HETERODIMER FORMATION BY RETINOID-X-RECEPTOR - REGULATION BY LIGANDS AND BY THE RECEPTORS SELF-ASSOCIATION PROPERTIES

The retinoid X receptor (RXR), a nuclear receptor that is activated by 9-cis-retinoic acid (9cRA), can regulate transcription as a homodimer or as a heterodimer with numerous other receptors. It was previously shown that, in the absence of ligand, RXR self-associates into homotet ramers which are transcriptionally silent, and that ligand-binding ind uces dissociation of RXR tetramers into active species, dimers and mon omers. Here, the implications of tetramer formation by RXR for the abi lity of the receptor to heterodimerize with the retinoic acid and the vitamin D receptors (RAR and VDR) were studied. In addition, the effec ts of cognate ligands for RXR and for RAR and VDR on formation of the respective heterodimers were examined. The data indicate that RXR subu nits that are sequestered in tetramers were not available for interact ions with RAR or VDR and, consequently, that in the absence of a RXR l igand, only a small fraction of this receptor became involved in heter odimers. RXR-selective ligands led to tetramer dissociation, but also inhibited the formation of heterodimers, directing a significant fract ion of RXR into homodimers. Ligand binding by either heterodimerizatio n partner significantly stabilized the respective heterodimer. Thus, m aximal heterodimerization was observed in the presence of both 9cRA, a cting to release active RXR species from tetramers, and the partner's cognate ligand, acting to overcome the inhibitory effect of 9cRA on he terodimer formation. These observations suggest that, by modulating pr otein-protein interactions within homo- and hetero-oligomers of RXR, c ognate ligands control the relative distribution of potential RXR-cont aining complexes, thereby determining the transcriptional pathways tha t may be invoked under particular conditions in vivo.