Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor's ligand binding domain.

RXR is a nuclear hormone receptor that is activated by the vitamin A metabolite 9-cis-retinoic acid. Previously, it was shown that, in the absence of a cognate ligand, RXR self-associates into tetramers, thereby silencing its own transcriptional activity. It was also shown that the tetramerization region of RXR critically contains two of three consecutive phenylalanine residues found in helix 11 (H11) of the receptor's ligand binding domain. Mutation of these residues abolishes the ability of RXR to form tetramers but also results in a receptor that is defective in its ligand-induced transcriptional activity. These observations suggest that the region may be involved in the association of RXR with transcriptional coactivators. Here, it is demonstrated that mutation of the H11 phenylalanine residues diminishes the ability of RXR to associate with the p160 coactivators TIF2 and p/CIP, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator TIF1. It is further shown that a peptide comprised of the H11 sequence effectively competes with RXR for binding of TIF2 but not of TIF1. Finally, transactivation assays demonstrate that the defective transcriptional activity of the H11 mutant can be rescued by ectopic expression of TIF1 but not of TIF2. Taken together, the results indicate that H11 is directly involved in stabilizing the interactions of RXR with p160 coactivators, but is not required for association with TIF1. This region is thus a novel coactivator interaction surface which selectively mediates the association of RXR with transcriptional coactivators.