Retinoic acid receptors (RARs) are members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. Three RAR family members exist, alpha, beta and gamma, each gene being expressed as several isomers that vary in their N-terminus. Of note, retinoic acid can also modulate the transcriptional activity of other members of the nuclear receptor superfamily, such as PPARbeta/delta, RORbeta and COUP-TFII.^[1][2][3]

RARs share the common nuclear receptor organization in several regions of homology, corresponding to different functional domains.^[4] The N-terminal A/B region contains the AF-1 transactivation domain, which functions independently of ligand binding. The DNA binding domain, located in region C, is composed of two C4-type zinc fingers and its structure is characteristic of the nuclear receptor superfamily. Finally, the D/E/F regions contain the ligand-binding domain and a second transactivation domain, AF-2, which functions in a ligand-dependent fashion. The structure of ligand binding domain is also typical of the nuclear receptor superfamily, and is formed by a sandwich of 12 alpha helices. The RAR ligand binding domains all bind the all-trans and 9-cis isomers of retinoic acid, but divergence in the ligand-contacting residues has been exploited for the developement of RAR-specific ligands. Ligand binding stabilizes a conformation of the ligand binding domain that allows recruitment of co-activators, often through insertion of an alpha-helical LXXLL coactivator motif into a pocket formed by residues of helices 3, 4 and 12 in the ligand binding domain. The integrity of the C-terminal helix H12, whose positioning differs markedly in the apo- and holo-forms for RARs, was shown to be crucial for induction of F9 cell differentiation by retinoids.^[5]

RARs bind DNA as heterodimers with members of another family of NRs, the retinoid X receptors (RXRs), which also include three genes expressed as different isoforms.^[6][7][8] RAR/RXR heterodimers bind specific retinoic acid response elements (RAREs), usually composed of two or more repeats of the motif PuG(G/T)TCA arranged as direct repeats but also inverted or everted repeats.^[9] In the absence of the ligand retinoic acid (RA), the RAR/RXR heterodimers bound to DNA repress transcription through recruitment of corepressors such as NCoR or SMRT and their associated complexes with histone deacetylase activity. Ligand binding induces a conformational change that induces the dissociation of corepressors and the recruitment of coactivators, including histone acetyl-transferases, histone methyl-transferases, ATP-dependent chromatin remodeling complexes, and of components of the mediator complex and basal transcription machinery.^[10][11][12]

RARs play important roles during development and control cell differentiation, proliferation, apoptosis and metabolism through direct DNA binding, but also through tethering to DNA via protein-protein interactions with other transcription factors and through non-genomic mechanisms of action.^[12][13][14] Although RARs differ in their patterns of expression, functional redundancy has been observed in mouse knock-out models. Their patterns of DNA binding appear largely similar,^[15] although differences in their transcriptional activation function should result in receptor-specific target gene networks.