Protein-protein interactions in the regulation of RAR–RXR heterodimers transcriptional activity

The three retinoic acid receptor subtypes (RARα, RARβ and RARγ) act as ligand-inducible transcription factors binding to DNA regulatory elements in the promoter regions of target genes by forming heterodimers with the retinoid X receptors (RXRα, RXRβ and RXRγ). They act as ligand-dependent transcription factors that regulate a large variety of genes involved in cell growth, differentiation, survival and death. The (patho)physiological functions of RAR-RXR heterodimers rely on a dynamic sequence of protein-protein interactions, many of which being modulated by natural (retinoic acid) or synthetic ligands. Direct protein-protein interactions include heterodimerization between RARs and RXRs, recruitment (and release) of transcriptional coactivators and corepressors, cross-talk with other transcription factors, including nuclear receptors, or transient association with many enzymes involved in post-translational modifications to cite the most prominent ones. This chapter describes structural, biochemical, biophysical and cell-based assays to monitor protein-protein interactions relevant to the retinoic acid signaling pathways with a focus on those for which a structural description has been provided.