MGP Database

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MGP004074

UniProt Annotations

Entry Information
Gene Namenuclear receptor subfamily 1, group D, member 2
Protein EntryNR1D2_HUMAN
UniProt IDQ14995
SpeciesHuman
Comments
Comment typeDescription
DomainComposed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
Enzyme RegulationThe heme-bound form can bind gaseous signaling molecules such as CO and nitric oxide (NO) and NO can reverse its transcriptional repressor activity. {ECO:0000269|PubMed:19243223}.
FunctionTranscriptional 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 ARNTL/BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the 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 nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle. {ECO:0000269|PubMed:17892483, ECO:0000269|PubMed:17996965}.
InteractionO08785:Clock (xeno); NbExp=2; IntAct=EBI-6144053, EBI-79859; Q96LA8:PRMT6; NbExp=2; IntAct=EBI-6144053, EBI-912440;
PtmDeacetylated by HDAC1. Acetylation and deacetylation regulate its transcriptional regulatory activity. {ECO:0000269|PubMed:17996965}.
PtmUnder more reducing intracellular redox conditions, Cys-384 is in its heme-bound state, which is optimal for recruitment of the NCOR1/HDAC3 corepressor complex and repression of target genes. When subjected to oxidative stress conditions, Cys-384 undergoes oxidation to form a disulfide bridge with Cys-374, also triggering a ligand switch that results in release of bound heme and derepression of target genes.
SimilarityBelongs to the nuclear hormone receptor family. NR1 subfamily. {ECO:0000305}.
SimilarityContains 1 nuclear receptor DNA-binding domain. {ECO:0000255|PROSITE-ProRule:PRU00407}.
Subcellular LocationNucleus {ECO:0000255|PROSITE- ProRule:PRU00407, ECO:0000269|PubMed:17892483, ECO:0000269|PubMed:17996965}.
SubunitBinds DNA as a monomer or a homodimer. Interacts with NCOA5 coactivator, leading to a strong increase of transcription of target genes. Interacts (via N-terminus) with KAT5. Interacts (via C-terminus) with HDAC1. Interacts with ZNHIT1. {ECO:0000269|PubMed:11113208, ECO:0000269|PubMed:17892483, ECO:0000269|PubMed:17996965}.
Tissue SpecificityWidely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues.
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