tissues, including liver and adipose, and highly expressed in skeletal muscle. Isoform 2 is primarily expressed in immature thymocytes.

Induction

Up-regulated in the state of obesity. Ref.6 Ref.8

Domain

The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs such as NCOA1 and NCOA2 By similarity.

Sequence similarities

Belongs to the nuclear hormone receptor family. NR1 subfamily.

Contains 1 nuclear receptor DNA-binding domain.

Sequence caution

The sequence AAA64751.1 differs from that shown. Reason: Frameshift at position 516.

Ontologies

Keywords
   Biological processBiological rhythms
Transcription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityAlternative promoter usage
   DomainZinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionDevelopmental protein
Receptor
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processPeyer's patch development

Inferred from sequence or structural similarity. Source: UniProtKB

T cell differentiation in thymus

Inferred from electronic annotation. Source: Ensembl

T-helper 17 cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

T-helper cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

adipose tissue development

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to sterol

Inferred from direct assay Ref.7. Source: UniProtKB

circadian regulation of gene expression

Inferred from sequence or structural similarity. Source: UniProtKB

gene expression

Traceable author statement. Source: Reactome

intracellular receptor signaling pathway

Traceable author statement Ref.1. Source: GOC

lymph node development

Inferred from electronic annotation. Source: Ensembl

mucosal-associated lymphoid tissue development

Inferred from electronic annotation. Source: Ensembl

negative regulation of thymocyte apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from electronic annotation. Source: Ensembl

regulation of fat cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of glucose metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of steroid metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of transcription involved in cell fate commitment

Inferred from sequence or structural similarity. Source: UniProtKB

transcription initiation from RNA polymerase II promoter

Traceable author statement. Source: Reactome

xenobiotic metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentnucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.7. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

direct ligand regulated sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.7. Source: UniProtKB

ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity

Traceable author statement Ref.1. Source: ProtInc

oxysterol binding

Inferred from direct assay Ref.7. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.10. Source: UniProtKB

sequence-specific DNA binding

Inferred from electronic annotation. Source: InterPro

sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

steroid hormone receptor activity

Inferred from electronic annotation. Source: InterPro

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ArntlQ9WTL82EBI-3908771,EBI-644534From a different organism.
ClockO087852EBI-3908771,EBI-79859From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative promoter usage. [Align] [Select]
Isoform 1 (identifier: P51449-1)

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: P51449-2)

Also known as: RORgT;

The sequence of this isoform differs from the canonical sequence as follows:
     1-21: Missing.
     22-24: HTS → MRT

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 518518Nuclear receptor ROR-gamma
PRO_0000053517

Regions

DNA binding31 – 9666Nuclear receptor
Zinc finger31 – 5121NR C4-type
Zinc finger67 – 9125NR C4-type
Region1 – 3030Modulating Potential
Region97 – 268172Hinge Potential
Region269 – 518250Ligand-binding
Motif501 – 5066AF-2
Compositional bias121 – 13010Poly-Gln

Natural variations

Alternative sequence1 – 2121Missing in isoform 2.
VSP_010632
Alternative sequence22 – 243HTS → MRT in isoform 2.
VSP_010633

Experimental info

Mutagenesis3271A → F: Completely abolishes transcriptional activity. Ref.12
Mutagenesis3781F → Q: Completely abolishes transcriptional activity. Ref.12
Mutagenesis3971I → N: Nearly abolishes transcriptional activity. Ref.12

Secondary structure

..................................... 518
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified June 21, 2004. Version 2.
Checksum: 7F423140BD7922BE

FASTA51858,195
        10         20         30         40         50         60 
MDRAPQRQHR ASRELLAAKK THTSQIEVIP CKICGDKSSG IHYGVITCEG CKGFFRRSQR 

        70         80         90        100        110        120 
CNAAYSCTRQ QNCPIDRTSR NRCQHCRLQK CLALGMSRDA VKFGRMSKKQ RDSLHAEVQK 

       130        140        150        160        170        180 
QLQQRQQQQQ EPVVKTPPAG AQGADTLTYT LGLPDGQLPL GSSPDLPEAS ACPPGLLKAS 

       190        200        210        220        230        240 
GSGPSYSNNL AKAGLNGASC HLEYSPERGK AEGRESFYST GSQLTPDRCG LRFEEHRHPG 

       250        260        270        280        290        300 
LGELGQGPDS YGSPSFRSTP EAPYASLTEI EHLVQSVCKS YRETCQLRLE DLLRQRSNIF 

       310        320        330        340        350        360 
SREEVTGYQR KSMWEMWERC AHHLTEAIQY VVEFAKRLSG FMELCQNDQI VLLKAGAMEV 

       370        380        390        400        410        420 
VLVRMCRAYN ADNRTVFFEG KYGGMELFRA LGCSELISSI FDFSHSLSAL HFSEDEIALY 

       430        440        450        460        470        480 
TALVLINAHR PGLQEKRKVE QLQYNLELAF HHHLCKTHRQ SILAKLPPKG KLRSLCSQHV 

       490        500        510 
ERLQIFQHLH PIVVQAAFPP LYKELFSTET ESPVGLSK 

« Hide

Isoform 2 (RORgT) [UniParc].

Checksum: 6D0048673483EA11
Show »

FASTA49755,813

References

« Hide 'large scale' references
[1]"ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle."
Hirose T., Smith R.J., Jetten A.M.
Biochem. Biophys. Res. Commun. 205:1976-1983(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Skeletal muscle.
[2]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Lymph node.
[3]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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 1).
Tissue: Colon and Kidney.
[5]"Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism."
Jetten A.M.
Nucl. Recept. Signal. 7:3-35(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[6]"A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol)."
Wang Y., Kumar N., Crumbley C., Griffin P.R., Burris T.P.
Biochim. Biophys. Acta 1801:917-923(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, INTERACTION WITH NCOA2.
[7]"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, IDENTIFICATION OF LIGANDS.
[8]"Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma."
Meissburger B., Ukropec J., Roeder E., Beaton N., Geiger M., Teupser D., Civan B., Langhans W., Nawroth P.P., Gasperikova D., Rudofsky G., Wolfrum C.
EMBO Mol. Med. 3:637-651(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION BY OBESITY.
[9]"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, IDENTIFICATION OF LIGANDS.
[10]"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.
[11]"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.
[12]"Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma."
Jin L., Martynowski D., Zheng S., Wada T., Xie W., Li Y.
Mol. Endocrinol. 24:923-929(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.74 ANGSTROMS) OF 260-507 IN COMPLEX WITH HYDROXYCHOLESTEROLS, FUNCTION TRANSCRIPTION ACTIVATOR, MUTAGENESIS OF ALA-327; PHE-378 AND ILE-397.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U16997 mRNA. Translation: AAA64751.1. Frameshift.
AL834219 mRNA. Translation: CAD38900.1.
AL589765 Genomic DNA. Translation: CAI17179.1.
BC031554 mRNA. Translation: AAH31554.1.
CCDSCCDS1004.1. [P51449-1]
CCDS30856.1. [P51449-2]
PIRJC2494.
RefSeqNP_001001523.1. NM_001001523.1. [P51449-2]
NP_005051.2. NM_005060.3. [P51449-1]
UniGeneHs.256022.
Hs.607993.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3B0WX-ray2.20A/B265-507[»]
3KYTX-ray2.35A265-507[»]
3L0JX-ray2.40A265-507[»]
3L0LX-ray1.74A/B260-507[»]
4NB6X-ray2.85A/B262-507[»]
4NIEX-ray2.01A/B263-509[»]
ProteinModelPortalP51449.
SMRP51449. Positions 29-507.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112024. 3 interactions.
DIPDIP-60622N.
IntActP51449. 21 interactions.
MINTMINT-4720467.
STRING9606.ENSP00000327025.

Chemistry

ChEMBLCHEMBL1741186.
GuidetoPHARMACOLOGY600.

PTM databases

PhosphoSiteP51449.

Polymorphism databases

DMDM49066040.

Proteomic databases

PaxDbP51449.
PRIDEP51449.

Protocols and materials databases

DNASU6097.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000318247; ENSP00000327025; ENSG00000143365. [P51449-1]
ENST00000356728; ENSP00000349164; ENSG00000143365. [P51449-2]
GeneID6097.
KEGGhsa:6097.
UCSCuc001ezh.3. human. [P51449-1]

Organism-specific databases

CTD6097.
GeneCardsGC01M151778.
HGNCHGNC:10260. RORC.
MIM602943. gene.
neXtProtNX_P51449.
PharmGKBPA34632.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG317095.
HOVERGENHBG106848.
KOK08534.
PhylomeDBP51449.
TreeFamTF319910.

Enzyme and pathway databases

ReactomeREACT_71. Gene Expression.

Gene expression databases

ArrayExpressP51449.
BgeeP51449.
CleanExHS_RORC.
GenevestigatorP51449.

Family and domain databases

Gene3D1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProIPR008946. Nucl_hormone_rcpt_ligand-bd.
IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
IPR003079. ROR_rcpt.
IPR001723. Str_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSPR01293. RORNUCRECPTR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMSSF48508. SSF48508. 1 hit.
PROSITEPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP51449.
GeneWikiRAR-related_orphan_receptor_gamma.
GenomeRNAi6097.
NextBio23717.
PROP51449.
SOURCESearch...

Entry information

Entry nameRORG_HUMAN
AccessionPrimary (citable) accession number: P51449
Secondary accession number(s): Q5SZR9, Q8N5V7, Q8NCY8
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: June 21, 2004
Last modified: July 9, 2014
This is version 133 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM