NR1D1_RAT
ID NR1D1_RAT Reviewed; 615 AA.
AC Q63503; Q6P6S7;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 13-NOV-2007, sequence version 2.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Nuclear receptor subfamily 1 group D member 1;
DE AltName: Full=Rev-erbA-alpha;
DE AltName: Full=V-erbA-related protein 1;
DE Short=EAR-1;
GN Name=Nr1d1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 11-615.
RX PubMed=2542765; DOI=10.1128/mcb.9.3.1128-1136.1989;
RA Lazar M.A., Hodin R.A., Darling D.S., Chin W.W.;
RT "A novel member of the thyroid/steroid hormone receptor family is encoded
RT by the opposite strand of the rat c-erbA alpha transcriptional unit.";
RL Mol. Cell. Biol. 9:1128-1136(1989).
RN [3]
RP INTERACTION WITH OPHN1.
RX PubMed=21874017; DOI=10.1038/nn.2911;
RA Valnegri P., Khelfaoui M., Dorseuil O., Bassani S., Lagneaux C.,
RA Gianfelice A., Benfante R., Chelly J., Billuart P., Sala C., Passafaro M.;
RT "A circadian clock in hippocampus is regulated by interaction between
RT oligophrenin-1 and Rev-erbalpha.";
RL Nat. Neurosci. 14:1293-1301(2011).
RN [4]
RP FUNCTION.
RX PubMed=22425774; DOI=10.1016/j.bbrc.2012.02.164;
RA Chen H., Chu G., Zhao L., Yamauchi N., Shigeyoshi Y., Hashimoto S.,
RA Hattori M.A.;
RT "Rev-erbalpha regulates circadian rhythms and StAR expression in rat
RT granulosa cells as identified by the agonist GSK4112.";
RL Biochem. Biophys. Res. Commun. 420:374-379(2012).
RN [5]
RP INDUCTION.
RX PubMed=22549838; DOI=10.1038/ncomms1812;
RA Negoro H., Kanematsu A., Doi M., Suadicani S.O., Matsuo M., Imamura M.,
RA Okinami T., Nishikawa N., Oura T., Matsui S., Seo K., Tainaka M., Urabe S.,
RA Kiyokage E., Todo T., Okamura H., Tabata Y., Ogawa O.;
RT "Involvement of urinary bladder Connexin43 and the circadian clock in
RT coordination of diurnal micturition rhythm.";
RL Nat. Commun. 3:809-809(2012).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Transcriptional repressor which coordinates circadian rhythm
CC and metabolic pathways in a heme-dependent manner. Integral component
CC of the complex transcription machinery that governs circadian
CC rhythmicity and forms a critical negative limb of the circadian clock
CC by directly repressing the expression of core clock components
CC ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic
CC functions, including lipid and bile acid metabolism, adipogenesis,
CC gluconeogenesis and the macrophage inflammatory response. Acts as a
CC receptor for heme which stimulates its interaction with the NCOR1/HDAC3
CC corepressor complex, enhancing transcriptional repression. Recognizes
CC two classes of DNA response elements within the promoter of its target
CC genes and can bind to DNA as either monomers or homodimers, depending
CC on the nature of the response element. Binds as a monomer to a response
CC element composed of the consensus half-site motif 5'-[A/G]GGTCA-3'
CC preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a
CC direct repeat of the core motif spaced by two nucleotides (RevDR-2).
CC Acts as a potent competitive repressor of ROR alpha (RORA) function and
CC regulates the levels of its ligand heme by repressing the expression of
CC PPARGC1A, a potent inducer of heme synthesis. Regulates lipid
CC metabolism by repressing the expression of APOC3 and by influencing the
CC activity of sterol response element binding proteins (SREBPs);
CC represses INSIG2 which interferes with the proteolytic activation of
CC SREBPs which in turn govern the rhythmic expression of enzymes with key
CC functions in sterol and fatty acid synthesis. Regulates gluconeogenesis
CC via repression of G6PC1 and PEPCK and adipocyte differentiation via
CC repression of PPARG. Regulates glucagon release in pancreatic alpha-
CC cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-
CC induced insulin secretion and expression of key lipogenic genes in
CC pancreatic-beta cells. Positively regulates bile acid synthesis by
CC increasing hepatic expression of CYP7A1 via repression of NR0B2 and
CC NFIL3 which are negative regulators of CYP7A1. Modulates skeletal
CC muscle oxidative capacity by regulating mitochondrial biogenesis and
CC autophagy; controls mitochondrial biogenesis and respiration by
CC interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway.
CC Represses the expression of SERPINE1/PAI1, an important modulator of
CC cardiovascular disease and the expression of inflammatory cytokines and
CC chemokines in macrophages. Represses gene expression at a distance in
CC macrophages by inhibiting the transcription of enhancer-derived RNAs
CC (eRNAs). Plays a role in the circadian regulation of body temperature
CC and negatively regulates thermogenic transcriptional programs in brown
CC adipose tissue (BAT); imposes a circadian oscillation in BAT activity,
CC increasing body temperature when awake and depressing thermogenesis
CC during sleep. In concert with NR2E3, regulates transcriptional networks
CC critical for photoreceptor development and function. In addition to its
CC activity as a repressor, can also act as a transcriptional activator
CC (By similarity). In the ovarian granulosa cells acts as a
CC transcriptional activator of STAR which plays a role in steroid
CC biosynthesis (PubMed:22425774). In collaboration with SP1, activates
CC GJA1 transcription in a heme-independent manner (By similarity).
CC Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By
CC similarity). Represses the transcription of CES2 (By similarity).
CC Represses and regulates the circadian expression of TSHB in a NCOR1-
CC dependent manner (By similarity). Negatively regulates the protein
CC stability of NR3C1 and influences the time-dependent subcellular
CC distribution of NR3C1, thereby affecting its transcriptional regulatory
CC activity (By similarity). Plays a critical role in the circadian
CC control of neutrophilic inflammation in the lung; under resting, non-
CC stress conditions, acts as a rhythmic repressor to limit inflammatory
CC activity whereas in the presence of inflammatory triggers undergoes
CC ubiquitin-mediated degradation thereby relieving inhibition of the
CC inflammatory response (By similarity). Plays a key role in the
CC circadian regulation of microglial activation and neuroinflammation;
CC suppresses microglial activation through the NF-kappaB pathway in the
CC central nervous system (By similarity). Plays a role in the regulation
CC of the diurnal rhythms of lipid and protein metabolism in the skeletal
CC muscle via transcriptional repression of genes controlling lipid and
CC amino acid metabolism in the muscle (By similarity).
CC {ECO:0000250|UniProtKB:Q3UV55, ECO:0000269|PubMed:22425774}.
CC -!- SUBUNIT: Binds DNA as a monomer or a homodimer (By similarity).
CC Interacts with C1D, NR2E3, SP1 and ZNHIT1 (By similarity). Interacts
CC with OPHN1 (via C-terminus) (PubMed:21874017). Interacts with PER2; the
CC interaction associates PER2 to ARNTL promoter region (By similarity).
CC Interacts with CRY1 (By similarity). Interacts with CCAR2 (By
CC similarity). Interacts with SIAH2 (By similarity). Interacts with FBXW7
CC and CDK1 (By similarity). Interacts with HUWE1 (By similarity).
CC Interacts with NR0B2 (By similarity). Interacts with NFIL3 (By
CC similarity). Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1
CC (By similarity). {ECO:0000250|UniProtKB:P20393,
CC ECO:0000250|UniProtKB:Q3UV55, ECO:0000269|PubMed:21874017}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407}.
CC Cytoplasm {ECO:0000250|UniProtKB:Q3UV55}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:Q3UV55}. Cell projection, dendritic spine
CC {ECO:0000250|UniProtKB:Q3UV55}. Note=Localizes to the cytoplasm,
CC dendrites and dendritic spine in the presence of OPHN1. Localizes
CC predominantly to the nucleus at ZT8 whereas it is cytoplasmic at ZT20.
CC Phosphorylation by CSNK1E enhances its cytoplasmic localization.
CC {ECO:0000250|UniProtKB:Q3UV55}.
CC -!- INDUCTION: In bladder smooth muscle cells, exhibits night/day
CC variations with a peak time at circadian time (CT) 4-12 and a trough at
CC CT16-24. {ECO:0000269|PubMed:22549838}.
CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain, a
CC DNA-binding domain and a C-terminal ligand-binding domain.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation (By
CC similarity). Ubiquitinated by the SCF(FBXW7) complex when
CC phosphorylated by CDK1 leading to its proteasomal degradation (By
CC similarity). Ubiquitinated by SIAH2; leading to its proteasomal
CC degradation (By similarity). Rapidly ubiquitinated in response to
CC inflammatory triggers and sumoylation is a prerequisite to its
CC ubiquitination (By similarity). {ECO:0000250|UniProtKB:P20393,
CC ECO:0000250|UniProtKB:Q3UV55}.
CC -!- PTM: Sumoylated by UBE2I, desumoylated by SENP1, and sumoylation is a
CC prerequisite to its ubiquitination. {ECO:0000250|UniProtKB:Q3UV55}.
CC -!- PTM: Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic
CC localization. {ECO:0000250|UniProtKB:Q3UV55}.
CC -!- PTM: Undergoes lysosome-mediated degradation in a time-dependent manner
CC in the liver. {ECO:0000250|UniProtKB:Q3UV55}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA74939.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; BC062047; AAH62047.1; -; mRNA.
DR EMBL; M25804; AAA74939.1; ALT_INIT; mRNA.
DR PIR; A30226; A30226.
DR RefSeq; NP_001106893.1; NM_001113422.1.
DR RefSeq; NP_665718.2; NM_145775.2.
DR AlphaFoldDB; Q63503; -.
DR SMR; Q63503; -.
DR IntAct; Q63503; 1.
DR STRING; 10116.ENSRNOP00000012537; -.
DR iPTMnet; Q63503; -.
DR PhosphoSitePlus; Q63503; -.
DR PaxDb; Q63503; -.
DR GeneID; 252917; -.
DR KEGG; rno:252917; -.
DR UCSC; RGD:628827; rat.
DR CTD; 9572; -.
DR RGD; 628827; Nr1d1.
DR eggNOG; KOG4846; Eukaryota.
DR InParanoid; Q63503; -.
DR OrthoDB; 1240230at2759; -.
DR PhylomeDB; Q63503; -.
DR Reactome; R-RNO-383280; Nuclear Receptor transcription pathway.
DR PRO; PR:Q63503; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0000785; C:chromatin; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0030425; C:dendrite; IDA:RGD.
DR GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0070888; F:E-box binding; ISS:UniProtKB.
DR GO; GO:0020037; F:heme binding; ISO:RGD.
DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:RGD.
DR GO; GO:0001222; F:transcription corepressor binding; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0001678; P:cellular glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0071347; P:cellular response to interleukin-1; ISS:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:RGD.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IEP:RGD.
DR GO; GO:0060086; P:circadian temperature homeostasis; ISS:UniProtKB.
DR GO; GO:0005978; P:glycogen biosynthetic process; ISS:UniProtKB.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0061889; P:negative regulation of astrocyte activation; ISS:UniProtKB.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:1903979; P:negative regulation of microglial cell activation; ISS:UniProtKB.
DR GO; GO:0150079; P:negative regulation of neuroinflammatory response; ISS:UniProtKB.
DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0009648; P:photoperiodism; IEP:RGD.
DR GO; GO:0070859; P:positive regulation of bile acid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; IDA:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0010498; P:proteasomal protein catabolic process; ISS:UniProtKB.
DR GO; GO:0031648; P:protein destabilization; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; IDA:UniProtKB.
DR GO; GO:0042749; P:regulation of circadian sleep/wake cycle; ISS:UniProtKB.
DR GO; GO:0045598; P:regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:2000489; P:regulation of hepatic stellate cell activation; IDA:RGD.
DR GO; GO:0061178; P:regulation of insulin secretion involved in cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0061469; P:regulation of type B pancreatic cell proliferation; ISS:UniProtKB.
DR GO; GO:0044321; P:response to leptin; ISS:UniProtKB.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Biological rhythms; Cell projection; Cytoplasm;
KW Differentiation; DNA-binding; Heme; Iron; Metal-binding; Nucleus;
KW Phosphoprotein; Receptor; Reference proteome; Repressor; Synapse;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..615
FT /note="Nuclear receptor subfamily 1 group D member 1"
FT /id="PRO_0000053500"
FT DOMAIN 285..615
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 130..206
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 133..153
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 170..194
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..129
FT /note="Modulating"
FT REGION 1..120
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1..70
FT /note="Required for phosphorylation by CSNK1E and
FT cytoplasmic localization"
FT /evidence="ECO:0000250|UniProtKB:Q3UV55"
FT REGION 49..285
FT /note="Crucial for activation of GJA1"
FT /evidence="ECO:0000250"
FT REGION 235..287
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 312..337
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 357..385
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 248..264
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 419
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /evidence="ECO:0000250"
FT BINDING 603
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /evidence="ECO:0000250"
FT MOD_RES 55
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:P20393"
FT MOD_RES 59
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:P20393"
FT MOD_RES 192
FT /note="N6-acetyllysine; by KAT5"
FT /evidence="ECO:0000250"
FT MOD_RES 193
FT /note="N6-acetyllysine; by KAT5"
FT /evidence="ECO:0000250"
FT MOD_RES 275
FT /note="Phosphothreonine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q3UV55"
FT MOD_RES 401
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P20393"
FT MOD_RES 592
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P20393"
FT CONFLICT 457
FT /note="H -> Q (in Ref. 2; AAA74939)"
FT /evidence="ECO:0000305"
FT CONFLICT 550..551
FT /note="DR -> EG (in Ref. 2; AAA74939)"
FT /evidence="ECO:0000305"
FT CONFLICT 565
FT /note="K -> E (in Ref. 2; AAA74939)"
FT /evidence="ECO:0000305"
FT CONFLICT 569
FT /note="R -> G (in Ref. 2; AAA74939)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 615 AA; 66693 MW; 3CC44132F82A25F6 CRC64;
MTTLDSNNNT GGVITYIGSS GSSPSRTSPE SLYSDSSNGS FQSLTQGCPT YFPPSPTGSL
TQDPARSFGT VPPSLSDDSS PSSASSSSSS SSSSFYNGSP PGSLQVAMED SSRVSPSKGT
SNITKLNGMV LLCKVCGDVA SGFHYGVHAC EGCKGFFRRS IQQNIQYKRC LKNENCSIVR
INRNRCQQCR FKKCLSVGMS RDAVRFGRIP KREKQRMLAE MQNAMNLANN QLSSLCPLET
SPAPHPTSGS VGPSPPPAPA PTPLVGFSQF PQQLTPPRSP SPEPTVEDVI SQVARAHREI
FTYAHDKLGT SPGNFNANHA SGSPPATTPQ CWESQGCPST PNDNNLLAAQ RHNEALNGLR
QGPSSYPPTW PSGPAHHSCH QPNSNGHRLC PTHVYSAPEG KAPANGLRQG NTKNVLLACP
MNMYPHGRSG RTVQEIWEDF SMSFTPAVRE VVEFAKHIPG FRDLSQHDQV TLLKAGTFEV
LMVRFASLFN VKDQTVMFLS RTTYSLQELG AMGMGDLLNA MFDFSEKLNS LALTEEELGL
FTAVVLVSAD RSGMENSASV EQLQKTLLRA LRALVLKNRP SETSRFTKLL LKLPDLRTLN
NMHSEKLLSF RVDAQ
