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Protein

Nuclear receptor subfamily 1 group D member 1

Gene

NR1D1

Organism
Homo sapiens (Human)
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.10 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei418HemeBy similarity1
Binding sitei602Heme1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi129 – 205Nuclear receptorPROSITE-ProRule annotationAdd BLAST77
Zinc fingeri132 – 152NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri169 – 193NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, DNA-binding, Receptor, Repressor
Biological processBiological rhythms, Differentiation, Transcription, Transcription regulation
LigandHeme, Iron, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-1368071 NR1D1 (REV-ERBA) represses gene expression
R-HSA-1989781 PPARA activates gene expression
R-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
R-HSA-383280 Nuclear Receptor transcription pathway
R-HSA-400253 Circadian Clock
SignaLinkiP20393
SIGNORiP20393

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, HREV, THRAL
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000126368.5
HGNCiHGNC:7962 NR1D1
MIMi602408 gene
neXtProtiNX_P20393

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

Organism-specific databases

DisGeNETi9572
OpenTargetsiENSG00000126368
PharmGKBiPA31748

Chemistry databases

ChEMBLiCHEMBL1961783
GuidetoPHARMACOLOGYi596

Polymorphism and mutation databases

DMDMi119100

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000534991 – 614Nuclear receptor subfamily 1 group D member 1Add BLAST614

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei55Phosphoserine; by GSK3-beta2 Publications1
Modified residuei59Phosphoserine; by GSK3-beta2 Publications1
Modified residuei191N6-acetyllysine; by KAT5By similarity1
Modified residuei192N6-acetyllysine; by KAT5By similarity1
Modified residuei400N6-acetyllysine1 Publication1
Modified residuei591N6-acetyllysine1 Publication1

Post-translational modificationi

Ubiquitinated, leading to its proteasomal degradation.2 Publications

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP20393
MaxQBiP20393
PaxDbiP20393
PeptideAtlasiP20393
PRIDEiP20393
ProteomicsDBi53759

PTM databases

iPTMnetiP20393
PhosphoSitePlusiP20393

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiENSG00000126368 Expressed in 227 organ(s), highest expression level in skin of abdomen
CleanExiHS_NR1D1
ExpressionAtlasiP20393 baseline and differential
GenevisibleiP20393 HS

Organism-specific databases

HPAiHPA007935

Interactioni

Subunit structurei

Binds DNA as a monomer or a homodimer. Interacts with C1D, NR2E3 and SP1. Interacts with OPHN1 (via C-terminus). Interacts with ZNHIT1. Interacts with PER2; the interaction associates PER2 to ARNTL promoter region. Interacts with CRY1. Interacts with CCAR2.4 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114941, 10 interactors
DIPiDIP-48396N
IntActiP20393, 11 interactors
STRINGi9606.ENSP00000246672

Chemistry databases

BindingDBiP20393

Structurei

Secondary structure

1614
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP20393
SMRiP20393
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP20393

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini284 – 614NR LBDPROSITE-ProRule annotationAdd BLAST331

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 128ModulatingAdd BLAST128
Regioni49 – 284Crucial for activation of GJA1By similarityAdd BLAST236
Regioni206 – 283HingeAdd BLAST78

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi82 – 93Poly-SerAdd BLAST12

Domaini

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

Sequence similaritiesi

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri132 – 152NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri169 – 193NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410IMDK Eukaryota
ENOG410ZPPI LUCA
GeneTreeiENSGT00870000136388
HOGENOMiHOG000261691
HOVERGENiHBG106790
InParanoidiP20393
KOiK03728
OMAiSCHQPNS
OrthoDBiEOG091G066Y
PhylomeDBiP20393
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.

P20393-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MTTLDSNNNT GGVITYIGSS GSSPSRTSPE SLYSDNSNGS FQSLTQGCPT
60 70 80 90 100
YFPPSPTGSL TQDPARSFGS IPPSLSDDGS PSSSSSSSSS SSSFYNGSPP
110 120 130 140 150
GSLQVAMEDS SRVSPSKSTS NITKLNGMVL LCKVCGDVAS GFHYGVHACE
160 170 180 190 200
GCKGFFRRSI QQNIQYKRCL KNENCSIVRI NRNRCQQCRF KKCLSVGMSR
210 220 230 240 250
DAVRFGRIPK REKQRMLAEM QSAMNLANNQ LSSQCPLETS PTQHPTPGPM
260 270 280 290 300
GPSPPPAPVP SPLVGFSQFP QQLTPPRSPS PEPTVEDVIS QVARAHREIF
310 320 330 340 350
TYAHDKLGSS PGNFNANHAS GSPPATTPHR WENQGCPPAP NDNNTLAAQR
360 370 380 390 400
HNEALNGLRQ APSSYPPTWP PGPAHHSCHQ SNSNGHRLCP THVYAAPEGK
410 420 430 440 450
APANSPRQGN SKNVLLACPM NMYPHGRSGR TVQEIWEDFS MSFTPAVREV
460 470 480 490 500
VEFAKHIPGF RDLSQHDQVT LLKAGTFEVL MVRFASLFNV KDQTVMFLSR
510 520 530 540 550
TTYSLQELGA MGMGDLLSAM FDFSEKLNSL ALTEEELGLF TAVVLVSADR
560 570 580 590 600
SGMENSASVE QLQETLLRAL RALVLKNRPL ETSRFTKLLL KLPDLRTLNN
610
MHSEKLLSFR VDAQ
Length:614
Mass (Da):66,805
Last modified:February 1, 1991 - v1
Checksum:i67C71758E166508A
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti147H → L in CAB53540 (PubMed:1971514).Curated1
Sequence conflicti564E → Q (PubMed:1971514).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M24898 mRNA Translation: AAA52335.1
M24900 mRNA Translation: AAA52332.1
X55066 Genomic DNA No translation available.
X55067 Genomic DNA No translation available.
X72631 mRNA Translation: CAB53540.1
BC047875 mRNA Translation: AAH47875.1
BC056148 mRNA Translation: AAH56148.1
M34339 mRNA Translation: AAA36561.1
M34340 mRNA Translation: AAA36562.2
CCDSiCCDS11361.1
PIRiA32286 A32608
RefSeqiNP_068370.1, NM_021724.4
UniGeneiHs.592130
Hs.724

Genome annotation databases

EnsembliENST00000246672; ENSP00000246672; ENSG00000126368
GeneIDi9572
KEGGihsa:9572
UCSCiuc002htz.4 human

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M24898 mRNA Translation: AAA52335.1
M24900 mRNA Translation: AAA52332.1
X55066 Genomic DNA No translation available.
X55067 Genomic DNA No translation available.
X72631 mRNA Translation: CAB53540.1
BC047875 mRNA Translation: AAH47875.1
BC056148 mRNA Translation: AAH56148.1
M34339 mRNA Translation: AAA36561.1
M34340 mRNA Translation: AAA36562.2
CCDSiCCDS11361.1
PIRiA32286 A32608
RefSeqiNP_068370.1, NM_021724.4
UniGeneiHs.592130
Hs.724

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1A6YX-ray2.30A/B123-216[»]
1EF6model-A281-301[»]
B430-614[»]
1GA5X-ray2.40A/B/E/F123-216[»]
1HLZX-ray2.80A/B123-216[»]
3N00X-ray2.60A281-614[»]
ProteinModelPortaliP20393
SMRiP20393
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114941, 10 interactors
DIPiDIP-48396N
IntActiP20393, 11 interactors
STRINGi9606.ENSP00000246672

Chemistry databases

BindingDBiP20393
ChEMBLiCHEMBL1961783
GuidetoPHARMACOLOGYi596

PTM databases

iPTMnetiP20393
PhosphoSitePlusiP20393

Polymorphism and mutation databases

DMDMi119100

Proteomic databases

EPDiP20393
MaxQBiP20393
PaxDbiP20393
PeptideAtlasiP20393
PRIDEiP20393
ProteomicsDBi53759

Protocols and materials databases

DNASUi9572
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000246672; ENSP00000246672; ENSG00000126368
GeneIDi9572
KEGGihsa:9572
UCSCiuc002htz.4 human

Organism-specific databases

CTDi9572
DisGeNETi9572
EuPathDBiHostDB:ENSG00000126368.5
GeneCardsiNR1D1
HGNCiHGNC:7962 NR1D1
HPAiHPA007935
MIMi602408 gene
neXtProtiNX_P20393
OpenTargetsiENSG00000126368
PharmGKBiPA31748
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IMDK Eukaryota
ENOG410ZPPI LUCA
GeneTreeiENSGT00870000136388
HOGENOMiHOG000261691
HOVERGENiHBG106790
InParanoidiP20393
KOiK03728
OMAiSCHQPNS
OrthoDBiEOG091G066Y
PhylomeDBiP20393
TreeFamiTF328382

Enzyme and pathway databases

ReactomeiR-HSA-1368071 NR1D1 (REV-ERBA) represses gene expression
R-HSA-1989781 PPARA activates gene expression
R-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
R-HSA-383280 Nuclear Receptor transcription pathway
R-HSA-400253 Circadian Clock
SignaLinkiP20393
SIGNORiP20393

Miscellaneous databases

ChiTaRSiNR1D1 human
EvolutionaryTraceiP20393
GeneWikiiRev-ErbA_alpha
GenomeRNAii9572
PROiPR:P20393
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000126368 Expressed in 227 organ(s), highest expression level in skin of abdomen
CleanExiHS_NR1D1
ExpressionAtlasiP20393 baseline and differential
GenevisibleiP20393 HS

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_HUMAN
AccessioniPrimary (citable) accession number: P20393
Secondary accession number(s): Q0P5Z4, Q15304
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1991
Last sequence update: February 1, 1991
Last modified: November 7, 2018
This is version 205 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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