NR1D2_RAT
ID NR1D2_RAT Reviewed; 578 AA.
AC Q63504; Q62756; Q63542;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Nuclear receptor subfamily 1 group D member 2 {ECO:0000305};
DE AltName: Full=EAR4;
DE AltName: Full=Rev-erb-beta;
GN Name=Nr1d2 {ECO:0000312|RGD:628828};
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 [MRNA], AND ALTERNATIVE SPLICING.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=8747539;
RA Giambiagi N., Cassia R., Petropoulos I., Part D., Cereghini S., Zakin M.M.,
RA Ochoa A.;
RT "Rev-erb beta 2, a novel isoform of the Rev-erb family of orphan nuclear
RT receptors.";
RL Biochem. Mol. Biol. Int. 37:1091-1102(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 46-578.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=7945391; DOI=10.1006/bbrc.1994.2424;
RA Enmark E., Kainu T., Pelto-Huikko M., Gustafsson J.-A.;
RT "Identification of a novel member of the nuclear receptor superfamily which
RT is closely related to Rev-ErbA.";
RL Biochem. Biophys. Res. Commun. 204:49-56(1994).
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 ARNTL/BMAL1 and CLOCK. Also regulates genes involved in metabolic
CC functions, including lipid metabolism and the inflammatory response.
CC Acts as a receptor for heme which stimulates its interaction with the
CC NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression.
CC Recognizes two classes of DNA response elements within the promoter of
CC its target genes and can bind to DNA as either monomers or homodimers,
CC depending on the nature of the response element. Binds as a monomer to
CC a response element composed of the consensus half-site motif 5'-
CC [A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a
CC homodimer to a direct repeat of the core motif spaced by two
CC nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR
CC alpha (RORA) function and also negatively regulates the expression of
CC NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle
CC via repression of genes involved in lipid metabolism and myogenesis
CC including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic
CC lipid metabolism via the repression of APOC3. Represses gene expression
CC at a distance in macrophages by inhibiting the transcription of
CC enhancer-derived RNAs (eRNAs). In addition to its activity as a
CC repressor, can also act as a transcriptional activator. Acts as a
CC transcriptional activator of the sterol regulatory element-binding
CC protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in
CC the skeletal muscle (By similarity). Plays a role in the regulation of
CC circadian sleep/wake cycle; essential for maintaining wakefulness
CC during the dark phase or active period (By similarity). Key regulator
CC of skeletal muscle mitochondrial function; negatively regulates the
CC skeletal muscle expression of core clock genes and genes involved in
CC mitochondrial biogenesis, fatty acid beta-oxidation and lipid
CC metabolism (By similarity). May play a role in the circadian control of
CC neutrophilic inflammation in the lung (By similarity).
CC {ECO:0000250|UniProtKB:Q60674}.
CC -!- ACTIVITY REGULATION: The heme-bound form can bind gaseous signaling
CC molecules such as CO and nitric oxide (NO) and NO can reverse its
CC transcriptional repressor activity. {ECO:0000250}.
CC -!- SUBUNIT: Binds DNA as a monomer or a homodimer (By similarity).
CC Interacts with NCOA5 coactivator, leading to a strong increase of
CC transcription of target genes (By similarity). Interacts (via N-
CC terminus) with KAT5 (By similarity). Interacts (via C-terminus) with
CC HDAC1 (By similarity). Interacts with ZNHIT1 (By similarity). Interacts
CC with SIAH2 (By similarity). {ECO:0000250|UniProtKB:Q14995}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407}.
CC Cytoplasm {ECO:0000250|UniProtKB:Q60674}. Note=Phosphorylation by
CC CSNK1E enhances its cytoplasmic localization.
CC {ECO:0000250|UniProtKB:Q60674}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Rev-erb-beta-1;
CC IsoId=Q63504-1; Sequence=Displayed;
CC Name=Rev-erb-beta-2;
CC IsoId=Q63504-2; Sequence=VSP_003650, VSP_003651;
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: Deacetylated by HDAC1 (By similarity). Acetylation and
CC deacetylation regulate its transcriptional regulatory activity (By
CC similarity). {ECO:0000250|UniProtKB:Q14995}.
CC -!- PTM: Under more reducing intracellular redox conditions, Cys-383 is in
CC its heme-bound state, which is optimal for recruitment of the
CC NCOR1/HDAC3 corepressor complex and repression of target genes (By
CC similarity). When subjected to oxidative stress conditions, Cys-383
CC undergoes oxidation to form a disulfide bridge with Cys-373, also
CC triggering a ligand switch that results in release of bound heme and
CC derepression of target genes (By similarity).
CC {ECO:0000250|UniProtKB:Q14995}.
CC -!- PTM: Ubiquitinated by SIAH2; leading to its proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q14995}.
CC -!- PTM: Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic
CC localization. {ECO:0000250|UniProtKB:Q60674}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
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DR EMBL; X82777; CAA58021.1; -; mRNA.
DR EMBL; X78135; CAA55014.1; -; mRNA.
DR EMBL; U20796; AAA62508.1; -; mRNA.
DR PIR; S52913; S52913.
DR RefSeq; NP_671743.2; NM_147210.2. [Q63504-1]
DR AlphaFoldDB; Q63504; -.
DR SMR; Q63504; -.
DR STRING; 10116.ENSRNOP00000065585; -.
DR PhosphoSitePlus; Q63504; -.
DR PaxDb; Q63504; -.
DR PRIDE; Q63504; -.
DR Ensembl; ENSRNOT00000081845; ENSRNOP00000075553; ENSRNOG00000046912. [Q63504-1]
DR GeneID; 259241; -.
DR KEGG; rno:259241; -.
DR CTD; 9975; -.
DR RGD; 628828; Nr1d2.
DR eggNOG; KOG4846; Eukaryota.
DR GeneTree; ENSGT00940000155168; -.
DR HOGENOM; CLU_007368_2_4_1; -.
DR InParanoid; Q63504; -.
DR OMA; PASCHSD; -.
DR OrthoDB; 1240230at2759; -.
DR PhylomeDB; Q63504; -.
DR Reactome; R-RNO-383280; Nuclear Receptor transcription pathway.
DR PRO; PR:Q63504; -.
DR Proteomes; UP000002494; Chromosome 15.
DR Bgee; ENSRNOG00000046912; Expressed in skeletal muscle tissue and 20 other tissues.
DR ExpressionAtlas; Q63504; baseline and differential.
DR Genevisible; Q63504; RN.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; 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:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:RGD.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0048512; P:circadian behavior; ISS:UniProtKB.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0055088; P:lipid homeostasis; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; 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:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISS:UniProtKB.
DR GO; GO:2001014; P:regulation of skeletal muscle cell differentiation; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
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 2: Evidence at transcript level;
KW Acetylation; Activator; Alternative splicing; Biological rhythms;
KW Cytoplasm; Disulfide bond; DNA-binding; Heme; Iron; Metal-binding; Nucleus;
KW Phosphoprotein; Receptor; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..578
FT /note="Nuclear receptor subfamily 1 group D member 2"
FT /id="PRO_0000053503"
FT DOMAIN 368..578
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 100..176
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 103..123
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 140..164
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..99
FT /note="Modulating"
FT REGION 1..60
FT /note="Required for phosphorylation by CSNK1E and
FT cytoplasmic localization"
FT /evidence="ECO:0000250|UniProtKB:Q60674"
FT REGION 13..89
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 214..247
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 396..578
FT /note="Interaction with ZNHIT1"
FT /evidence="ECO:0000250"
FT COMPBIAS 13..65
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 383
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /evidence="ECO:0000250"
FT BINDING 567
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /evidence="ECO:0000250"
FT MOD_RES 46
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250"
FT MOD_RES 162
FT /note="N6-acetyllysine; by KAT5"
FT /evidence="ECO:0000250|UniProtKB:Q14995"
FT MOD_RES 163
FT /note="N6-acetyllysine; by KAT5"
FT /evidence="ECO:0000250|UniProtKB:Q14995"
FT DISULFID 336..342
FT /evidence="ECO:0000250"
FT DISULFID 373..383
FT /evidence="ECO:0000250"
FT VAR_SEQ 383
FT /note="C -> Q (in isoform Rev-erb-beta-2)"
FT /evidence="ECO:0000305"
FT /id="VSP_003650"
FT VAR_SEQ 384..578
FT /note="Missing (in isoform Rev-erb-beta-2)"
FT /evidence="ECO:0000305"
FT /id="VSP_003651"
FT CONFLICT 46
FT /note="S -> R (in Ref. 2; AAA62508)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 578 AA; 64192 MW; E2E5370D1617AB35 CRC64;
MELNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNCD ANGNPKNTDV
SSIDGVLKSD RTDCPVKTGK PGAPGMTKSH SGMTKFSGMV LLCKVCGDVA SGFHYGVHAC
EGCKGFFRRS IQQNIQYKKC LKNENCSIMR MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP
KREKQRMLIE MQSAMKTMMS TQFGGHLQSD TLAEPHEQSV PPAQEQLRPK PQLEQENIKS
TPPPSDFAKE EVIGMVTRAH KDTFLYNQEH RENSSESMPP HRGERIPRNV EQYNLNHDHR
GGGLHSHFPC SESQQHLSGQ YKGRNMMHYP NGHTVCISNG HCVNFSSAYP QRVCDRIPVG
GCSQTESRNS YLCSTGGRMH LVCPMSKSPY VDPQKSGHEI WEEFSMSFTP AVKEVVEFAK
RIPGFRDLSQ HDQVNLLKAG TFEVLMVRFA SLFDAKERTV TFLSGKKYSV DDLHSMGAGD
LLSSMFEFSE KLNGLQLSDE EMSLFTAVVL VSADRSGIEN VNSVEALQET LIRALRTLIM
KNHPNEASIF TKLLLKLPDL RSLNNMHSEE LLAFKVHP
