P28700 (RXRA_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Retinoic acid receptor RXR-alpha

Alternative name(s):
Nuclear receptor subfamily 2 group B member 1
Retinoid X receptor alpha

Gene names

Name:	Rxra
Synonyms:	Nr2b1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. 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. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. Ref.1 Ref.4 Ref.6
Subunit structure	Homodimer By similarity. Heterodimer with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity. Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity. Also heterodimerizes with PPARG By similarity. Interacts with coactivator NCOA3, PELP1, SENP6, SFPQ, DNTTIP2 and RNF8. Interacts with PRMT2 By similarity. Interacts with coactivator NCOA6, and FAM120B. Interacts with ASXL1 and NCOA1. Ref.1 Ref.3 Ref.5 Ref.7 Ref.8
Subcellular location	Nucleus.
Domain	Composed of three domains: a modulating N-terminal or AF1 domain, a DNA-binding domain and a C-terminal ligand-binding or AF2 domain.
Post-translational modification	Phosphorylated on serine and threonine residues mainly in the N-terminal modulating domain. Phosphorylated on Ser-28, in vitro, by PKA. This phosphorylation is required for repression of cAMP-mediated transcriptional activity of RARA By similarity. Constiutively phosphorylated on Ser-22 in the presence or absence of ligand. Under stress conditions, hyperphosphorylated by activated JNK on Ser-61, Ser-75, Thr-87 and Ser-265. Ref.4 Ref.6 Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6 By similarity.
Sequence similarities	Belongs to the nuclear hormone receptor family. NR2 subfamily. Contains 1 nuclear receptor DNA-binding domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Receptor
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis involved in coronary vascular morphogenesis Traceable author statement PubMed 20299672. Source: DFLAT cardiac muscle cell proliferation Traceable author statement PubMed 20299672. Source: DFLAT embryo implantation Inferred from genetic interaction PubMed 9892670. Source: MGI in utero embryonic development Inferred from genetic interaction PubMed 9892670. Source: MGI maternal placenta development Inferred from genetic interaction PubMed 9892670. Source: MGI mesenchyme development Traceable author statement PubMed 20299672. Source: DFLAT negative regulation of gene expression Traceable author statement PubMed 20299672. Source: DFLAT negative regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara peroxisome proliferator activated receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 17107947. Source: BHF-UCL regulation of branching involved in prostate gland morphogenesis Inferred from mutant phenotype PubMed 12183441. Source: MGI secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development Inferred from mutant phenotype PubMed 12183441. Source: MGI ventricular cardiac muscle cell differentiation Inferred from mutant phenotype PubMed 9428411. Source: MGI ventricular cardiac muscle tissue morphogenesis Inferred from mutant phenotype PubMed 9428411. Source: MGI virus-host interaction Inferred from electronic annotation. Source: Compara visceral serous pericardium development Traceable author statement PubMed 20299672. Source: DFLAT
Cellular_component	nuclear chromatin Inferred from electronic annotation. Source: Compara nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	9-cis retinoic acid receptor activity Inferred from direct assay Ref.2. Source: MGI chromatin DNA binding Inferred from direct assay PubMed 17952069. Source: MGI retinoic acid-responsive element binding Inferred from electronic annotation. Source: Compara sequence-specific DNA binding Inferred from genetic interaction PubMed 7823919. Source: MGI steroid hormone receptor activity Inferred from electronic annotation. Source: InterPro vitamin D response element binding Inferred from electronic annotation. Source: Compara zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ASXL1	Q8IXJ9	2	EBI-346715,EBI-1646500	From a different organism.
Asxl1	P59598	2	EBI-346715,EBI-5743705
SFPQ	P23246-1	3	EBI-346715,EBI-355463	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 467

467

Retinoic acid receptor RXR-alpha

PRO_0000053567

Regions

DNA binding

140 – 205

66

Nuclear receptor

Zinc finger

140 – 160

21

NR C4-type

Zinc finger

176 – 200

25

NR C4-type

Region

1 – 139

139

Modulating domain By similarity

Region

206 – 229

24

Hinge

Region

230 – 467

238

Ligand-binding domain

Amino acid modifications

Modified residue

22

1

Phosphoserine Ref.4 Ref.6

Modified residue

28

1

Phosphoserine By similarity

Modified residue

61

1

Phosphoserine; by MAPK8 and MAPK9 Ref.4

Modified residue

75

1

Phosphoserine; by MAPK8 and MAPK9 Ref.4

Modified residue

87

1

Phosphothreonine; by MAPK8 and MAPK9 Ref.4

Modified residue

265

1

Phosphoserine; by MAPK8 and MAPK9 Ref.4

Cross-link

113

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Experimental info

Mutagenesis

22

1

S → A: Loss of constituitive phosphorylation. No effect on RXRA transcriptional activity. Ref.4 Ref.6 Ref.7

Mutagenesis

44

1

S → A: No effect on constituitive phosphorylation. Ref.4 Ref.7

Mutagenesis

48

1

S → A: No effect on constituitive phosphorylation. Ref.4 Ref.7

Mutagenesis

54

1

S → A: No effect on constituitive phosphorylation. Ref.4 Ref.7

Mutagenesis

61

1

S → A: No effect on constituitive phosphorylation, decreased stress-induced phosphorylation but no effect on RXRA transcriptional activity. Abolishes stress-induced phosphorylation but no effect on RXRA transcriptional activity; when associated with A-75 and A-87. No effect on RXRA transcriptional activity. Ref.4 Ref.7

Mutagenesis

75

1

S → A: No effect on constituitive phosphorylation, decreased stress-induced phosphorylation but no effect on RXRA transcriptional activity. Abolishes stress-induced phosphorylation but no effect on RXRA transcriptional activity; when associated with A-61 and A-87. Ref.4 Ref.7

Mutagenesis

87

1

T → A: No effect on constituitive phosphorylation, decreased stress-induced phosphorylation but no effect on RXRA transcriptional activity. Abolishes stress-induced phosphorylation but no effect on RXRA transcriptional activity; when associated with A-61 and A-75. phosphorylation. No effect on RXRA transcriptional activity. Ref.4 Ref.7

Mutagenesis

96

1

S → A: No effect on constituitive phosphorylation. Ref.4 Ref.7

Mutagenesis

101

1

S → A: No effect on constituitive phosphorylation. Ref.4 Ref.7

Mutagenesis

265

1

S → A: No effect on constiuitive phosphorylation but loss of stress-induced phosphorylation. No effect on RXRA transcriptional activity. Ref.4 Ref.7

Mutagenesis

455 – 456

2

FL → AA: Abolishes interaction with ASXL1 and NCOA1. Ref.7

Mutagenesis

459 – 460

2

ML → AA: Abolishes interaction with ASXL1 and NCOA1. Ref.7

Secondary structure

1

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467

Helix Strand Turn

Details...

Helix

231 – 234

4

Helix

237 – 246

10

Helix

269 – 282

14

Helix

284 – 289

6

Turn

292 – 296

5

Helix

299 – 321

23

Beta strand

323 – 330

8

Beta strand

336 – 338

3

Helix

339 – 344

6

Helix

348 – 357

10

Helix

359 – 364

6

Helix

369 – 380

12

Helix

391 – 412

22

Helix

419 – 424

6

Helix

426 – 438

13

Turn

439 – 443

5

Helix

447 – 449

3

Helix

452 – 461

10

Sequences

	Sequence		Length	Mass (Da)
	P28700 [UniParc]. Last modified December 1, 1992. Version 1. Checksum: 0AF62396BCDC87DB	FASTA	467	51,217
	10 20 30 40 50 60 MDTKHFLPLD FSTQVNSSSL NSPTGRGSMA VPSLHPSLGP GIGSPLGSPG QLHSPISTLS 70 80 90 100 110 120 SPINGMGPPF SVISSPMGPH SMSVPTTPTL GFGTGSPQLN SPMNPVSSTE DIKPPLGLNG 130 140 150 160 170 180 VLKVPAHPSG NMASFTKHIC AICGDRSSGK HYGVYSCEGC KGFFKRTVRK DLTYTCRDNK 190 200 210 220 230 240 DCLIDKRQRN RCQYCRYQKC LAMGMKREAV QEERQRGKDR NENEVESTSS ANEDMPVEKI 250 260 270 280 290 300 LEAELAVEPK TETYVEANMG LNPSSPNDPV TNICQAADKQ LFTLVEWAKR IPHFSELPLD 310 320 330 340 350 360 DQVILLRAGW NELLIASFSH RSIAVKDGIL LATGLHVHRN SAHSAGVGAI FDRVLTELVS 370 380 390 400 410 420 KMRDMQMDKT ELGCLRAIVL FNPDSKGLSN PAEVEALREK VYASLEAYCK HKYPEQPGRF 430 440 450 460 AKLLLRLPAL RSIGLKCLEH LFFFKLIGDT PIDTFLMEML EAPHQAT

References

[1]	"Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently." Leid M., Kastner P., Lyons R., Nakshatri H., Saunders M., Zacharewsi T., Chen J.Y., Staub A., Garnier J.-M., Mader S., Chambon P. Cell 68:377-395(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], HETERODIMERIZATION WITH RARA, FUNCTION.
[2]	"Characterization of three RXR genes that mediate the action of 9-cis retinoic acid." Mangelsdorf D.J., Borgmeyer U., Heyman R.A., Zhou J.Y., Ong E.S., Oro A.E., Kakizuka A., Evans R.M. Genes Dev. 6:329-344(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], IDENTIFICATION OF LIGAND.
[3]	"Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha." Tontonoz P., Graves R.A., Budavari A.I., Erdjument-Bromage H., Lui M., Hu E., Tempst P., Spiegelman B.M. Nucleic Acids Res. 22:5628-5634(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 5-16; 27-46; 291-307 AND 446-465, SUBUNIT. Tissue: Adipose tissue.
[4]	"Hyperphosphorylation of the retinoid X receptor alpha by activated c-Jun NH2-terminal kinases." Adam-Stitah S., Penna L., Chambon P., Rochette-Egly C. J. Biol. Chem. 274:18932-18941(1999) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-22; SER-61; SER-75; THR-87 AND SER-265, FUNCTION, MUTAGENESIS OF SER-22; SER-44; SER-48; SER-54; SER-61; SER-75; THR-87; SER-96; SER-101 AND SER-265.
[5]	"Isolation and characterization of peroxisome proliferator-activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR." Zhu Y.-J., Kan L., Qi C., Kanwar Y.S., Yeldandi A.V., Rao M.S., Reddy J.K. J. Biol. Chem. 275:13510-13516(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NCOA6.
[6]	"The phosphorylation site located in the A region of retinoic X receptor alpha is required for the antiproliferative effect of retinoic acid (RA) and the activation of RA target genes in F9 cells." Bastien J., Adam-Stitah S., Plassat J.L., Chambon P., Rochette-Egly C. J. Biol. Chem. 277:28683-28689(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-22, FUNCTION, MUTAGENESIS OF SER-22.
[7]	"Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor." Cho Y.S., Kim E.J., Park U.H., Sin H.S., Um S.J. J. Biol. Chem. 281:17588-17598(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ASXL1 AND NCOA1, MUTAGENESIS OF 455-PHE-LEU-456 AND 459-MET-LEU-460.
[8]	"Constitutive coactivator of peroxisome proliferator-activated receptor (PPARgamma), a novel coactivator of PPARgamma that promotes adipogenesis." Li D., Kang Q., Wang D.-M. Mol. Endocrinol. 21:2320-2333(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FAM120B.
[9]	"Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains." Bourguet W., Vivat V., Wurtz J.M., Chambon P., Gronemeyer H., Moras D. Mol. Cell 5:289-298(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 230-462 OF MUTANT ALA-318 IN COMPLEX WITH H.SAPIENS RARA.
[10]	"Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies." Pogenberg V., Guichou J.F., Vivat-Hannah V., Kammerer S., Perez E., Germain P., de Lera A.R., Gronemeyer H., Royer C.A., Bourguet W. J. Biol. Chem. 280:1625-1633(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 230-467 IN COMPLEX WITH RARB AND MED1.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M84817 mRNA. Translation: AAA40080.1.
X66223 mRNA. Translation: CAA46962.1.

IPI

IPI00467109.

PIR

S26668.

RefSeq

NP_035435.1. NM_011305.3.

UniGene

Mm.24624.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DKF	X-ray	2.50	A	230-462	[»]
1XDK	X-ray	2.90	A/E	230-467	[»]
3A9E	X-ray	2.75	A	228-467	[»]

ProteinModelPortal

P28700.

SMR

P28700. Positions 137-464.

ModBase

Search...

Protein-protein interaction databases

IntAct

P28700. 9 interactions.

MINT

MINT-2775018.

PTM databases

PhosphoSite

P28700.

Proteomic databases

PaxDb

P28700.

PRIDE

P28700.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000077257; ENSMUSP00000076491; ENSMUSG00000015846.
ENSMUST00000166775; ENSMUSP00000133044; ENSMUSG00000015846.

GeneID

20181.

KEGG

mmu:20181.

UCSC

uc008ixs.1. mouse.

Organism-specific databases

CTD

6256.

MGI

MGI:98214. Rxra.

Phylogenomic databases

eggNOG

NOG327099.

GeneTree

ENSGT00690000101777.

HOGENOM

HOG000260821.

HOVERGEN

HBG005606.

InParanoid

P28700.

KO

K08524.

OMA

KHFLPLD.

OrthoDB

EOG4SJ5DV.

Enzyme and pathway databases

Reactome

REACT_127416. Developmental Biology.
REACT_27166. Transcriptional Regulation of Adipocyte Differentiation in 3T3-L1 Pre-adipocytes.

Gene expression databases

ArrayExpress

P28700.

Bgee

P28700.

CleanEx

MM_RXRA.

Genevestigator

P28700.

GermOnline

ENSMUSG00000015846. Mus musculus.

Family and domain databases

Gene3D

1.10.565.10. 1 hit.
3.30.50.10. 1 hit.

InterPro

IPR021780. Nuc_recep-AF1.
IPR008946. Nucl_hormone_rcpt_ligand-bd.
IPR000536. Nucl_hrmn_rcpt_lig-bd_core.
IPR000003. Retinoid-X_rcpt/HNF4.
IPR001723. Str_hrmn_rcpt.
IPR001628. Znf_hrmn_rcpt.
IPR013088. Znf_NHR/GATA.
[Graphical view]

Pfam

PF00104. Hormone_recep. 1 hit.
PF11825. Nuc_recep-AF1. 1 hit.
PF00105. zf-C4. 1 hit.
[Graphical view]

PRINTS

PR00545. RETINOIDXR.
PR00398. STRDHORMONER.
PR00047. STROIDFINGER.

SMART

SM00430. HOLI. 1 hit.
SM00399. ZnF_C4. 1 hit.
[Graphical view]

SUPFAM

SSF48508. Str_ncl_receptor. 1 hit.

PROSITE

PS00031. NUCLEAR_REC_DBD_1. 1 hit.
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P28700.

ChEMBL

CHEMBL3084.

ChiTaRS

RXRA. mouse.

EvolutionaryTrace

P28700.

NextBio

297705.

SOURCE

Search...

Entry information

Entry name

RXRA_MOUSE

Accession

Primary (citable) accession number: P28700

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 1992
Last sequence update:	December 1, 1992
Last modified:	May 29, 2013
This is version 137 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program