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Q60674

- NR1D2_MOUSE

UniProt

Q60674 - NR1D2_MOUSE

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Protein

Nuclear receptor subfamily 1 group D member 2

Gene

Nr1d2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.6 Publications

Enzyme regulationi

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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei381 – 3811HemeBy similarity
Binding sitei565 – 5651HemeBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi100 – 17677Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri103 – 12321NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri140 – 16425NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  1. core promoter sequence-specific DNA binding Source: UniProtKB
  2. DNA binding Source: MGI
  3. sequence-specific DNA binding transcription factor activity Source: MGI
  4. steroid hormone receptor activity Source: InterPro
  5. thyroid hormone receptor activity Source: InterPro
  6. zinc ion binding Source: InterPro

GO - Biological processi

  1. lipid homeostasis Source: UniProtKB
  2. negative regulation of transcription, DNA-templated Source: UniProtKB
  3. positive regulation of transcription, DNA-templated Source: UniProtKB
  4. regulation of circadian rhythm Source: UniProtKB
  5. regulation of energy homeostasis Source: UniProtKB
  6. regulation of inflammatory response Source: UniProtKB
  7. regulation of lipid metabolic process Source: UniProtKB
  8. regulation of skeletal muscle cell differentiation Source: UniProtKB
  9. regulation of transcription, DNA-templated Source: MGI
  10. rhythmic process Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator, Receptor, Repressor

Keywords - Biological processi

Biological rhythms, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Heme, Iron, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_234105. Nuclear Receptor transcription pathway.

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear receptor subfamily 1 group D member 2
Alternative name(s):
Orphan nuclear receptor RVR
Rev-erb-beta
Gene namesi
Name:Nr1d2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 14

Organism-specific databases

MGIiMGI:2449205. Nr1d2.

Subcellular locationi

Nucleus PROSITE-ProRule annotation

GO - Cellular componenti

  1. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 576576Nuclear receptor subfamily 1 group D member 2PRO_0000053502Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei46 – 461Phosphoserine; by GSK3-betaBy similarity
Modified residuei162 – 1621N6-acetyllysine; by KAT5By similarity
Modified residuei163 – 1631N6-acetyllysine; by KAT5By similarity
Disulfide bondi334 ↔ 340By similarity
Disulfide bondi371 ↔ 381By similarity

Post-translational modificationi

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

Keywords - PTMi

Acetylation, Disulfide bond, Phosphoprotein

Proteomic databases

PRIDEiQ60674.

PTM databases

PhosphoSiteiQ60674.

Expressioni

Tissue specificityi

Ubiquitious. Expressed abundantly in skeletal muscle and brown adipose tissue. Expressed during skeletal muscle myogenesis.2 Publications

Inductioni

Activated by the CLOCK-ARNTL/BMLA1 heterodimer and DBP and repressed by CRY1.1 Publication

Gene expression databases

BgeeiQ60674.
CleanExiMM_NR1D2.
ExpressionAtlasiQ60674. baseline and differential.
GenevestigatoriQ60674.

Interactioni

Subunit structurei

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).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
NCOA5Q9HCD52EBI-5326205,EBI-2863498From a different organism.

Protein-protein interaction databases

BioGridi237266. 1 interaction.
IntActiQ60674. 1 interaction.
STRINGi10090.ENSMUSP00000088031.

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1EFJmodel-A243-263[»]
B393-576[»]
ProteinModelPortaliQ60674.
SMRiQ60674. Positions 98-181, 370-573.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 9999ModulatingAdd
BLAST
Regioni124 – 246123HingeAdd
BLAST
Regioni247 – 567321Ligand-bindingAdd
BLAST
Regioni394 – 576183Interaction with ZNHIT1By similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi13 – 208Poly-Ser
Compositional biasi35 – 395Poly-Ser

Domaini

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

Sequence similaritiesi

Contains 1 nuclear receptor DNA-binding domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri103 – 12321NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri140 – 16425NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiNOG324222.
GeneTreeiENSGT00760000119049.
HOGENOMiHOG000261691.
HOVERGENiHBG106790.
InParanoidiQ60674.
KOiK08531.
OMAiPGMTKSH.
OrthoDBiEOG776SQ0.
PhylomeDBiQ60674.
TreeFamiTF328382.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR008946. 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]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q60674-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MELNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNCD
60 70 80 90 100
ANGNPKNADI SSIDGVLKSD RTDCPVKTGK TSAPGMTKSH SGMTKFSGMV
110 120 130 140 150
LLCKVCGDVA SGFHYGVHAC EGCKGFFRRS IQQNIQYKKC LKNENCSIMR
160 170 180 190 200
MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP KREKQRMLIE MQSAMKTMMN
210 220 230 240 250
TQFSGHLQND TLAEQHDQSA LPAQEQLRPK SQLEQENIKN TPSDFAKEEV
260 270 280 290 300
IGMVTRAHKD TFLYNQEHRE NSSESMPPQR GERIPRNMEQ YNLNQDHRGS
310 320 330 340 350
GIHNHFPCSE RQQHLSGQYK GRNIMHYPNG HAVCIANGHC MNFSSAYTQR
360 370 380 390 400
VCDRIPVGGC SQTENRNSYL CNTGGRMHLV CPMSKSPYVD PQKSGHEIWE
410 420 430 440 450
EFSMSFTPAV KEVVEFAKRI PGFRDLSQHD QVNLLKAGTF EVLMVRFASL
460 470 480 490 500
FDAKERTVTF LSGKKYSVDD LHSMGAGDLL SSMFEFSEKL NALQLSDEEM
510 520 530 540 550
SLFTAVVLVS ADRSGIENVN SVEALQETLI RALRTLIMKN HPNEASIFTK
560 570
LLLKLPDLRS LNNMHSEELL AFKVHP
Length:576
Mass (Da):64,302
Last modified:November 1, 1996 - v1
Checksum:i6620629052D2CD42
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U12142 mRNA. Translation: AAA79513.1.
U09504 mRNA. Translation: AAC52144.1.
CCDSiCCDS36811.1.
PIRiA57048.
RefSeqiNP_035714.3. NM_011584.4.
UniGeneiMm.26587.

Genome annotation databases

EnsembliENSMUST00000090543; ENSMUSP00000088031; ENSMUSG00000021775.
GeneIDi353187.
KEGGimmu:353187.
UCSCiuc007shp.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U12142 mRNA. Translation: AAA79513.1 .
U09504 mRNA. Translation: AAC52144.1 .
CCDSi CCDS36811.1.
PIRi A57048.
RefSeqi NP_035714.3. NM_011584.4.
UniGenei Mm.26587.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1EFJ model - A 243-263 [» ]
B 393-576 [» ]
ProteinModelPortali Q60674.
SMRi Q60674. Positions 98-181, 370-573.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 237266. 1 interaction.
IntActi Q60674. 1 interaction.
STRINGi 10090.ENSMUSP00000088031.

PTM databases

PhosphoSitei Q60674.

Proteomic databases

PRIDEi Q60674.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000090543 ; ENSMUSP00000088031 ; ENSMUSG00000021775 .
GeneIDi 353187.
KEGGi mmu:353187.
UCSCi uc007shp.2. mouse.

Organism-specific databases

CTDi 9975.
MGIi MGI:2449205. Nr1d2.

Phylogenomic databases

eggNOGi NOG324222.
GeneTreei ENSGT00760000119049.
HOGENOMi HOG000261691.
HOVERGENi HBG106790.
InParanoidi Q60674.
KOi K08531.
OMAi PGMTKSH.
OrthoDBi EOG776SQ0.
PhylomeDBi Q60674.
TreeFami TF328382.

Enzyme and pathway databases

Reactomei REACT_234105. Nuclear Receptor transcription pathway.

Miscellaneous databases

NextBioi 400331.
PROi Q60674.
SOURCEi Search...

Gene expression databases

Bgeei Q60674.
CleanExi MM_NR1D2.
ExpressionAtlasi Q60674. baseline and differential.
Genevestigatori Q60674.

Family and domain databases

Gene3Di 1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProi IPR008946. 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 ]
Pfami PF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view ]
PRINTSi PR00398. STRDHORMONER.
PR00047. STROIDFINGER.
PR00546. THYROIDHORMR.
SMARTi SM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view ]
SUPFAMi SSF48508. SSF48508. 1 hit.
PROSITEi PS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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. Cited for: FUNCTION.

Entry informationi

Entry nameiNR1D2_MOUSE
AccessioniPrimary (citable) accession number: Q60674
Secondary accession number(s): Q60646
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 1, 1996
Last modified: November 26, 2014
This is version 133 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3