THE TETRAMERIZATION REGION OF THE RETINOID-X-RECEPTOR IS IMPORTANT FOR TRANSCRIPTIONAL ACTIVATION BY THE RECEPTOR

The retinoid X receptor (RXR), a member of the superfamily of hormone nuclear receptors, is a ligand-inducible transcription factor that is activated by the vitamin A derivative 9-cis-retinoic acid. We previous ly showed that RXR self-associates into tetramers with a high affinity and that ligand binding induces rapid dissociation of receptor tetram ers to smaller species. Here, the RXR region that is responsible for m ediating tetramer formation is identified. It is shown that this inter face, which we term the ''tetramerization domain,'' critically contain s two consecutive phenylalanine residues located at the C-terminal reg ion of the receptor. Mutation of these residues is sufficient to disru pt RXR tetramers without affecting the overall fold of the protein or interfering with ligand binding, dimer formation, or DNA binding by th e receptor. Nevertheless, the tetramer-impaired mutant was found to be transcriptionally defective. The newly characterized tetramerization domain and the previously identified main dimerization interface of RX R act autonomously to affect separate intersubunit interactions that, overall, lead to formation of tetramers, Protein-protein interactions mediated by the tetramerization domain, but not those that involve the dimerization interface, are disrupted following ligand binding by RXR Overall, these data attest to the specificity of the interaction and implicate the tetramerization interface in playing a direct role in re gulating transcriptional activation by RXR.