Ligands and DNA in the allosteric control of retinoid receptors function

Abstract

Abstract Retinoids are a family of compounds that include both vitamin A (all-trans retinol) and its naturally occurring metabolites such as retinoic acids (e.g. all-trans retinoic acid) as well as synthetic analogs. They are critically involved in the regulation of a wide variety of essential biological processes, such as embryogenesis and organogenesis, apoptosis, reproduction, vision, and the growth and differentiation of normal and neoplastic cells in vertebrates. The ability of these small molecules to control the expression of several hundred genes through binding to nuclear ligand-dependent transcription factors accounts for most of their functions. Three retinoic acid receptor (RARα,β,γ) and three retinoid X receptor (RXRα,β,γ) subtypes form a variety of RXR–RAR heterodimers that have been shown to mediate the pleiotropic effects of retinoids through the recruitment of high-molecular weight co-regulatory complexes to response-element DNA sequences found in the promoter region of their target genes. Hence, heterodimeric retinoid receptors are multidomain entities that respond to various incoming signals, such as ligand and DNA binding, by allosteric structural alterations which are the basis of further signal propagation. Here, we provide an overview of the current state of knowledge with regard to the structural mechanisms by which retinoids and DNA response elements act as allosteric effectors that may combine to finely tune RXR–RAR heterodimers activity.