UniProtKB - Q3UV55 (NR1D1_MOUSE)
Nuclear receptor subfamily 1 group D member 1
Nr1d1
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 G6PC1 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. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (PubMed:30555544).
Represses the transcription of CES2 (PubMed:29653076).
Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (PubMed:24794873).
Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (PubMed:27686098).
Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (PubMed:29533925).
Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (PubMed:30792350).
Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (PubMed:30096135).
26 PublicationsSites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 419 | HemeBy similarity | 1 | |
Binding sitei | 603 | HemeBy similarity | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
DNA bindingi | 130 – 206 | Nuclear receptorPROSITE-ProRule annotationAdd BLAST | 77 | |
Zinc fingeri | 133 – 153 | NR C4-typePROSITE-ProRule annotationAdd BLAST | 21 | |
Zinc fingeri | 170 – 194 | NR C4-typePROSITE-ProRule annotationAdd BLAST | 25 |
GO - Molecular functioni
- DNA binding Source: MGI
- DNA-binding transcription factor activity Source: MGI
- DNA-binding transcription repressor activity, RNA polymerase II-specific Source: MGI
- E-box binding Source: UniProtKB
- heme binding Source: MGI
- nuclear receptor activity Source: GO_Central
- RNA polymerase II cis-regulatory region sequence-specific DNA binding Source: MGI
- RNA polymerase II transcription regulatory region sequence-specific DNA binding Source: MGI
- sequence-specific double-stranded DNA binding Source: MGI
- transcription cis-regulatory region binding Source: MGI
- transcription corepressor binding Source: UniProtKB
- zinc ion binding Source: InterPro
GO - Biological processi
- cell differentiation Source: GO_Central
- cellular glucose homeostasis Source: UniProtKB
- cellular response to interleukin-1 Source: UniProtKB
- cellular response to lipopolysaccharide Source: MGI
- cellular response to tumor necrosis factor Source: UniProtKB
- cholesterol homeostasis Source: UniProtKB
- circadian regulation of gene expression Source: UniProtKB
- circadian rhythm Source: MGI
- circadian temperature homeostasis Source: UniProtKB
- glycogen biosynthetic process Source: UniProtKB
- hormone-mediated signaling pathway Source: GO_Central
- negative regulation of astrocyte activation Source: UniProtKB
- negative regulation of cold-induced thermogenesis Source: YuBioLab
- negative regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
- negative regulation of inflammatory response Source: UniProtKB
- negative regulation of microglial cell activation Source: UniProtKB
- negative regulation of neuroinflammatory response Source: UniProtKB
- negative regulation of toll-like receptor 4 signaling pathway Source: MGI
- negative regulation of transcription, DNA-templated Source: UniProtKB
- negative regulation of transcription by RNA polymerase II Source: MGI
- positive regulation of bile acid biosynthetic process Source: UniProtKB
- positive regulation of circadian rhythm Source: MGI
- positive regulation of transcription, DNA-templated Source: UniProtKB
- positive regulation of transcription by RNA polymerase II Source: GO_Central
- proteasomal protein catabolic process Source: UniProtKB
- protein destabilization Source: UniProtKB
- regulation of circadian rhythm Source: UniProtKB
- regulation of circadian sleep/wake cycle Source: UniProtKB
- regulation of fat cell differentiation Source: UniProtKB
- regulation of hepatic stellate cell activation Source: MGI
- regulation of insulin secretion involved in cellular response to glucose stimulus Source: UniProtKB
- regulation of lipid metabolic process Source: UniProtKB
- regulation of transcription, DNA-templated Source: MGI
- regulation of type B pancreatic cell proliferation Source: UniProtKB
- response to leptin Source: UniProtKB
Keywordsi
Molecular function | Activator, DNA-binding, Receptor, Repressor |
Biological process | Biological rhythms, Differentiation, Transcription, Transcription regulation |
Ligand | Heme, Iron, Metal-binding, Zinc |
Enzyme and pathway databases
Reactomei | R-MMU-383280, Nuclear Receptor transcription pathway |
Names & Taxonomyi
Protein namesi | Recommended name: Nuclear receptor subfamily 1 group D member 1Alternative name(s): Rev-erbA-alpha V-erbA-related protein 1 Short name: EAR-1 |
Gene namesi | Name:Nr1d1 Synonyms:Ear1 |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:2444210, Nr1d1 |
VEuPathDBi | HostDB:ENSMUSG00000020889 |
Subcellular locationi
Cytoplasm and Cytosol
- Cytoplasm 3 Publications
Nucleus
- Nucleus PROSITE-ProRule annotation3 Publications
Other locations
- dendrite 1 Publication
- dendritic spine 1 Publication
Note: Localizes to the cytoplasm, dendrites and dendritic spine in the presence of OPHN1 (PubMed:21874017). Localizes predominantly to the nucleus at ZT8 whereas it is cytoplasmic at ZT20 (PubMed:27686098). Phosphorylation by CSNK1E enhances its cytoplasmic localization (PubMed:29508494).3 Publications
Nucleus
- nuclear body Source: MGI
- nucleoplasm Source: Reactome
- nucleus Source: UniProtKB
Other locations
- chromatin Source: MGI
- cytoplasm Source: UniProtKB
- dendrite Source: UniProtKB
- dendritic spine Source: UniProtKB
- neuronal cell body Source: MGI
Keywords - Cellular componenti
Cell junction, Cell projection, Cytoplasm, Nucleus, SynapsePathology & Biotechi
Disruption phenotypei
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 275 | T → A: Loss of interaction with FBXW7 and loss of CDK1-mediated phosphorylation. 1 Publication | 1 | |
Mutagenesisi | 279 | S → A: Loss of interaction with FBXW7. 1 Publication | 1 | |
Mutagenesisi | 456 | K → A: Reduces interaction with PER2 by 60%. 1 Publication | 1 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000311182 | 1 – 615 | Nuclear receptor subfamily 1 group D member 1Add BLAST | 615 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 55 | Phosphoserine; by GSK3-betaBy similarity | 1 | |
Modified residuei | 59 | Phosphoserine; by GSK3-betaBy similarity | 1 | |
Modified residuei | 192 | N6-acetyllysine; by KAT5By similarity | 1 | |
Modified residuei | 193 | N6-acetyllysine; by KAT5By similarity | 1 | |
Modified residuei | 275 | Phosphothreonine; by CDK11 Publication | 1 | |
Modified residuei | 592 | N6-acetyllysineBy similarity | 1 |
Post-translational modificationi
Keywords - PTMi
Acetylation, Phosphoprotein, Ubl conjugationProteomic databases
MaxQBi | Q3UV55 |
PaxDbi | Q3UV55 |
PeptideAtlasi | Q3UV55 |
PRIDEi | Q3UV55 |
ProteomicsDBi | 295516 |
PTM databases
iPTMneti | Q3UV55 |
PhosphoSitePlusi | Q3UV55 |
Expressioni
Tissue specificityi
Developmental stagei
Inductioni
Gene expression databases
Bgeei | ENSMUSG00000020889, Expressed in retinal neural layer and 190 other tissues |
Genevisiblei | Q3UV55, MM |
Interactioni
Subunit structurei
Binds DNA as a monomer or a homodimer (By similarity).
Interacts with NR2E3 and ZNHIT1 (By similarity).
Interacts with C1D (PubMed:9405624).
Interacts with SP1 (PubMed:22549838).
Interacts with OPHN1 (via C-terminus) (PubMed:21874017).
Interacts with PER2; the interaction associates PER2 to ARNTL promoter region (PubMed:20159955, PubMed:22170608).
Interacts with CRY1 (By similarity).
Interacts with CCAR2 (PubMed:23398316).
Interacts with SIAH2 (By similarity).
Interacts with FBXW7 and CDK1 (PubMed:27238018).
Interacts with HUWE1 (By similarity).
Interacts with NR0B2 (PubMed:25212631, PubMed:30555544).
Interacts with NFIL3 (PubMed:29653076).
Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1 (PubMed:27686098).
By similarity11 PublicationsGO - Molecular functioni
- transcription corepressor binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 229856, 3 interactors |
DIPi | DIP-59440N |
IntActi | Q3UV55, 1 interactor |
STRINGi | 10090.ENSMUSP00000069505 |
Miscellaneous databases
RNActi | Q3UV55, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 285 – 615 | NR LBDPROSITE-ProRule annotationAdd BLAST | 331 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 129 | ModulatingAdd BLAST | 129 | |
Regioni | 1 – 120 | DisorderedSequence analysisAdd BLAST | 120 | |
Regioni | 1 – 70 | Required for phosphorylation by CSNK1E and cytoplasmic localization1 PublicationAdd BLAST | 70 | |
Regioni | 49 – 285 | Crucial for activation of GJA1Add BLAST | 237 | |
Regioni | 235 – 286 | DisorderedSequence analysisAdd BLAST | 52 | |
Regioni | 312 – 337 | DisorderedSequence analysisAdd BLAST | 26 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 248 – 264 | Pro residuesSequence analysisAdd BLAST | 17 |
Domaini
Sequence similaritiesi
Zinc finger
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Zinc fingeri | 133 – 153 | NR C4-typePROSITE-ProRule annotationAdd BLAST | 21 | |
Zinc fingeri | 170 – 194 | NR C4-typePROSITE-ProRule annotationAdd BLAST | 25 |
Keywords - Domaini
Zinc-fingerPhylogenomic databases
eggNOGi | KOG4846, Eukaryota |
GeneTreei | ENSGT00940000160548 |
HOGENOMi | CLU_007368_2_4_1 |
InParanoidi | Q3UV55 |
OMAi | YPPAWPP |
OrthoDBi | 1240230at2759 |
PhylomeDBi | Q3UV55 |
TreeFami | TF328382 |
Family and domain databases
Gene3Di | 1.10.565.10, 1 hit 3.30.50.10, 1 hit |
InterProi | View 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 |
Pfami | View protein in Pfam PF00104, Hormone_recep, 1 hit PF00105, zf-C4, 1 hit |
PRINTSi | PR00398, STRDHORMONER PR00047, STROIDFINGER |
SMARTi | View protein in SMART SM00430, HOLI, 1 hit SM00399, ZnF_C4, 1 hit |
SUPFAMi | SSF48508, SSF48508, 1 hit |
PROSITEi | View protein in PROSITE PS51843, NR_LBD, 1 hit PS00031, NUCLEAR_REC_DBD_1, 1 hit PS51030, NUCLEAR_REC_DBD_2, 1 hit |
i Sequence
Sequence statusi: Complete.
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
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 36 | S → R in CAA59997 (Ref. 5) Curated | 1 | |
Sequence conflicti | 40 | S → R in CAA59997 (Ref. 5) Curated | 1 | |
Sequence conflicti | 84 | A → T in BAE27164 (PubMed:16141072).Curated | 1 | |
Sequence conflicti | 84 | A → T in AAH08989 (PubMed:15489334).Curated | 1 | |
Sequence conflicti | 440 | F → L in BAE27164 (PubMed:16141072).Curated | 1 |
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 No translation available. BC008989 mRNA Translation: AAH08989.1 AF291821 mRNA Translation: AAG01345.1 X86010 mRNA Translation: CAA59997.1 AY336125 Genomic DNA Translation: AAS48348.1 |
CCDSi | CCDS25363.1 |
PIRi | S52813 |
RefSeqi | NP_663409.2, NM_145434.4 |
Genome annotation databases
Ensembli | ENSMUST00000064941; ENSMUSP00000069505; ENSMUSG00000020889 |
GeneIDi | 217166 |
KEGGi | mmu:217166 |
UCSCi | uc007lhh.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 No translation available. BC008989 mRNA Translation: AAH08989.1 AF291821 mRNA Translation: AAG01345.1 X86010 mRNA Translation: CAA59997.1 AY336125 Genomic DNA Translation: AAS48348.1 |
CCDSi | CCDS25363.1 |
PIRi | S52813 |
RefSeqi | NP_663409.2, NM_145434.4 |
3D structure databases
SMRi | Q3UV55 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 229856, 3 interactors |
DIPi | DIP-59440N |
IntActi | Q3UV55, 1 interactor |
STRINGi | 10090.ENSMUSP00000069505 |
PTM databases
iPTMneti | Q3UV55 |
PhosphoSitePlusi | Q3UV55 |
Proteomic databases
MaxQBi | Q3UV55 |
PaxDbi | Q3UV55 |
PeptideAtlasi | Q3UV55 |
PRIDEi | Q3UV55 |
ProteomicsDBi | 295516 |
Protocols and materials databases
Antibodypediai | 16433, 499 antibodies from 36 providers |
DNASUi | 217166 |
Genome annotation databases
Ensembli | ENSMUST00000064941; ENSMUSP00000069505; ENSMUSG00000020889 |
GeneIDi | 217166 |
KEGGi | mmu:217166 |
UCSCi | uc007lhh.2, mouse |
Organism-specific databases
CTDi | 9572 |
MGIi | MGI:2444210, Nr1d1 |
VEuPathDBi | HostDB:ENSMUSG00000020889 |
Phylogenomic databases
eggNOGi | KOG4846, Eukaryota |
GeneTreei | ENSGT00940000160548 |
HOGENOMi | CLU_007368_2_4_1 |
InParanoidi | Q3UV55 |
OMAi | YPPAWPP |
OrthoDBi | 1240230at2759 |
PhylomeDBi | Q3UV55 |
TreeFami | TF328382 |
Enzyme and pathway databases
Reactomei | R-MMU-383280, Nuclear Receptor transcription pathway |
Miscellaneous databases
BioGRID-ORCSi | 217166, 2 hits in 64 CRISPR screens |
PROi | PR:Q3UV55 |
RNActi | Q3UV55, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSMUSG00000020889, Expressed in retinal neural layer and 190 other tissues |
Genevisiblei | Q3UV55, MM |
Family and domain databases
Gene3Di | 1.10.565.10, 1 hit 3.30.50.10, 1 hit |
InterProi | View 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 |
Pfami | View protein in Pfam PF00104, Hormone_recep, 1 hit PF00105, zf-C4, 1 hit |
PRINTSi | PR00398, STRDHORMONER PR00047, STROIDFINGER |
SMARTi | View protein in SMART SM00430, HOLI, 1 hit SM00399, ZnF_C4, 1 hit |
SUPFAMi | SSF48508, SSF48508, 1 hit |
PROSITEi | View protein in PROSITE PS51843, NR_LBD, 1 hit PS00031, NUCLEAR_REC_DBD_1, 1 hit PS51030, NUCLEAR_REC_DBD_2, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | NR1D1_MOUSE | |
Accessioni | Q3UV55Primary (citable) accession number: Q3UV55 Secondary accession number(s): Q3UJJ1 Q9ESY4 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | November 13, 2007 |
Last sequence update: | October 11, 2005 | |
Last modified: | February 23, 2022 | |
This is version 153 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- MGD cross-references
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot - SIMILARITY comments
Index of protein domains and families