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UniProtKB - P51449 (RORG_HUMAN)

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Protein

Nuclear receptor ROR-gamma

Gene

RORC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). 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 (PubMed:19965867, PubMed:22789990). 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 (PubMed:19965867). 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 (PubMed:19965867). Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376).By similarity5 Publications
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.1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi31 – 96Nuclear receptorPROSITE-ProRule annotationAdd BLAST66
Zinc fingeri31 – 51NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri67 – 91NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionActivator, Developmental protein, DNA-binding, Receptor
Biological processBiological rhythms, Transcription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-383280 Nuclear Receptor transcription pathway
R-HSA-6785807 Interleukin-4 and 13 signaling
R-HSA-8949275 RUNX3 Regulates Immune Response and Cell Migration
SIGNORiP51449

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:RORC
Synonyms:NR1F3, RORG, RZRG
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000143365.16
HGNCiHGNC:10260 RORC
MIMi602943 gene
neXtProtiNX_P51449

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Immunodeficiency 42 (IMD42)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive primary immunodeficiency characterized by increased susceptibility to concomitant candidiasis and mycobacteriosis. Candidiasis is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida. Mycobacteriosis is characterized by infections caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. IMD42 patients vaccinated with BCG are particularly at risk for developing disseminated mycobacterial infections.
See also OMIM:616622
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07372538S → L in IMD42; does not affect nuclear localization; loss of transcription regulatory region sequence-specific DNA binding; loss of transcriptional activity. 1 PublicationCorresponds to variant dbSNP:rs774357869EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi327A → F: Completely abolishes transcriptional activity. 1 Publication1
Mutagenesisi378F → Q: Completely abolishes transcriptional activity. 1 Publication1
Mutagenesisi397I → N: Nearly abolishes transcriptional activity. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi6097
MalaCardsiRORC
MIMi616622 phenotype
OpenTargetsiENSG00000143365
PharmGKBiPA34632

Chemistry databases

ChEMBLiCHEMBL1741186
GuidetoPHARMACOLOGYi600

Polymorphism and mutation databases

BioMutaiRORC
DMDMi49066040

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000535171 – 518Nuclear receptor ROR-gammaAdd BLAST518

Proteomic databases

PaxDbiP51449
PeptideAtlasiP51449
PRIDEiP51449
ProteomicsDBi56305
56306 [P51449-2]

PTM databases

iPTMnetiP51449
PhosphoSitePlusiP51449

Expressioni

Tissue specificityi

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.

Inductioni

Up-regulated in the state of obesity.1 Publication

Gene expression databases

BgeeiENSG00000143365
CleanExiHS_RORC
ExpressionAtlasiP51449 baseline and differential
GenevisibleiP51449 HS

Organism-specific databases

HPAiHPA065620

Interactioni

Subunit structurei

Interacts (via AF-2 motif) with the coactivator NCOA2 (via LXXLL motif). Interacts with the corepressor NCOR1. Interacts with CRY1. Interacts (via AF-2 motif) with the coactivators NCOA1 and PPARGC1A (via LXXLL motif) (By similarity). Interacts (via AF-2 motif) with PROX1 (By similarity). Interacts with FOXP3.By similarity4 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi112024, 34 interactors
DIPiDIP-60622N
IntActiP51449, 28 interactors
MINTiP51449
STRINGi9606.ENSP00000327025

Chemistry databases

BindingDBiP51449

Structurei

Secondary structure

1518
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi267 – 282Combined sources16
Beta strandi285 – 287Combined sources3
Helixi289 – 294Combined sources6
Helixi295 – 297Combined sources3
Helixi302 – 310Combined sources9
Helixi313 – 337Combined sources25
Helixi341 – 343Combined sources3
Helixi346 – 364Combined sources19
Helixi365 – 368Combined sources4
Turni371 – 374Combined sources4
Beta strandi375 – 378Combined sources4
Beta strandi381 – 383Combined sources3
Helixi385 – 391Combined sources7
Helixi394 – 408Combined sources15
Turni409 – 411Combined sources3
Helixi414 – 425Combined sources12
Beta strandi430 – 432Combined sources3
Helixi436 – 456Combined sources21
Helixi460 – 465Combined sources6
Helixi469 – 489Combined sources21
Helixi491 – 497Combined sources7
Helixi500 – 506Combined sources7

3D structure databases

ProteinModelPortaliP51449
SMRiP51449
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP51449

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini269 – 508NR LBDPROSITE-ProRule annotationAdd BLAST240

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 30ModulatingSequence analysisAdd BLAST30
Regioni97 – 268HingeSequence analysisAdd BLAST172

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi501 – 506AF-26

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi121 – 130Poly-Gln10

Domaini

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

Sequence similaritiesi

Belongs to the nuclear hormone receptor family. NR1 subfamily.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri31 – 51NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri67 – 91NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4216 Eukaryota
ENOG410XUGR LUCA
GeneTreeiENSGT00870000136388
HOVERGENiHBG106848
InParanoidiP51449
KOiK08534
OMAiCRAYNAD
OrthoDBiEOG091G0649
PhylomeDBiP51449
TreeFamiTF319910

Family and domain databases

Gene3Di3.30.50.10, 1 hit
InterProiView protein in InterPro
IPR035500 NHR_like_dom_sf
IPR000536 Nucl_hrmn_rcpt_lig-bd
IPR001723 Nuclear_hrmn_rcpt
IPR003079 ROR_rcpt
IPR001628 Znf_hrmn_rcpt
IPR013088 Znf_NHR/GATA
PfamiView protein in Pfam
PF00104 Hormone_recep, 1 hit
PF00105 zf-C4, 1 hit
PRINTSiPR01293 RORNUCRECPTR
PR00398 STRDHORMONER
PR00047 STROIDFINGER
SMARTiView protein in SMART
SM00430 HOLI, 1 hit
SM00399 ZnF_C4, 1 hit
SUPFAMiSSF48508 SSF48508, 1 hit
PROSITEiView protein in PROSITE
PS51843 NR_LBD, 1 hit
PS00031 NUCLEAR_REC_DBD_1, 1 hit
PS51030 NUCLEAR_REC_DBD_2, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative promoter usage. AlignAdd to basket

Isoform 1 (identifier: P51449-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MDRAPQRQHR ASRELLAAKK THTSQIEVIP CKICGDKSSG IHYGVITCEG 
        60         70         80         90        100
CKGFFRRSQR CNAAYSCTRQ QNCPIDRTSR NRCQHCRLQK CLALGMSRDA 
       110        120        130        140        150
VKFGRMSKKQ RDSLHAEVQK QLQQRQQQQQ EPVVKTPPAG AQGADTLTYT 
       160        170        180        190        200
LGLPDGQLPL GSSPDLPEAS ACPPGLLKAS GSGPSYSNNL AKAGLNGASC 
       210        220        230        240        250
HLEYSPERGK AEGRESFYST GSQLTPDRCG LRFEEHRHPG LGELGQGPDS 
       260        270        280        290        300
YGSPSFRSTP EAPYASLTEI EHLVQSVCKS YRETCQLRLE DLLRQRSNIF 
       310        320        330        340        350
SREEVTGYQR KSMWEMWERC AHHLTEAIQY VVEFAKRLSG FMELCQNDQI 
       360        370        380        390        400
VLLKAGAMEV VLVRMCRAYN ADNRTVFFEG KYGGMELFRA LGCSELISSI 
       410        420        430        440        450
FDFSHSLSAL HFSEDEIALY TALVLINAHR PGLQEKRKVE QLQYNLELAF 
       460        470        480        490        500
HHHLCKTHRQ SILAKLPPKG KLRSLCSQHV ERLQIFQHLH PIVVQAAFPP 
       510 
LYKELFSTET ESPVGLSK
Length:518
Mass (Da):58,195
Last modified:June 21, 2004 - v2
Checksum:i7F423140BD7922BE
GO
Isoform 2 (identifier: P51449-2) [UniParc]FASTAAdd to basket
Also known as: RORgT

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

Show »
Length:497
Mass (Da):55,813
Checksum:i6D0048673483EA11
GO

Sequence cautioni

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

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07372538S → L in IMD42; does not affect nuclear localization; loss of transcription regulatory region sequence-specific DNA binding; loss of transcriptional activity. 1 PublicationCorresponds to variant dbSNP:rs774357869EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0106321 – 21Missing in isoform 2. 1 PublicationAdd BLAST21
Alternative sequenceiVSP_01063322 – 24HTS → MRT in isoform 2. 1 Publication3

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U16997 mRNA Translation: AAA64751.1 Frameshift.
AL834219 mRNA Translation: CAD38900.1
AL589765 Genomic DNA No translation available.
BC031554 mRNA Translation: AAH31554.1
CCDSiCCDS1004.1 [P51449-1]
CCDS30856.1 [P51449-2]
PIRiJC2494
RefSeqiNP_001001523.1, NM_001001523.1 [P51449-2]
NP_005051.2, NM_005060.3 [P51449-1]
UniGeneiHs.256022
Hs.607993

Genome annotation databases

EnsembliENST00000318247; ENSP00000327025; ENSG00000143365 [P51449-1]
ENST00000356728; ENSP00000349164; ENSG00000143365 [P51449-2]
GeneIDi6097
KEGGihsa:6097
UCSCiuc001ezg.4 human [P51449-1]

Keywords - Coding sequence diversityi

Alternative promoter usage

Similar proteinsi

Entry informationi

Entry nameiRORG_HUMAN
AccessioniPrimary (citable) accession number: P51449
Secondary accession number(s): Q5SZR9, Q8N5V7, Q8NCY8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: June 21, 2004
Last modified: July 18, 2018
This is version 178 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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