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Q60674 (NR1D2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Nuclear receptor subfamily 1 group D member 2
Alternative name(s):
Orphan nuclear receptor RVR
Rev-erb-beta
Gene names
Name:Nr1d2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length576 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARNTL/BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8

Enzyme regulation

The heme-bound form can bind gaseous signaling molecules such as CO and nitric oxide (NO) and NO can reverse its transcriptional repressor activity By similarity.

Subunit structure

Binds DNA as a monomer or a homodimer. Interacts with NCOA5 coactivator, leading to a strong increase of transcription of target genes. Interacts (via N-terminus) with KAT5. Interacts (via C-terminus) with HDAC1. Interacts with ZNHIT1 By similarity.

Subcellular location

Nucleus By similarity.

Tissue specificity

Ubiquitious. Expressed abundantly in skeletal muscle and brown adipose tissue. Expressed during skeletal muscle myogenesis. Ref.3 Ref.4

Induction

Activated by the CLOCK-ARNTL/BMLA1 heterodimer and DBP and repressed by CRY1. Ref.7

Domain

Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.

Post-translational modification

Deacetylated by HDAC1. Acetylation and deacetylation regulate its transcriptional regulatory activity By similarity.

Under more reducing intracellular redox conditions, Cys-381 is in its heme-bound state, which is optimal for recruitment of the NCOR1/HDAC3 corepressor complex and repression of target genes. When subjected to oxidative stress conditions, Cys-381 undergoes oxidation to form a disulfide bridge with Cys-371, also triggering a ligand switch that results in release of bound heme and derepression of target genes By similarity.

Sequence similarities

Belongs to the nuclear hormone receptor family. NR1 subfamily.

Contains 1 nuclear receptor DNA-binding domain.

Ontologies

Keywords
   Biological processBiological rhythms
Transcription
Transcription regulation
   Cellular componentNucleus
   DomainZinc-finger
   LigandDNA-binding
Heme
Iron
Metal-binding
Zinc
   Molecular functionActivator
Receptor
Repressor
   PTMAcetylation
Disulfide bond
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processlipid homeostasis

Inferred from mutant phenotype Ref.3. Source: UniProtKB

negative regulation of transcription, DNA-templated

Inferred from direct assay Ref.7. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from mutant phenotype Ref.5. Source: UniProtKB

regulation of circadian rhythm

Inferred from direct assay Ref.7. Source: UniProtKB

regulation of energy homeostasis

Inferred from mutant phenotype Ref.3. Source: UniProtKB

regulation of inflammatory response

Inferred from mutant phenotype Ref.3. Source: UniProtKB

regulation of lipid metabolic process

Inferred from mutant phenotype Ref.3. Source: UniProtKB

regulation of skeletal muscle cell differentiation

Inferred from mutant phenotype Ref.3. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from direct assay Ref.2. Source: MGI

rhythmic process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentnucleus

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from direct assay Ref.1Ref.2. Source: MGI

core promoter sequence-specific DNA binding

Inferred from direct assay Ref.5Ref.7. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 11113208. Source: IntAct

sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.1Ref.2. Source: MGI

steroid hormone receptor activity

Inferred from electronic annotation. Source: InterPro

thyroid 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

NCOA5Q9HCD52EBI-5326205,EBI-2863498From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 576576Nuclear receptor subfamily 1 group D member 2
PRO_0000053502

Regions

DNA binding100 – 17677Nuclear receptor
Zinc finger103 – 12321NR C4-type
Zinc finger140 – 16425NR C4-type
Region1 – 9999Modulating
Region124 – 246123Hinge
Region247 – 567321Ligand-binding
Region394 – 576183Interaction with ZNHIT1 By similarity
Compositional bias13 – 208Poly-Ser
Compositional bias35 – 395Poly-Ser

Sites

Binding site3811Heme By similarity
Binding site5651Heme By similarity

Amino acid modifications

Modified residue461Phosphoserine; by GSK3-beta By similarity
Modified residue1621N6-acetyllysine; by KAT5 By similarity
Modified residue1631N6-acetyllysine; by KAT5 By similarity
Disulfide bond334 ↔ 340 By similarity
Disulfide bond371 ↔ 381 By similarity

Secondary structure

................................ 576
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q60674 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 6620629052D2CD42

FASTA57664,302
        10         20         30         40         50         60 
MELNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNCD ANGNPKNADI 

        70         80         90        100        110        120 
SSIDGVLKSD RTDCPVKTGK TSAPGMTKSH SGMTKFSGMV LLCKVCGDVA SGFHYGVHAC 

       130        140        150        160        170        180 
EGCKGFFRRS IQQNIQYKKC LKNENCSIMR MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP 

       190        200        210        220        230        240 
KREKQRMLIE MQSAMKTMMN TQFSGHLQND TLAEQHDQSA LPAQEQLRPK SQLEQENIKN 

       250        260        270        280        290        300 
TPSDFAKEEV IGMVTRAHKD TFLYNQEHRE NSSESMPPQR GERIPRNMEQ YNLNQDHRGS 

       310        320        330        340        350        360 
GIHNHFPCSE RQQHLSGQYK GRNIMHYPNG HAVCIANGHC MNFSSAYTQR VCDRIPVGGC 

       370        380        390        400        410        420 
SQTENRNSYL CNTGGRMHLV CPMSKSPYVD PQKSGHEIWE EFSMSFTPAV KEVVEFAKRI 

       430        440        450        460        470        480 
PGFRDLSQHD QVNLLKAGTF EVLMVRFASL FDAKERTVTF LSGKKYSVDD LHSMGAGDLL 

       490        500        510        520        530        540 
SSMFEFSEKL NALQLSDEEM SLFTAVVLVS ADRSGIENVN SVEALQETLI RALRTLIMKN 

       550        560        570 
HPNEASIFTK LLLKLPDLRS LNNMHSEELL AFKVHP 

« Hide

References

[1]"Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator."
Retnakaran R., Flock G., Giguere V.
Mol. Endocrinol. 8:1234-1244(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: BALB/c.
Tissue: Brain.
[2]"Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors."
Forman B.M., Chen J., Blumberg B., Kliewer S.A., Henshaw R., Ong E., Evans R.M.
Mol. Endocrinol. 8:1253-1261(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 35-576.
Strain: C57BL/6 X CBA.
Tissue: Liver.
[3]"Rev-erbbeta regulates the expression of genes involved in lipid absorption in skeletal muscle cells: evidence for cross-talk between orphan nuclear receptors and myokines."
Ramakrishnan S.N., Lau P., Burke L.J., Muscat G.E.
J. Biol. Chem. 280:8651-8659(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[4]"Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms."
Liu A.C., Tran H.G., Zhang E.E., Priest A.A., Welsh D.K., Kay S.A.
PLoS Genet. 4:E1000023-E1000023(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[5]"Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells."
Ramakrishnan S.N., Lau P., Crowther L.M., Cleasby M.E., Millard S., Leong G.M., Cooney G.J., Muscat G.E.
Biochem. Biophys. Res. Commun. 388:654-659(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Rev-erbalpha and Rev-erbbeta coordinately protect the circadian clock and normal metabolic function."
Bugge A., Feng D., Everett L.J., Briggs E.R., Mullican S.E., Wang F., Jager J., Lazar M.A.
Genes Dev. 26:657-667(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"Real-time analysis of the circadian oscillation of the Rev-Erb beta promoter."
Yang F., Inoue I., Kumagai M., Takahashi S., Nakajima Y., Ikeda M.
J. Atheroscler. Thromb. 20:267-276(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
[8]"Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription."
Lam M.T., Cho H., Lesch H.P., Gosselin D., Heinz S., Tanaka-Oishi Y., Benner C., Kaikkonen M.U., Kim A.S., Kosaka M., Lee C.Y., Watt A., Grossman T.R., Rosenfeld M.G., Evans R.M., Glass C.K.
Nature 498:511-515(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U12142 mRNA. Translation: AAA79513.1.
U09504 mRNA. Translation: AAC52144.1.
CCDSCCDS36811.1.
PIRA57048.
RefSeqNP_035714.3. NM_011584.4.
UniGeneMm.26587.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1EFJmodel-A243-263[»]
B393-576[»]
ProteinModelPortalQ60674.
SMRQ60674. Positions 98-574.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid237266. 1 interaction.
IntActQ60674. 1 interaction.
STRING10090.ENSMUSP00000088031.

PTM databases

PhosphoSiteQ60674.

Proteomic databases

PRIDEQ60674.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000090543; ENSMUSP00000088031; ENSMUSG00000021775.
GeneID353187.
KEGGmmu:353187.
UCSCuc007shp.2. mouse.

Organism-specific databases

CTD9975.
MGIMGI:2449205. Nr1d2.

Phylogenomic databases

eggNOGNOG324222.
GeneTreeENSGT00740000114909.
HOGENOMHOG000261691.
HOVERGENHBG106790.
InParanoidQ60674.
KOK08531.
OMAPGMTKSH.
OrthoDBEOG776SQ0.
PhylomeDBQ60674.
TreeFamTF328382.

Gene expression databases

ArrayExpressQ60674.
BgeeQ60674.
CleanExMM_NR1D2.
GenevestigatorQ60674.

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.
IPR001723. Str_hrmn_rcpt.
IPR001728. ThyrH_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
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

NextBio400331.
PROQ60674.
SOURCESearch...

Entry information

Entry nameNR1D2_MOUSE
AccessionPrimary (citable) accession number: Q60674
Secondary accession number(s): Q60646
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 1, 1996
Last modified: July 9, 2014
This is version 130 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot