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Protein

Nuclear receptor subfamily 1 group D member 2

Gene

NR1D2

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 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.2 Publications

Enzyme regulationi

The heme-bound form can bind gaseous signaling molecules such as CO and nitric oxide (NO) and NO can reverse its transcriptional repressor activity.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei384Heme1
Binding sitei568Heme1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi100 – 176Nuclear receptorPROSITE-ProRule annotationAdd BLAST77
Zinc fingeri103 – 123NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri140 – 164NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

GO - Biological processi

Keywordsi

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

Enzyme and pathway databases

ReactomeiR-HSA-383280 Nuclear Receptor transcription pathway

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear receptor subfamily 1 group D member 2
Alternative name(s):
Orphan nuclear hormone receptor BD73
Rev-erb alpha-related receptor
Short name:
RVR
Rev-erb-beta
V-erbA-related protein 1-related
Short name:
EAR-1R
Gene namesi
Name:NR1D2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi

Organism-specific databases

EuPathDBiHostDB:ENSG00000174738.12
HGNCiHGNC:7963 NR1D2
MIMi602304 gene
neXtProtiNX_Q14995

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

Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi9975
PharmGKBiPA31749

Chemistry databases

ChEMBLiCHEMBL1961784
GuidetoPHARMACOLOGYi597

Polymorphism and mutation databases

BioMutaiNR1D2
DMDMi215274122

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000535011 – 579Nuclear receptor subfamily 1 group D member 2Add BLAST579

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei46Phosphoserine; by GSK3-betaBy similarity1
Modified residuei162N6-acetyllysine; by KAT51 Publication1
Modified residuei163N6-acetyllysine; by KAT51 Publication1
Disulfide bondi337 ↔ 3431 Publication
Disulfide bondi374 ↔ 3841 Publication

Post-translational modificationi

Deacetylated by HDAC1. Acetylation and deacetylation regulate its transcriptional regulatory activity.1 Publication
Under 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.

Keywords - PTMi

Acetylation, Disulfide bond, Phosphoprotein

Proteomic databases

EPDiQ14995
MaxQBiQ14995
PaxDbiQ14995
PeptideAtlasiQ14995
PRIDEiQ14995

PTM databases

iPTMnetiQ14995
PhosphoSitePlusiQ14995

Expressioni

Tissue specificityi

Widely 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.

Gene expression databases

BgeeiENSG00000174738
CleanExiHS_NR1D2
ExpressionAtlasiQ14995 baseline and differential
GenevisibleiQ14995 HS

Organism-specific databases

HPAiHPA053868
HPA054798

Interactioni

Subunit structurei

Binds 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 ZNHIT1.3 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi115299, 26 interactors
IntActiQ14995, 7 interactors
MINTiQ14995
STRINGi9606.ENSP00000310006

Chemistry databases

BindingDBiQ14995

Structurei

Secondary structure

1579
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi398 – 420Combined sources23
Helixi424 – 428Combined sources5
Helixi431 – 449Combined sources19
Helixi451 – 453Combined sources3
Turni456 – 459Combined sources4
Beta strandi460 – 462Combined sources3
Beta strandi468 – 470Combined sources3
Helixi471 – 476Combined sources6
Helixi481 – 495Combined sources15
Helixi500 – 512Combined sources13
Helixi516 – 518Combined sources3
Helixi522 – 543Combined sources22
Helixi549 – 573Combined sources25

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2V0VX-ray2.40A/B/C/D387-579[»]
2V7CX-ray2.40A/B387-579[»]
3CQVX-ray1.90A381-579[»]
4N73X-ray1.87A381-578[»]
ProteinModelPortaliQ14995
SMRiQ14995
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ14995

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini369 – 579NR LBDPROSITE-ProRule annotationAdd BLAST211

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 99ModulatingAdd BLAST99
Regioni124 – 249HingeAdd BLAST126
Regioni397 – 579Interaction with ZNHIT11 PublicationAdd BLAST183

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi13 – 20Poly-Ser8
Compositional biasi35 – 39Poly-Ser5

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 fingeri103 – 123NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri140 – 164NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4846 Eukaryota
ENOG4110581 LUCA
HOGENOMiHOG000261691
HOVERGENiHBG106790
InParanoidiQ14995
KOiK08531
OrthoDBiEOG091G066Y
PhylomeDBiQ14995
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.

Q14995-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MEVNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNSD
60 70 80 90 100
TNGNPKNGDL ANIEGILKND RIDCSMKTSK SSAPGMTKSH SGVTKFSGMV
110 120 130 140 150
LLCKVCGDVA SGFHYGVHAC EGCKGFFRRS IQQNIQYKKC LKNENCSIMR
160 170 180 190 200
MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP KREKQRMLIE MQSAMKTMMN
210 220 230 240 250
SQFSGHLQND TLVEHHEQTA LPAQEQLRPK PQLEQENIKS SSPPSSDFAK
260 270 280 290 300
EEVIGMVTRA HKDTFMYNQE QQENSAESMQ PQRGERIPKN MEQYNLNHDH
310 320 330 340 350
CGNGLSSHFP CSESQQHLNG QFKGRNIMHY PNGHAICIAN GHCMNFSNAY
360 370 380 390 400
TQRVCDRVPI DGFSQNENKN SYLCNTGGRM HLVCPLSKSP YVDPHKSGHE
410 420 430 440 450
IWEEFSMSFT PAVKEVVEFA KRIPGFRDLS QHDQVNLLKA GTFEVLMVRF
460 470 480 490 500
ASLFDAKERT VTFLSGKKYS VDDLHSMGAG DLLNSMFEFS EKLNALQLSD
510 520 530 540 550
EEMSLFTAVV LVSADRSGIE NVNSVEALQE TLIRALRTLI MKNHPNEASI
560 570
FTKLLLKLPD LRSLNNMHSE ELLAFKVHP
Length:579
Mass (Da):64,625
Last modified:November 25, 2008 - v3
Checksum:i39BDDCD323BD14BF
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti519 – 520IE → NRK in AAA65937 (PubMed:7997240).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04737721P → H1 PublicationCorresponds to variant dbSNP:rs17854365Ensembl.1
Natural variantiVAR_047378282Q → K1 PublicationCorresponds to variant dbSNP:rs17857305Ensembl.1
Natural variantiVAR_047379288P → R1 PublicationCorresponds to variant dbSNP:rs17857306Ensembl.1
Natural variantiVAR_047380386L → M3 PublicationsCorresponds to variant dbSNP:rs4858097Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D16815 mRNA Translation: BAA20088.1
AK313464 mRNA Translation: BAG36250.1
AC124914 Genomic DNA No translation available.
BC045613 mRNA Translation: AAH45613.1
L31785 mRNA Translation: AAA65937.1
CCDSiCCDS33718.1
PIRiA57057
RefSeqiNP_005117.3, NM_005126.4
UniGeneiHs.37288

Genome annotation databases

EnsembliENST00000312521; ENSP00000310006; ENSG00000174738
GeneIDi9975
KEGGihsa:9975
UCSCiuc003ccs.2 human

Keywords - Coding sequence diversityi

Polymorphism

Entry informationi

Entry nameiNR1D2_HUMAN
AccessioniPrimary (citable) accession number: Q14995
Secondary accession number(s): B2R8Q3, O00402, Q86XD4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 25, 2008
Last modified: May 23, 2018
This is version 171 of the entry and version 3 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. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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