P20393 · NR1D1_HUMAN
- ProteinNuclear receptor subfamily 1 group D member 1
- GeneNR1D1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids614 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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 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 (By similarity).
Represses the transcription of CES2 (By similarity).
Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity).
Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Represses the transcription of CES2 (By similarity).
Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity).
Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Features
Showing features for dna binding, binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameNuclear receptor subfamily 1 group D member 1
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP20393
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Localizes to the cytoplasm, dendrites and dendritic spine in the presence of OPHN1. Localizes predominantly to the nucleus at ZT8 whereas it is cytoplasmic at ZT20. Phosphorylation by CSNK1E enhances its cytoplasmic localization.
Keywords
- Cellular component
Disease & Variants
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 629 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000053499 | 1-614 | UniProt | Nuclear receptor subfamily 1 group D member 1 | |||
Sequence: MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSLTQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKSTSNITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKNENCSIVRINRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQLSSQCPLETSPTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPTVEDVISQVARAHREIFTYAHDKLGSSPGNFNANHASGSPPATTPHRWENQGCPPAPNDNNTLAAQRHNEALNGLRQAPSSYPPTWPPGPAHHSCHQSNSNGHRLCPTHVYAAPEGKAPANSPRQGNSKNVLLACPMNMYPHGRSGRTVQEIWEDFSMSFTPAVREVVEFAKHIPGFRDLSQHDQVTLLKAGTFEVLMVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLSAMFDFSEKLNSLALTEEELGLFTAVVLVSADRSGMENSASVEQLQETLLRALRALVLKNRPLETSRFTKLLLKLPDLRTLNNMHSEKLLSFRVDAQ | |||||||
Modified residue | 55 | UniProt | Phosphoserine; by GSK3-beta | ||||
Sequence: S | |||||||
Modified residue | 59 | UniProt | Phosphoserine; by GSK3-beta | ||||
Sequence: S | |||||||
Modified residue | 191 | UniProt | N6-acetyllysine; by KAT5 | ||||
Sequence: K | |||||||
Modified residue | 192 | UniProt | N6-acetyllysine; by KAT5 | ||||
Sequence: K | |||||||
Modified residue | 274 | UniProt | Phosphothreonine; by CDK1 | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 280 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 310 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 322 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 394 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 400 | UniProt | N6-acetyllysine | ||||
Sequence: K | |||||||
Modified residue | 591 | UniProt | N6-acetyllysine | ||||
Sequence: K |
Post-translational modification
Ubiquitinated, leading to its proteasomal degradation (PubMed:16484495, PubMed:20534529, PubMed:23398316).
Ubiquitinated by SIAH2; leading to its proteasomal degradation (PubMed:26392558).
Ubiquitinated by the SCF(FBXW7) complex when phosphorylated by CDK1 leading to its proteasomal degradation (By similarity).
Rapidly ubiquitinated in response to inflammatory triggers and sumoylation is a prerequisite to its ubiquitination (By similarity).
Ubiquitinated by SIAH2; leading to its proteasomal degradation (PubMed:26392558).
Ubiquitinated by the SCF(FBXW7) complex when phosphorylated by CDK1 leading to its proteasomal degradation (By similarity).
Rapidly ubiquitinated in response to inflammatory triggers and sumoylation is a prerequisite to its ubiquitination (By similarity).
Sumoylated by UBE2I, desumoylated by SENP1, and sumoylation is a prerequisite to its ubiquitination.
Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic localization.
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Also expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and macrophages. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. Expression increases during the differentiation of pre-adipocytes into mature adipocytes. Expressed at high levels in some squamous carcinoma cell lines.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Binds DNA as a monomer or a homodimer (PubMed:9660968).
Interacts with C1D, NR2E3 and SP1 (By similarity).
Interacts with OPHN1 (via C-terminus) (PubMed:21874017).
Interacts with ZNHIT1 (PubMed:17892483).
Interacts with PER2; the interaction associates PER2 to BMAL1 promoter region (PubMed:22170608).
Interacts with CRY1 (PubMed:22170608).
Interacts with CCAR2 (PubMed:23398316).
Interacts with SIAH2 (PubMed:26392558).
Interacts with CDK1 (By similarity).
Interacts with FBXW7 (PubMed:27238018).
Interacts with HUWE1 (PubMed:20534529).
Interacts with NR0B2 (By similarity).
Interacts with NFIL3 (By similarity).
Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1 (By similarity).
Interacts with C1D, NR2E3 and SP1 (By similarity).
Interacts with OPHN1 (via C-terminus) (PubMed:21874017).
Interacts with ZNHIT1 (PubMed:17892483).
Interacts with PER2; the interaction associates PER2 to BMAL1 promoter region (PubMed:22170608).
Interacts with CRY1 (PubMed:22170608).
Interacts with CCAR2 (PubMed:23398316).
Interacts with SIAH2 (PubMed:26392558).
Interacts with CDK1 (By similarity).
Interacts with FBXW7 (PubMed:27238018).
Interacts with HUWE1 (PubMed:20534529).
Interacts with NR0B2 (By similarity).
Interacts with NFIL3 (By similarity).
Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1 (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P20393 | APOA4 P06727 | 3 | EBI-2811738, EBI-1222447 | |
BINARY | P20393 | HUWE1 Q7Z6Z7 | 3 | EBI-2811738, EBI-625934 | |
BINARY | P20393 | INPP1 A0A0S2Z3X1 | 3 | EBI-2811738, EBI-16430606 | |
BINARY | P20393 | NCOR1 O75376 | 3 | EBI-2811738, EBI-347233 | |
XENO | P20393 | Per2 O54943 | 2 | EBI-2811738, EBI-1266779 | |
BINARY | P20393 | SPG21 Q9NZD8 | 3 | EBI-2811738, EBI-742688 | |
BINARY | P20393 | TDO2 P48775 | 3 | EBI-2811738, EBI-743494 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, zinc finger, compositional bias, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-70 | Required for phosphorylation by CSNK1E and cytoplasmic localization | ||||
Sequence: MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSLTQDPARSFGS | ||||||
Region | 1-119 | Disordered | ||||
Sequence: MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSLTQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKST | ||||||
Region | 1-128 | Modulating | ||||
Sequence: MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSLTQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKSTSNITKLNGM | ||||||
Region | 49-284 | Crucial for activation of GJA1 | ||||
Sequence: PTYFPPSPTGSLTQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKSTSNITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKNENCSIVRINRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQLSSQCPLETSPTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPT | ||||||
Zinc finger | 132-152 | NR C4-type | ||||
Sequence: CKVCGDVASGFHYGVHACEGC | ||||||
Zinc finger | 169-193 | NR C4-type | ||||
Sequence: CLKNENCSIVRINRNRCQQCRFKKC | ||||||
Region | 233-285 | Disordered | ||||
Sequence: SQCPLETSPTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPTV | ||||||
Compositional bias | 242-263 | Pro residues | ||||
Sequence: TQHPTPGPMGPSPPPAPVPSPL | ||||||
Domain | 284-614 | NR LBD | ||||
Sequence: TVEDVISQVARAHREIFTYAHDKLGSSPGNFNANHASGSPPATTPHRWENQGCPPAPNDNNTLAAQRHNEALNGLRQAPSSYPPTWPPGPAHHSCHQSNSNGHRLCPTHVYAAPEGKAPANSPRQGNSKNVLLACPMNMYPHGRSGRTVQEIWEDFSMSFTPAVREVVEFAKHIPGFRDLSQHDQVTLLKAGTFEVLMVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLSAMFDFSEKLNSLALTEEELGLFTAVVLVSADRSGMENSASVEQLQETLLRALRALVLKNRPLETSRFTKLLLKLPDLRTLNNMHSEKLLSFRVDAQ | ||||||
Compositional bias | 311-329 | Polar residues | ||||
Sequence: PGNFNANHASGSPPATTPH | ||||||
Region | 311-345 | Disordered | ||||
Sequence: PGNFNANHASGSPPATTPHRWENQGCPPAPNDNNT |
Domain
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
Sequence similarities
Belongs to the nuclear hormone receptor family. NR1 subfamily.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length614
- Mass (Da)66,805
- Last updated1991-02-01 v1
- Checksum67C71758E166508A
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 147 | in Ref. 2; CAB53540 | ||||
Sequence: H → L | ||||||
Compositional bias | 242-263 | Pro residues | ||||
Sequence: TQHPTPGPMGPSPPPAPVPSPL | ||||||
Compositional bias | 311-329 | Polar residues | ||||
Sequence: PGNFNANHASGSPPATTPH | ||||||
Sequence conflict | 564 | in Ref. 2 | ||||
Sequence: E → Q |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M24898 EMBL· GenBank· DDBJ | AAA52335.1 EMBL· GenBank· DDBJ | mRNA | ||
M24900 EMBL· GenBank· DDBJ | AAA52332.1 EMBL· GenBank· DDBJ | mRNA | ||
X55066 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
X55067 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
X72631 EMBL· GenBank· DDBJ | CAB53540.1 EMBL· GenBank· DDBJ | mRNA | ||
BC047875 EMBL· GenBank· DDBJ | AAH47875.1 EMBL· GenBank· DDBJ | mRNA | ||
BC056148 EMBL· GenBank· DDBJ | AAH56148.1 EMBL· GenBank· DDBJ | mRNA | ||
M34339 EMBL· GenBank· DDBJ | AAA36561.1 EMBL· GenBank· DDBJ | mRNA | ||
M34340 EMBL· GenBank· DDBJ | AAA36562.2 EMBL· GenBank· DDBJ | mRNA |