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Protein

Nuclear receptor subfamily 1 group D member 2

Gene

Nr1d2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript 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 (By similarity).By similarity

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.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei383 – 3831HemeBy similarity
Binding sitei567 – 5671HemeBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi100 – 17677Nuclear receptorPROSITE-ProRule annotationAdd
BLAST
Zinc fingeri103 – 12321NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri140 – 16425NR C4-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Activator, Receptor, Repressor

Keywords - Biological processi

Biological rhythms, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Heme, Iron, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-RNO-383280. Nuclear Receptor transcription pathway.

Names & Taxonomyi

Protein namesi
Recommended name:
Nuclear receptor subfamily 1 group D member 2
Alternative name(s):
EAR4
Rev-erb-beta
Gene namesi
Name:Nr1d2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 15

Organism-specific databases

RGDi628828. Nr1d2.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotation

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 578578Nuclear receptor subfamily 1 group D member 2PRO_0000053503Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei46 – 461Phosphoserine; by GSK3-betaBy similarity
Modified residuei162 – 1621N6-acetyllysine; by KAT5By similarity
Modified residuei163 – 1631N6-acetyllysine; by KAT5By similarity
Disulfide bondi336 ↔ 342By similarity
Disulfide bondi373 ↔ 383By similarity

Post-translational modificationi

Deacetylated by HDAC1. Acetylation and deacetylation regulate its transcriptional regulatory activity (By similarity).By similarity
Under more reducing intracellular redox conditions, Cys-383 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-383 undergoes oxidation to form a disulfide bridge with Cys-373, also triggering a ligand switch that results in release of bound heme and derepression of target genes (By similarity).By similarity

Keywords - PTMi

Acetylation, Disulfide bond, Phosphoprotein

Proteomic databases

PaxDbiQ63504.
PRIDEiQ63504.

PTM databases

PhosphoSiteiQ63504.

Expressioni

Gene expression databases

ExpressionAtlasiQ63504. baseline and differential.
GenevisibleiQ63504. RN.

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 (By similarity).By similarity

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000065585.

Structurei

3D structure databases

ProteinModelPortaliQ63504.
SMRiQ63504. Positions 98-181, 380-575.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 9999ModulatingAdd
BLAST
Regioni124 – 248125HingeAdd
BLAST
Regioni249 – 569321Ligand-bindingAdd
BLAST
Regioni396 – 578183Interaction with ZNHIT1By similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi13 – 208Poly-Ser
Compositional biasi35 – 395Poly-Ser

Domaini

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

Sequence similaritiesi

Contains 1 nuclear receptor DNA-binding domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri103 – 12321NR C4-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri140 – 16425NR C4-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG4846. Eukaryota.
ENOG4110581. LUCA.
GeneTreeiENSGT00840000129707.
HOVERGENiHBG106790.
InParanoidiQ63504.
KOiK08531.
OMAiENSAETM.
OrthoDBiEOG776SQ0.
PhylomeDBiQ63504.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Rev-erb-beta-1 (identifier: Q63504-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MELNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNCD
60 70 80 90 100
ANGNPKNTDV SSIDGVLKSD RTDCPVKTGK PGAPGMTKSH SGMTKFSGMV
110 120 130 140 150
LLCKVCGDVA SGFHYGVHAC EGCKGFFRRS IQQNIQYKKC LKNENCSIMR
160 170 180 190 200
MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP KREKQRMLIE MQSAMKTMMS
210 220 230 240 250
TQFGGHLQSD TLAEPHEQSV PPAQEQLRPK PQLEQENIKS TPPPSDFAKE
260 270 280 290 300
EVIGMVTRAH KDTFLYNQEH RENSSESMPP HRGERIPRNV EQYNLNHDHR
310 320 330 340 350
GGGLHSHFPC SESQQHLSGQ YKGRNMMHYP NGHTVCISNG HCVNFSSAYP
360 370 380 390 400
QRVCDRIPVG GCSQTESRNS YLCSTGGRMH LVCPMSKSPY VDPQKSGHEI
410 420 430 440 450
WEEFSMSFTP AVKEVVEFAK RIPGFRDLSQ HDQVNLLKAG TFEVLMVRFA
460 470 480 490 500
SLFDAKERTV TFLSGKKYSV DDLHSMGAGD LLSSMFEFSE KLNGLQLSDE
510 520 530 540 550
EMSLFTAVVL VSADRSGIEN VNSVEALQET LIRALRTLIM KNHPNEASIF
560 570
TKLLLKLPDL RSLNNMHSEE LLAFKVHP
Length:578
Mass (Da):64,192
Last modified:November 1, 1996 - v1
Checksum:iE2E5370D1617AB35
GO
Isoform Rev-erb-beta-2 (identifier: Q63504-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     383-383: C → Q
     384-578: Missing.

Note: No experimental confirmation available.
Show »
Length:383
Mass (Da):42,271
Checksum:i71C8B3D759D13B35
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti46 – 461S → R in AAA62508 (PubMed:7945391).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei383 – 3831C → Q in isoform Rev-erb-beta-2. CuratedVSP_003650
Alternative sequencei384 – 578195Missing in isoform Rev-erb-beta-2. CuratedVSP_003651Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X82777 mRNA. Translation: CAA58021.1.
X78135 mRNA. Translation: CAA55014.1.
U20796 mRNA. Translation: AAA62508.1.
PIRiS52913.
RefSeqiNP_671743.2. NM_147210.2. [Q63504-1]
UniGeneiRn.10055.

Genome annotation databases

EnsembliENSRNOT00000081845; ENSRNOP00000075553; ENSRNOG00000046912. [Q63504-1]
GeneIDi259241.
KEGGirno:259241.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X82777 mRNA. Translation: CAA58021.1.
X78135 mRNA. Translation: CAA55014.1.
U20796 mRNA. Translation: AAA62508.1.
PIRiS52913.
RefSeqiNP_671743.2. NM_147210.2. [Q63504-1]
UniGeneiRn.10055.

3D structure databases

ProteinModelPortaliQ63504.
SMRiQ63504. Positions 98-181, 380-575.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000065585.

PTM databases

PhosphoSiteiQ63504.

Proteomic databases

PaxDbiQ63504.
PRIDEiQ63504.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000081845; ENSRNOP00000075553; ENSRNOG00000046912. [Q63504-1]
GeneIDi259241.
KEGGirno:259241.

Organism-specific databases

CTDi9975.
RGDi628828. Nr1d2.

Phylogenomic databases

eggNOGiKOG4846. Eukaryota.
ENOG4110581. LUCA.
GeneTreeiENSGT00840000129707.
HOVERGENiHBG106790.
InParanoidiQ63504.
KOiK08531.
OMAiENSAETM.
OrthoDBiEOG776SQ0.
PhylomeDBiQ63504.

Enzyme and pathway databases

ReactomeiR-RNO-383280. Nuclear Receptor transcription pathway.

Miscellaneous databases

PROiQ63504.

Gene expression databases

ExpressionAtlasiQ63504. baseline and differential.
GenevisibleiQ63504. RN.

Family and domain databases

Gene3Di1.10.565.10. 2 hits.
3.30.50.10. 1 hit.
InterProiIPR000536. Nucl_hrmn_rcpt_lig-bd.
IPR001723. Nuclear_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]
PfamiPF00104. Hormone_recep. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]
PRINTSiPR00398. STRDHORMONER.
PR00047. STROIDFINGER.
SMARTiSM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]
SUPFAMiSSF48508. SSF48508. 1 hit.
PROSITEiPS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Rev-erb beta 2, a novel isoform of the Rev-erb family of orphan nuclear receptors."
    Giambiagi N., Cassia R., Petropoulos I., Part D., Cereghini S., Zakin M.M., Ochoa A.
    Biochem. Mol. Biol. Int. 37:1091-1102(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING.
    Strain: Sprague-Dawley.
    Tissue: Brain.
  2. "Identification of a novel member of the nuclear receptor superfamily which is closely related to Rev-ErbA."
    Enmark E., Kainu T., Pelto-Huikko M., Gustafsson J.-A.
    Biochem. Biophys. Res. Commun. 204:49-56(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 46-578.
    Strain: Sprague-Dawley.
    Tissue: Brain.

Entry informationi

Entry nameiNR1D2_RAT
AccessioniPrimary (citable) accession number: Q63504
Secondary accession number(s): Q62756, Q63542
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 1, 1996
Last modified: May 11, 2016
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.