Agonist-controlled competition of RAR and VDR nuclear receptors for heterodimerization with RXR is manifested in their DNA-binding

The Protein Dynamics and Interactions Research Group found previously that nuclear receptors (NRs) compete for heterodimerization with their common partner, retinoid X receptor (RXR), in a ligand-dependent manner. To investigate potential competition in their DNA-binding, Bálint Rehó, György Vámosi and their colleagues monitored the mobility of retinoic acid receptor (RAR) and vitamin D receptor (VDR) in live cells by fluorescence correlation spectroscopy. When all three NRs were coexpressed, the DNA-bound fraction of either RAR or VDR was enhanced by its own and diminished by the competing NR's agonist. When treated with both ligands, the DNA-bound fraction of RAR increased as much as due to its own agonist, whereas that of VDR increased less. RXR agonist also increased DNA-binding of RAR at the expense of VDR. In summary, competition between RAR and VDR for RXR is also manifested in their DNA-binding in an agonist-dependent manner: RAR dominates over VDR in the absence of agonist or with both agonists present. Thus, side-effects of NR-ligand-based (retinoids, thiazolidinediones) therapies may be ameliorated by other NR ligands and be at least partly explained by reduced DNA-binding due to competition. These results also complement the model of NR action by involving competition both for RXR and for DNA-sites. Their results were published in the Journal of Biological Chemistry. DOI: 10.1016/j.jbc.2023.102896 

Graphical representation of the ligand-directed competition for DNA-binding between RAR and VDR

In the presence of the VDR ligand, calcitriol (top right), VDR dominates DNA-binding whereas in the presence of the RAR ligand, AM580 (top left), or both ligands (bottom left), RAR does so. The presence of RXR-specific LG268 agonist (bottom right) favors the binding of RAR (Created with BioRender.com).