Co-regulator recruitment and the mechanism of retinoic acid receptor synergy
- 1 January 2002
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 415 (6868), 187-192
- https://doi.org/10.1038/415187a
Abstract
Crystal structure and co-regulator interaction studies have led to a general mechanistic view of the initial steps of nuclear receptor (NR) action. Agonist-induced transconformation of the ligand-binding domain (holo-LBD) leads to the formation of co-activator complexes, and destabilizes the co-repressor complexes bound to the ligand-free (apo) LBD1,2,3. However, the molecular basis of retinoid-X receptor (RXR) ‘subordination’ in heterodimers, an essential mechanism to avoid signalling pathway promiscuity, has remained elusive. RXR, in contrast to its heterodimer partner, cannot autonomously induce transcription on binding of cognate agonists4,5,6,7. Here we show that RXR can bind ligand and recruit co-activators as a heterodimer with apo-retinoic-acid receptor (apo-RAR). However, in the usual cellular environment co-repressors do not dissociate and they prohibit co-activator access because co-regulator binding is mutually exclusive. Accordingly, RXR subordination can be overcome in heterodimers that bind co-repressor weakly or in cells with a high co-activator content. We identify two types of RAR antagonists that differentially modulate co-regulator interaction, and we demonstrate that synergy between RAR ligands and RXR agonists6,8 results from increased interaction efficiency of a single p160 with the heterodimer, requiring two intact receptor-binding surfaces on the co-activator.Keywords
This publication has 26 references indexed in Scilit:
- Determinants of CoRNR-Dependent Repression Complex Assembly on Nuclear Hormone ReceptorsMolecular and Cellular Biology, 2001
- Heterodimeric Complex of RAR and RXR Nuclear Receptor Ligand-Binding Domains: Purification, Crystallization, and Preliminary X-Ray Diffraction AnalysisProtein Expression and Purification, 2000
- Molecular determinants of nuclear receptor-corepressor interactionGenes & Development, 1999
- Versatile Copurification Procedure for Rapid Isolation of Homogeneous RAR-RXR HeterodimersProtein Expression and Purification, 1999
- Identification and Functional Separation of Retinoic Acid Receptor Neutral Antagonists and Inverse AgonistsPublished by Elsevier BV ,1996
- Two distinct actions of retinoid-receptor ligandsNature, 1996
- A transcriptional co-repressor that interacts with nuclear hormone receptorsNature, 1995
- Unique response pathways are established by allosteric interactions among nuclear hormone receptorsCell, 1995
- Regulation of retinoid signalling by receptor polarity and allosteric control of ligand bindingNature, 1994
- Retinoids Selective for Retinoid X Receptor Response PathwaysScience, 1992