Retinoic acid receptor alpha
Also known as: NR1B1, RARA
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 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 deacetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression. Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis (By similarity). Has a role in the survival of early spermatocytes at the beginning prophase of meiosis (By similarity). In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes (By similarity). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells. In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response.
Classification
- Family (Pfam)
- PF00104 Hormone_recep, PF00105 zf-C4
- InterPro
- NHR-like_dom_sf, NR_DBD_RAR, NR_LBD_RAR, Nucl_hrmn_rcpt_lig-bd, Nuclear_hrmn_rcpt, Retinoic_acid_rcpt, Znf_hrmn_rcpt, Znf_NHR/GATA
- Functional cluster
- Mixed Regulatory & Membrane Proteins
Experimental structures · PDB · 14
- 1DKF X-ray 2.50A
- 1DSZ X-ray 1.70A
- 3A9E X-ray 2.75A
- 3KMR X-ray 1.80A
- 3KMZ X-ray 2.10A
- 4DQM X-ray 2.75A
- 5K13 X-ray 1.85A
- 6XWG X-ray 2.40A
- 7AOS X-ray 2.55A
- 7APO X-ray 2.40A
- 7QAA X-ray 2.76A
- 7WQQ X-ray 1.90A
- … and 2 more
A predicted model is available from AlphaFold.
Gene Ontology · 73
- GO:0000785 chromatin
- GO:0005737 cytoplasm
- GO:0005829 cytosol
- GO:0030425 dendrite
- GO:0005730 nucleolus
- GO:0005654 nucleoplasm
- GO:0005634 nucleus
- GO:0048471 perinuclear region of cytoplasm
- GO:0005886 plasma membrane
- GO:0032991 protein-containing complex
- GO:0090575 RNA polymerase II transcription regulator complex
- GO:0051393 alpha-actinin binding
- GO:0003682 chromatin binding
- GO:0031490 chromatin DNA binding
- GO:0003700 DNA-binding transcription factor activity
- GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
- GO:0001217 DNA-binding transcription repressor activity
- GO:0019899 enzyme binding
- GO:1901363 heterocyclic compound binding
- GO:0042826 histone deacetylase binding
- GO:0048027 mRNA 5'-UTR binding
- GO:0000900 mRNA regulatory element binding translation repressor activity
- GO:0004879 nuclear receptor activity
- GO:0019904 protein domain specific binding
- GO:0051018 protein kinase A binding
- GO:0043422 protein kinase B binding
- GO:0001972 retinoic acid binding
- GO:0044323 retinoic acid-responsive element binding
- GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
- GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding
- GO:1990837 sequence-specific double-stranded DNA binding
- GO:0005102 signaling receptor binding
- GO:0001223 transcription coactivator binding
- GO:0008270 zinc ion binding
- GO:0043277 apoptotic cell clearance
- GO:0030154 cell differentiation
- GO:0071391 cellular response to estrogen stimulus
- GO:0071222 cellular response to lipopolysaccharide
- GO:0071300 cellular response to retinoic acid
- GO:0007565 female pregnancy
- GO:0007281 germ cell development
- GO:0021766 hippocampus development
- GO:0001889 liver development
- GO:0042789 mRNA transcription by RNA polymerase II
- GO:0008285 negative regulation of cell population proliferation
- GO:0045892 negative regulation of DNA-templated transcription
- GO:0030853 negative regulation of granulocyte differentiation
- GO:1902894 negative regulation of miRNA transcription
- GO:0000122 negative regulation of transcription by RNA polymerase II
- GO:0032720 negative regulation of tumor necrosis factor production
- GO:0032689 negative regulation of type II interferon production
- GO:0051099 positive regulation of binding
- GO:0045787 positive regulation of cell cycle
- GO:0008284 positive regulation of cell population proliferation
- GO:0045893 positive regulation of DNA-templated transcription
- GO:0032736 positive regulation of interleukin-13 production
- GO:0032753 positive regulation of interleukin-4 production
- GO:0032754 positive regulation of interleukin-5 production
- GO:0045666 positive regulation of neuron differentiation
- GO:0045630 positive regulation of T-helper 2 cell differentiation
- GO:0045944 positive regulation of transcription by RNA polymerase II
- GO:0030850 prostate gland development
- GO:0006468 protein phosphorylation
- GO:0042981 regulation of apoptotic process
- GO:0031641 regulation of myelination
- GO:0048167 regulation of synaptic plasticity
- GO:0034097 response to cytokine
- GO:0032355 response to estradiol
- GO:0045471 response to ethanol
- GO:0032526 response to retinoic acid
- GO:0033189 response to vitamin A
- GO:0048384 retinoic acid receptor signaling pathway
- GO:0060010 Sertoli cell fate commitment
Disease associations
- acute promyelocytic leukemia MONDO:0012883
Drugs targeting this protein · 10
- NRX195183 agonist
- ACITRETIN agonist
- ADAPALENE agonist
- MOFAROTENE modulator
- TAZAROTENE agonist
- TAMIBAROTENE agonist
- TRETINOIN agonist
- ETRETINATE agonist
- ISOTRETINOIN agonist
- ALITRETINOIN agonist
Related proteins · sequence + function similarity
- Retinoic acid receptor alpha 1.00
- Retinoic acid receptor alpha 1.00
- Retinoic acid receptor alpha 0.99
- Retinoic acid receptor alpha 0.99
- Retinoic acid receptor alpha 0.98
- Retinoic acid receptor alpha-B 0.98
- Retinoic acid receptor beta 0.97
- Retinoic acid receptor alpha 0.97
- Retinoic acid receptor beta 0.97
- Retinoic acid receptor beta 0.96
- Retinoic acid receptor beta 0.96
- Retinoic acid receptor alpha-A 0.96
Co-cited proteins · studied together in the literature
- Ligand-dependent nuclear receptor-interacting factor 1 1 shared papers
- Retinoic acid receptor RXR-alpha 5 shared papers
- Retinoic acid receptor RXR-alpha 10 shared papers
- Zinc finger protein 536 1 shared papers
- Zinc finger protein 536 1 shared papers
- Melanoma antigen preferentially expressed in tumors 1 shared papers
- Peroxisome proliferator-activated receptor gamma 5 shared papers
- Retinoic acid receptor RXR-beta 2 shared papers
- Protein PML 2 shared papers
- Nuclear receptor subfamily 4immunitygroup A member 1 1 shared papers
- Nucleophosmin 1 shared papers
- Vitamin D3 receptor 3 shared papers
Literature · 35 cited papers
- UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability. Mol. Cell · 2023
- Nuclear hormone receptors: Ancient 9aaTAD and evolutionally gained NCoA activation pathways. J. Steroid Biochem. Mol. Biol. · 2019
- MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases. Proc. Natl. Acad. Sci. U.S.A. · 2017
- Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain · 2015
- PMID 24336203 Nature · 2014
- Familial focal segmental glomerulosclerosis (FSGS)-linked alpha-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors. J. Biol. Chem. · 2012
- The 'phantom effect' of the rexinoid LG100754: structural and functional insights. PLoS ONE · 2010
- A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat. Struct. Mol. Biol. · 2010
- Activity of retinoic acid receptor-alpha is directly regulated at its protein kinase A sites in response to follicle-stimulating hormone signaling. Endocrinology · 2010
- The transforming acidic coiled coil (TACC1) protein modulates the transcriptional activity of the nuclear receptors TR and RAR. BMC Mol. Biol. · 2010
- Small ubiquitin-like modifier-2 modification of retinoic acid receptor-alpha regulates its subcellular localization and transcriptional activity. Endocrinology · 2009
- ZNF536, a novel zinc finger protein specifically expressed in the brain, negatively regulates neuron differentiation by repressing retinoic acid-induced gene transcription. Mol. Cell. Biol. · 2009
- … and 23 more in the literature graph