Retinoic acid receptor (Retinoic_acid_rcpt)
Type: Family

Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands . The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner . In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.

NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed 'orphan' receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature confusions in the literature. However, a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.

The retinoic acid receptors (RARs) belong to the large family of ligand responsive gene regulatory proteins that includes receptors for steroid and thyroid hormones. These proteins contain two highly conserved domains that are involved in determining their DNA and ligand-binding activities . RARs (also known as 1B nuclear receptors) mediate the biological effect of retinoids, including both naturally dietary vitamin A (retinol) metabolites and active synthetic analogs. Retinoids play key roles in a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, differentiation and apoptosis, and homeostasis. RARs function as heterodimers with retinoic X receptors by binding to specific RAR response elements (RAREs) found in the promoter regions of retinoid target genes. In the absence of ligand, the RAR-RXR heterodimer recruits the corepressor proteins NCoR or AMRT, and associated factors such as histone deacetylases or DNA-methyltransferases, leading to an inactive condensed chromatin structure, preventing transcription. Upon ligand binding, the corepressors are released, and coactivator complexes such as histone acetyltransferase or histone arginine methyltransferases are recruited to activate transcription. Three distinct RARs have been identified (termed RAR alpha, beta, and gamma) and are encoded by genes on separate chromosomes. Additional isoforms of the receptors have been described, all of which differ in the N-terminal regions. Comparison of the amino acid sequences of human and mouse RARs indicates that interspecies conservation in members of the RAR subfamily (either alpha, beta or gamma) is much higher than conservation of the receptors within species . These observations indicate that RAR-alpha, -beta and -gamma may perform specific functions. hRAR-gamma RNA has been shown to be the predominant RAR RNA species in human skin, suggesting that hRAR-gamma mediates some of the retinoid effects in this tissue .

The crystal structure of the ligand-binding domain (LBD) of the hRAR-gamma bound to all-trans retinoic acid has been determined to 2.0A resolution . Overall, the fold is similar to that of the human RXR-alpha apo-LBD, except for the C-terminal portion, which folds back towards the LBD core, contributing to the hydrophobic ligand pocket and `sealing' its entry site. A 'mouse trap' mechanism is thus proposed, whereby a ligand-induced conformational transition re-positions the amphipathic α-helix of the activating domain and forms a transcriptionally active receptor .