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Q60674

- NR1D2_MOUSE

UniProt

Q60674 - NR1D2_MOUSE

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
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    • History
      Entry version 131 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    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. protein binding Source: IntAct
    4. sequence-specific DNA binding transcription factor activity Source: MGI
    5. steroid hormone receptor activity Source: InterPro
    6. thyroid hormone receptor activity Source: InterPro
    7. 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

    Keywords - Molecular functioni

    Activator, Receptor, Repressor

    Keywords - Biological processi

    Biological rhythms, Transcription, Transcription regulation

    Keywords - Ligandi

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

    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

    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

    ArrayExpressiQ60674.
    BgeeiQ60674.
    CleanExiMM_NR1D2.
    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

    Secondary structure

    1
    576
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi249 – 2535
    Helixi254 – 2618
    Helixi396 – 41924
    Turni420 – 4223
    Helixi428 – 43811
    Helixi440 – 44910
    Turni453 – 4564
    Beta strandi457 – 4604
    Turni461 – 4633
    Beta strandi464 – 4674
    Helixi468 – 4736
    Helixi477 – 4793
    Helixi480 – 49112
    Helixi497 – 50812
    Helixi512 – 5143
    Beta strandi516 – 5183
    Helixi519 – 54022
    Beta strandi542 – 5443
    Helixi547 – 57125
    Turni572 – 5743

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1EFJmodel-A243-263[»]
    B393-576[»]
    ProteinModelPortaliQ60674.
    SMRiQ60674. Positions 98-574.
    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.
    GeneTreeiENSGT00740000114909.
    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

    MELNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNCD    50
    ANGNPKNADI SSIDGVLKSD RTDCPVKTGK TSAPGMTKSH SGMTKFSGMV 100
    LLCKVCGDVA SGFHYGVHAC EGCKGFFRRS IQQNIQYKKC LKNENCSIMR 150
    MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP KREKQRMLIE MQSAMKTMMN 200
    TQFSGHLQND TLAEQHDQSA LPAQEQLRPK SQLEQENIKN TPSDFAKEEV 250
    IGMVTRAHKD TFLYNQEHRE NSSESMPPQR GERIPRNMEQ YNLNQDHRGS 300
    GIHNHFPCSE RQQHLSGQYK GRNIMHYPNG HAVCIANGHC MNFSSAYTQR 350
    VCDRIPVGGC SQTENRNSYL CNTGGRMHLV CPMSKSPYVD PQKSGHEIWE 400
    EFSMSFTPAV KEVVEFAKRI PGFRDLSQHD QVNLLKAGTF EVLMVRFASL 450
    FDAKERTVTF LSGKKYSVDD LHSMGAGDLL SSMFEFSEKL NALQLSDEEM 500
    SLFTAVVLVS ADRSGIENVN SVEALQETLI RALRTLIMKN HPNEASIFTK 550
    LLLKLPDLRS LNNMHSEELL AFKVHP 576
    Length:576
    Mass (Da):64,302
    Last modified:November 1, 1996 - v1
    Checksum:i6620629052D2CD42
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1EFJ model - A 243-263 [» ]
    B 393-576 [» ]
    ProteinModelPortali Q60674.
    SMRi Q60674. Positions 98-574.
    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 ENSGT00740000114909.
    HOGENOMi HOG000261691.
    HOVERGENi HBG106790.
    InParanoidi Q60674.
    KOi K08531.
    OMAi PGMTKSH.
    OrthoDBi EOG776SQ0.
    PhylomeDBi Q60674.
    TreeFami TF328382.

    Miscellaneous databases

    NextBioi 400331.
    PROi Q60674.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q60674.
    Bgeei Q60674.
    CleanExi MM_NR1D2.
    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: October 1, 2014
    This is version 131 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