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UniProtKB - Q3UV55 (NR1D1_MOUSE)

Protein

Nuclear receptor subfamily 1 group D member 1

Gene

Nr1d1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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 ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage 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 nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner.18 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei419HemeBy similarity1
Binding sitei603HemeBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi130 – 206Nuclear receptorPROSITE-ProRule annotationAdd BLAST77
Zinc fingeri133 – 153NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri170 – 194NR 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, DNA-binding, Receptor, Repressor
Biological processBiological rhythms, Differentiation, Transcription, Transcription regulation
LigandHeme, Iron, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-383280 Nuclear Receptor transcription pathway

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear receptor subfamily 1 group D member 1
Alternative name(s):
Rev-erbA-alpha
V-erbA-related protein 1
Short name:
EAR-1
Gene namesi
Name:Nr1d1
Synonyms:Ear1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:2444210 Nr1d1

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

Cell projection, Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice display increased cold tolerance, higher oxygen consumption rates, enhanced brown adipose tissue metabolic capacity, maintenance of higher body temperature throughout the light phase and increased glucose uptake only during the day. They also show retinal abnormalities such as pan-retinal spotting and decreased response to light and decreased bile acid accumulation. Double knockout for NR1D1 and PER2 show a significantly shorter period length compared with wild type or single knockouts for both genes. 50% of double knockouts animals show a stable circadian throughout at least 5 weeks in constant darckness. The other 50% of animals lose their circadian rhythmicity when held in constant darkness for an average of 21 days. Animals have blunted steady-state levels of glycogen in the liver in spite of normal patterns of food consumption.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi456K → A: Reduces interaction with PER2 by 60%. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003111821 – 615Nuclear receptor subfamily 1 group D member 1Add BLAST615

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei55Phosphoserine; by GSK3-betaBy similarity1
Modified residuei59Phosphoserine; by GSK3-betaBy similarity1
Modified residuei192N6-acetyllysine; by KAT5By similarity1
Modified residuei193N6-acetyllysine; by KAT5By similarity1
Modified residuei592N6-acetyllysineBy similarity1

Post-translational modificationi

Ubiquitinated, leading to its proteasomal degradation.

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ3UV55
PaxDbiQ3UV55
PeptideAtlasiQ3UV55
PRIDEiQ3UV55

PTM databases

iPTMnetiQ3UV55
PhosphoSitePlusiQ3UV55

Expressioni

Tissue specificityi

Expressed during adipocyte differentiation (at protein level). Expressed in skeletal muscle, bladder, lumbar spinal cord, pancreatic islets and hypothalamus. Expressed in developing and adult retina. In the adult retina, predominantly expressed in the outer nuclear layer, where rod and cone cells reside, and also localized to the ganglion cell layer.7 Publications

Developmental stagei

During development at embryonic day E18.5, expressed in the outer neuroblastic layer of the retina where developing postmitotic photoreceptors and retinal progenitors reside (at protein level).1 Publication

Inductioni

Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. In bladder smooth muscle cells, pancreas and lumbar spinal cord, exhibits night/day variations with a peak time at circadian time (CT) 4-12 and a trough at CT16-24.4 Publications

Gene expression databases

BgeeiENSMUSG00000020889 Expressed in 163 organ(s), highest expression level in cerebellum
CleanExiMM_NR1D1
GenevisibleiQ3UV55 MM

Interactioni

Subunit structurei

Binds DNA as a monomer or a homodimer. Interacts with NR2E3 and ZNHIT1. Interacts with C1D and SP1. Interacts with OPHN1 (via C-terminus). Interacts with PER2; the interaction associates PER2 to ARNTL promoter region. Interacts with CRY1. Interacts with CCAR2.6 Publications

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi229856, 2 interactors
DIPiDIP-59440N
IntActiQ3UV55, 1 interactor
STRINGi10090.ENSMUSP00000069505

Structurei

3D structure databases

ProteinModelPortaliQ3UV55
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini285 – 615NR LBDPROSITE-ProRule annotationAdd BLAST331

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 129ModulatingAdd BLAST129
Regioni49 – 285Crucial for activation of GJA1Add BLAST237
Regioni207 – 284HingeAdd BLAST78

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi79 – 94Poly-SerAdd BLAST16

Domaini

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

Sequence similaritiesi

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

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri133 – 153NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri170 – 194NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410IMDK Eukaryota
ENOG410ZPPI LUCA
GeneTreeiENSGT00870000136388
HOGENOMiHOG000261691
HOVERGENiHBG106790
InParanoidiQ3UV55
KOiK03728
OMAiSCHQPNS
OrthoDBiEOG091G066Y
PhylomeDBiQ3UV55
TreeFamiTF328382

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
IPR001628 Znf_hrmn_rcpt
IPR013088 Znf_NHR/GATA
PfamiView protein in Pfam
PF00104 Hormone_recep, 1 hit
PF00105 zf-C4, 1 hit
PRINTSiPR00398 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

Sequencei

Sequence statusi: Complete.

Q3UV55-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MTTLDSNNNT GGVITYIGSS GSSPSRTSPE SLYSDSSNGS FQSLTQGCPT 
        60         70         80         90        100
YFPPSPTGSL TQDPARSFGS APPSLSDDSS PSSASSSSSS SSSSFYNGSP 
       110        120        130        140        150
PGSLQVAMED SSRVSPSKGT SNITKLNGMV LLCKVCGDVA SGFHYGVHAC 
       160        170        180        190        200
EGCKGFFRRS IQQNIQYKRC LKNENCSIVR INRNRCQQCR FKKCLSVGMS 
       210        220        230        240        250
RDAVRFGRIP KREKQRMLAE MQSAMNLANN QLSSLCPLET SPTPHPTSGS 
       260        270        280        290        300
MGPSPPPAPA PTPLVGFSQF PQQLTPPRSP SPEPTMEDVI SQVARAHREI 
       310        320        330        340        350
FTYAHDKLGT SPGNFNANHA SGSPSATTPH RWESQGCPSA PNDNNLLAAQ 
       360        370        380        390        400
RHNEALNGLR QGPSSYPPTW PSGPTHHSCH QPNSNGHRLC PTHVYSAPEG 
       410        420        430        440        450
EAPANSLRQG NTKNVLLACP MNMYPHGRSG RTVQEIWEDF SMSFTPAVRE 
       460        470        480        490        500
VVEFAKHIPG FRDLSQHDQV TLLKAGTFEV LMVRFASLFN VKDQTVMFLS 
       510        520        530        540        550
RTTYSLQELG AMGMGDLLNA MFDFSEKLNS LALTEEELGL FTAVVLVSAD 
       560        570        580        590        600
RSGMENSASV EQLQETLLRA LRALVLKNRP SETSRFTKLL LKLPDLRTLN 
       610 
NMHSEKLLSF RVDAQ
Length:615
Mass (Da):66,802
Last modified:October 11, 2005 - v1
Checksum:iFFEC491B616BB326
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti36S → R in CAA59997 (Ref. 5) Curated1
Sequence conflicti40S → R in CAA59997 (Ref. 5) Curated1
Sequence conflicti84A → T in BAE27164 (PubMed:16141072).Curated1
Sequence conflicti84A → T in AAH08989 (PubMed:15489334).Curated1
Sequence conflicti440F → L in BAE27164 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK137398 mRNA Translation: BAE23342.1
AK137582 mRNA Translation: BAE23418.1
AK146430 mRNA Translation: BAE27164.1
AK154931 mRNA Translation: BAE32932.1
AK155597 mRNA Translation: BAE33339.1
AL590963 Genomic DNA Translation: CAM46187.1
BC008989 mRNA Translation: AAH08989.1
AF291821 mRNA Translation: AAG01345.1
X86010 mRNA Translation: CAA59997.1
AY336125 Genomic DNA Translation: AAS48348.1
CCDSiCCDS25363.1
PIRiS52813
RefSeqiNP_663409.2, NM_145434.4
UniGeneiMm.390397

Genome annotation databases

EnsembliENSMUST00000064941; ENSMUSP00000069505; ENSMUSG00000020889
GeneIDi217166
KEGGimmu:217166
UCSCiuc007lhh.2 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK137398 mRNA Translation: BAE23342.1
AK137582 mRNA Translation: BAE23418.1
AK146430 mRNA Translation: BAE27164.1
AK154931 mRNA Translation: BAE32932.1
AK155597 mRNA Translation: BAE33339.1
AL590963 Genomic DNA Translation: CAM46187.1
BC008989 mRNA Translation: AAH08989.1
AF291821 mRNA Translation: AAG01345.1
X86010 mRNA Translation: CAA59997.1
AY336125 Genomic DNA Translation: AAS48348.1
CCDSiCCDS25363.1
PIRiS52813
RefSeqiNP_663409.2, NM_145434.4
UniGeneiMm.390397

3D structure databases

ProteinModelPortaliQ3UV55
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi229856, 2 interactors
DIPiDIP-59440N
IntActiQ3UV55, 1 interactor
STRINGi10090.ENSMUSP00000069505

PTM databases

iPTMnetiQ3UV55
PhosphoSitePlusiQ3UV55

Proteomic databases

MaxQBiQ3UV55
PaxDbiQ3UV55
PeptideAtlasiQ3UV55
PRIDEiQ3UV55

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000064941; ENSMUSP00000069505; ENSMUSG00000020889
GeneIDi217166
KEGGimmu:217166
UCSCiuc007lhh.2 mouse

Organism-specific databases

CTDi9572
MGIiMGI:2444210 Nr1d1

Phylogenomic databases

eggNOGiENOG410IMDK Eukaryota
ENOG410ZPPI LUCA
GeneTreeiENSGT00870000136388
HOGENOMiHOG000261691
HOVERGENiHBG106790
InParanoidiQ3UV55
KOiK03728
OMAiSCHQPNS
OrthoDBiEOG091G066Y
PhylomeDBiQ3UV55
TreeFamiTF328382

Enzyme and pathway databases

ReactomeiR-MMU-383280 Nuclear Receptor transcription pathway

Miscellaneous databases

PROiPR:Q3UV55
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000020889 Expressed in 163 organ(s), highest expression level in cerebellum
CleanExiMM_NR1D1
GenevisibleiQ3UV55 MM

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
IPR001628 Znf_hrmn_rcpt
IPR013088 Znf_NHR/GATA
PfamiView protein in Pfam
PF00104 Hormone_recep, 1 hit
PF00105 zf-C4, 1 hit
PRINTSiPR00398 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
ProtoNetiSearch...

Entry informationi

Entry nameiNR1D1_MOUSE
AccessioniPrimary (citable) accession number: Q3UV55
Secondary accession number(s): Q3UJJ1
, Q62171, Q6EEZ6, Q922A5, Q9ESY4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 13, 2007
Last sequence update: October 11, 2005
Last modified: November 7, 2018
This is version 131 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

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