Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding

Abstract

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of consensus sequence AGGTCA (ref. 1). RAR/RXR heterodimers activate transcription in response to all-trans or 9-cis retinoic acid by binding to direct repeats spaced by five base pairs (DR5 elements), such that RAR occupies the downstream half-site. RXR homodimers activate transcription in response to 9-cis retinoic acid by binding to direct repeats spaced by one base pair (DR1 elements). Although RXR/RAR heterodimers bind to DR1 elements with higher affinity than RXR homodimers, in most contexts they are unable to activate transcription in response to either all-trans or 9-cis retinoic acid. As a result, RARs inhibit RXR-dependent transcription from these sites. We report that the switching of the RAR from an activator to an inhibitor of retinoid-dependent transcription requires that it be bound to the upstream half-site of DR1 elements and that it allosterically block the binding of ligand to the RXR.

Specific teratogenic effects of different retinoic acid isomers and analogs in the developing anterior central nervous system of zebrafish

“…Unlike 9-cis RA itself, however, the 9-cis RA analog SR11217 fails to activate the DR5 system. This difference between 9-cis RA and its analog, SR11217, is consistent with suggestions (Kurokawa et al, 1994;Predki et al, 1994;Perlmann et al, 1993) that the topology of the DR5 response element forces the RARoRXR heterodimer to bind with the RAR moiety on the 3' side and the RXR moiety on the nonproductive 5' side. The RXR selective ligand, SR11217, is unable to activate the DNA-bound complex since it can only bind the more 5' receptor, RXR.…”

“…Although RXRoRAR has a higher affinity for DR1 than RXRoRXR (Kliewer et al, 1992;Zhang et al, 1992;Yu et al, 1991), it is normally unable to upregulate transcription through a DR1 (Kurokawa et al, 1994; see also Forman et al, 1995). Using mutant receptor proteins, Kurokawa et al were able to show that when RAR and RXR dimerize in a conformation that allows binding to a DR1 response element, ligand cannot bind RXR (Kurokawa et al, 1994).…”

“…Using mutant receptor proteins, Kurokawa et al were able to show that when RAR and RXR dimerize in a conformation that allows binding to a DR1 response element, ligand cannot bind RXR (Kurokawa et al, 1994). At the same time, the binding polarity imposed by DR1 topology forces the RAR element, which is still capable of binding ligand, into the nonproductive 5' position-thereby precluding activation through this element by all-trans or %cis RA.…”

“…Certain nuclear receptors and receptor-like proteins act through obligatory heterodimerization with RXR (Kurokawa et al, 1994, and references therein). They are called "type II" receptors (Stunnenberg, 19931, and in typical cases of dimer-based activation, specificity is generated, in part, by the number of nucleotides separating direct repeats of a loose consensus sequence (5'-RGKTCA-3') found in the response elements.…”

‘Mealthy’ food: meat as a healthy and valuable source of micronutrients

“…In its active form, retinoic acid, it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations (Morree, 1992;Kurokowa et al, 1994). Vitamin A plays a substantial role, especially in the respiratory epithelium and the lung.…”