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Protein

Retinoic acid receptor alpha

Gene

Rara

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.7 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi88 – 153Nuclear receptorPROSITE-ProRule annotationAdd BLAST66
Zinc fingeri88 – 108NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri124 – 148NR C4-typePROSITE-ProRule annotationAdd BLAST25

GO - Molecular functioni

GO - Biological processi

  • apoptotic cell clearance Source: MGI
  • bone development Source: MGI
  • cellular response to estrogen stimulus Source: MGI
  • cellular response to lipopolysaccharide Source: UniProtKB
  • cellular response to retinoic acid Source: MGI
  • chondroblast differentiation Source: MGI
  • embryonic camera-type eye development Source: MGI
  • face development Source: MGI
  • female pregnancy Source: Ensembl
  • germ cell development Source: UniProtKB
  • glandular epithelial cell development Source: MGI
  • growth plate cartilage development Source: MGI
  • hippocampus development Source: Ensembl
  • limb development Source: MGI
  • liver development Source: Ensembl
  • male gonad development Source: MGI
  • multicellular organism growth Source: MGI
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of cartilage development Source: MGI
  • negative regulation of cell differentiation Source: MGI
  • negative regulation of cell proliferation Source: MGI
  • negative regulation of gene expression Source: MGI
  • negative regulation of granulocyte differentiation Source: MGI
  • negative regulation of interferon-gamma production Source: MGI
  • negative regulation of transcription, DNA-templated Source: MGI
  • negative regulation of transcription by RNA polymerase II Source: MGI
  • negative regulation of translation Source: MGI
  • negative regulation of translational initiation Source: MGI
  • negative regulation of tumor necrosis factor production Source: MGI
  • neural tube closure Source: MGI
  • outflow tract septum morphogenesis Source: MGI
  • positive regulation of binding Source: MGI
  • positive regulation of cell cycle Source: MGI
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of ERK1 and ERK2 cascade Source: MGI
  • positive regulation of gene expression Source: UniProtKB
  • positive regulation of interleukin-13 production Source: MGI
  • positive regulation of interleukin-4 production Source: MGI
  • positive regulation of interleukin-5 production Source: MGI
  • positive regulation of neuron differentiation Source: MGI
  • positive regulation of phosphatidylinositol 3-kinase signaling Source: MGI
  • positive regulation of protein kinase B signaling Source: MGI
  • positive regulation of T-helper 2 cell differentiation Source: MGI
  • positive regulation of transcription, DNA-templated Source: MGI
  • positive regulation of transcription by RNA polymerase II Source: MGI
  • prostate gland development Source: Ensembl
  • protein phosphorylation Source: MGI
  • regulation of apoptotic process Source: MGI
  • regulation of granulocyte differentiation Source: MGI
  • regulation of myelination Source: MGI
  • regulation of synaptic plasticity Source: MGI
  • regulation of transcription, DNA-templated Source: MGI
  • response to cytokine Source: Ensembl
  • response to estradiol Source: Ensembl
  • response to ethanol Source: MGI
  • response to retinoic acid Source: MGI
  • response to vitamin A Source: Ensembl
  • retinoic acid receptor signaling pathway Source: MGI
  • Sertoli cell fate commitment Source: UniProtKB
  • signal transduction Source: MGI
  • spermatogenesis Source: MGI
  • trachea cartilage development Source: MGI
  • transcription, DNA-templated Source: UniProtKB-KW
  • ureteric bud development Source: MGI
  • ventricular cardiac muscle cell differentiation Source: MGI

Keywordsi

Molecular functionDNA-binding, Receptor
Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-383280 Nuclear Receptor transcription pathway
R-MMU-5362517 Signaling by Retinoic Acid

Names & Taxonomyi

Protein namesi
Recommended name:
Retinoic acid receptor alpha
Short name:
RAR-alpha
Alternative name(s):
Nuclear receptor subfamily 1 group B member 1
Gene namesi
Name:Rara
Synonyms:Nr1b1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:97856 Rara

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

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Seminiferous tubules of 6 month-old animals display varying degrees of testicular degeneration, with moderate to severe levels of germ-cell degeneration. Epithelial cells in the epididymis show general disorganization. Sperm count is reduced to about 1.7% of wild-type and sperm mobility reduced by half. Rara and Rarg, but not Rara and Rarb, double knockout mice exhibit growth retardation after 3 weeks. Defects are found in the growth plates with deficiency in cartilage. Growth retardation was noticable in limb sketal elements such as femurs. Early lethality and male sterility due to squamous metaplasia of the seminal vesicles and prostate are also observed.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi74S → A: No effect on phosphorylation, no effect on transcriptional activity. 1 Publication1
Mutagenesisi77S → A: Decreases phosphorylation and no effect on interaction with CDK7. Strongly reduces transcriptional activity. 2 Publications1
Mutagenesisi347K → A or Q: Greatly reduced interaction with RXRA and NCOR1 and transcriptional activation. 1 Publication1
Mutagenesisi347K → F: Reduced methylation levels. Little effect on interaction with RXRA or NCOR1. Small loss in transcriptional activation. 1 Publication1
Mutagenesisi369S → A: Abolishes phosphorylation and prevents phosphorylation of S-77. 1 Publication1
Mutagenesisi449S → A: No change in phosphorylation levels and no effect on transcriptional activity. 1 Publication1
Mutagenesisi456S → A: No change in phosphorylation levels and no effect on transcriptional activity. 1 Publication1
Mutagenesisi461S → A: No change in phosphorylation levels and no effect on transcriptional activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL2792
GuidetoPHARMACOLOGYi590

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000534621 – 462Retinoic acid receptor alphaAdd BLAST462

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei77Phosphoserine; by CDK72 Publications1
Modified residuei96Phosphoserine; by PKB/AKT1By similarity1
Cross-linki166Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity
Cross-linki171Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity
Modified residuei219Phosphoserine; by PKABy similarity1
Modified residuei347N6,N6,N6-trimethyllysine1 Publication1
Modified residuei369Phosphoserine; by PKA and RPS6KA51 Publication1
Cross-linki399Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity

Post-translational modificationi

Phosphorylated on serine and threonine residues. Phosphorylation does not change during cell cycle. Phosphorylation on Ser-77 is crucial for the N-terminal AF1 transcriptional activity. Under stress conditions, MAPK8 enhances phosphorylation on Thr-181, Ser-445 and Ser-461 leading to RARA ubiquitination and degradation. Phosphorylation by AKT1 inhibits the transactivation activity. On retinoic acid stimulation, phosphorylation on Ser-369 by RPS6KA5 promotes interaction with GTF2H3 and the CDK7-mediated phosphorylation of Ser-77.3 Publications
Sumoylated with SUMO2, mainly on Lys-399 which is also required for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a confromational change may occur that allows sumoylation on two additional site, Lys-166 and Lys-171. Probably desumoylated by SENP6. Sumoylation levels determine nuclear localization and regulate ATRA-mediated transcriptional activity (By similarity).By similarity

Keywords - PTMi

Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP11416
PRIDEiP11416

PTM databases

iPTMnetiP11416
PhosphoSitePlusiP11416

Expressioni

Tissue specificityi

Expressed in Sertoli cells and germ cells.1 Publication

Inductioni

By retinoic acid.1 Publication

Gene expression databases

BgeeiENSMUSG00000037992
CleanExiMM_RARA
ExpressionAtlasiP11416 baseline and differential
GenevisibleiP11416 MM

Interactioni

Subunit structurei

Interacts with PRMT2 (By similarity). Interacts with LRIF1 (By similarity). Interacts with NCOA7 in a ligand-inducible manner. Interacts (via the ligand-binding domain) with PRAME; interaction is direct and ligand (retinoic acid)-dependent. Interacts with PRKAR1A; the interaction negatively. regulates RARA transcriptional activity. Interacts with NCOR1 and NCOR2; the interaction occurs in the absence of ligand and represses transcriptional activity. Interacts with NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes. Interacts with CDK7; the interaction is enhanced by interaction with GTF2H3. Interacts with GTF2H3; the interaction requires prior phosphorylation on Ser-369 which then enhances interaction with CDK7. Interacts with ASXL1 and NCOA1. Interacts with ACTN4.By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Rps6ka5Q8C0502EBI-346736,EBI-8391218

GO - Molecular functioni

Protein-protein interaction databases

BioGridi202586, 73 interactors
ComplexPortaliCPX-584 RXRalpha-RARalpha retinoic acid receptor complex
CPX-818 RXRalpha-RARalpha-NCOA2 retinoic acid receptor complex
DIPiDIP-31480N
IntActiP11416, 12 interactors
MINTiP11416
STRINGi10090.ENSMUSP00000069744

Chemistry databases

BindingDBiP11416

Structurei

3D structure databases

ProteinModelPortaliP11416
SMRiP11416
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini183 – 417NR LBDPROSITE-ProRule annotationAdd BLAST235

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 87ModulatingAdd BLAST87
Regioni154 – 182HingeAdd BLAST29
Regioni404 – 419Required for binding corepressor NCOR1Add BLAST16

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 fingeri88 – 108NR C4-typePROSITE-ProRule annotationAdd BLAST21
Zinc fingeri124 – 148NR C4-typePROSITE-ProRule annotationAdd BLAST25

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG3575 Eukaryota
ENOG410XRZC LUCA
GeneTreeiENSGT00870000136372
HOGENOMiHOG000010312
HOVERGENiHBG005606
InParanoidiP11416
KOiK08527
OMAiQECSESY
OrthoDBiEOG091G0XCQ
PhylomeDBiP11416
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
IPR003078 Retinoic_acid_rcpt
IPR001628 Znf_hrmn_rcpt
IPR013088 Znf_NHR/GATA
PfamiView protein in Pfam
PF00104 Hormone_recep, 1 hit
PF00105 zf-C4, 1 hit
PRINTSiPR01292 RETNOICACIDR
PR00398 STRDHORMONER
PR00047 STROIDFINGER
SMARTiView protein in SMART
SM00430 HOLI, 1 hit
SM00399 ZnF_C4, 1 hit
SUPFAMiSSF48508 SSF48508, 2 hits
PROSITEiView protein in PROSITE
PS51843 NR_LBD, 1 hit
PS00031 NUCLEAR_REC_DBD_1, 1 hit
PS51030 NUCLEAR_REC_DBD_2, 1 hit

Sequences (2)i

Sequence statusi: Complete.

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

Isoform Alpha-1 (identifier: P11416-1) [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
MASNSSSCPT PGGGHLNGYP VPPYAFFFPP MLGGLSPPGA LTSLQHQLPV
60 70 80 90 100
SGYSTPSPAT IETQSSSSEE IVPSPPSPPP LPRIYKPCFV CQDKSSGYHY
110 120 130 140 150
GVSACEGCKG FFRRSIQKNM VYTCHRDKNC IINKVTRNRC QYCRLQKCFD
160 170 180 190 200
VGMSKESVRN DRNKKKKEAP KPECSESYTL TPEVGELIEK VRKAHQETFP
210 220 230 240 250
ALCQLGKYTT NNSSEQRVSL DIDLWDKFSE LSTKCIIKTV EFAKQLPGFT
260 270 280 290 300
TLTIADQITL LKAACLDILI LRICTRYTPE QDTMTFSDGL TLNRTQMHNA
310 320 330 340 350
GFGPLTDLVF AFANQLLPLE MDDAETGLLS AICLICGDRQ DLEQPDKVDM
360 370 380 390 400
LQEPLLEALK VYVRKRRPSR PHMFPKMLMK ITDLRSISAK GAERVITLKM
410 420 430 440 450
EIPGSMPPLI QEMLENSEGL DTLSGQSGGG TRDGGGLAPP PGSCSPSLSP
460
SSHRSSPATQ SP
Length:462
Mass (Da):50,735
Last modified:October 1, 1989 - v1
Checksum:i726F7799633A85AD
GO
Isoform Alpha-2 (identifier: P11416-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-60: MASNSSSCPT...SGYSTPSPAT → MYESVEVGGL...TPLWNGSNHS

Show »
Length:459
Mass (Da):50,935
Checksum:i15096242FF09896E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti163N → K in AAA40031 (PubMed:2174108).Curated1
Sequence conflicti179T → S in AAA40031 (PubMed:2174108).Curated1
Sequence conflicti284M → L in AAA40031 (PubMed:2174108).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti391G → A in embryonal carcinoma cell line RAC65. 1
Natural varianti392 – 462Missing in embryonal carcinoma cell line RAC65. Add BLAST71

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0036301 – 60MASNS…PSPAT → MYESVEVGGLTPAPNPFLVV DFYNQNRACLLQEKGLPAPG PYSTPLRTPLWNGSNHS in isoform Alpha-2. 1 PublicationAdd BLAST60

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X56572 mRNA Translation: CAA39919.1
X56565 mRNA Translation: CAA39917.1
S56656 mRNA Translation: AAB25783.1
X57528 mRNA Translation: CAA40749.1
M60909 mRNA Translation: AAA40031.1
BC010216 mRNA Translation: AAH10216.1
CCDSiCCDS36304.1 [P11416-1]
CCDS48905.1 [P11416-2]
PIRiS05050
RefSeqiNP_001169999.1, NM_001176528.1 [P11416-2]
NP_001170773.1, NM_001177302.1 [P11416-1]
NP_001170774.1, NM_001177303.1 [P11416-1]
NP_033050.2, NM_009024.2 [P11416-1]
XP_006532655.1, XM_006532592.3 [P11416-1]
XP_006532656.1, XM_006532593.2 [P11416-1]
XP_017169842.1, XM_017314353.1 [P11416-1]
UniGeneiMm.439744

Genome annotation databases

EnsembliENSMUST00000068133; ENSMUSP00000069744; ENSMUSG00000037992 [P11416-1]
ENSMUST00000107473; ENSMUSP00000103097; ENSMUSG00000037992 [P11416-2]
ENSMUST00000107474; ENSMUSP00000103098; ENSMUSG00000037992 [P11416-1]
ENSMUST00000107475; ENSMUSP00000103099; ENSMUSG00000037992 [P11416-1]
ENSMUST00000164748; ENSMUSP00000129791; ENSMUSG00000037992 [P11416-1]
GeneIDi19401
KEGGimmu:19401
UCSCiuc007lhx.1 mouse [P11416-1]
uc007lhz.2 mouse [P11416-2]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiRARA_MOUSE
AccessioniPrimary (citable) accession number: P11416
Secondary accession number(s): P22603
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: October 1, 1989
Last modified: June 20, 2018
This is version 203 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

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