Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix

The 9-cis-retinoic acid receptors (RXR alpha, RXR beta, and RXR gamma) are nuclear receptors that play key roles in multiple hormone-signaling pathway s. Biochemical data indicate that, in the absence of ligand, RXR can exist as an inactive tetramer and that its dissociation, induced by ligand, is im portant for receptor activation. In this article we report the inactivated tetramer structures of the RXR alpha ligand-binding domain (LBD), either in the absence of or in the presence of a nonactivating ligand. These structu res reveal that the RXR LED tetramer forms a compact, disc-shaped complex, consisting of two symmetric dimers that are packed along helices 3 and 11. In each monomer, the AF-2 helix protrudes away from the core domain and spa ns into the coactivator binding site in the adjacent monomer of the symmetr ic dimer. In this configuration, the AF-2 helix physically excludes the bin ding of coactivators and suggests an autorepression mechanism that is media ted by the AF-2 helix within the tetramer. The RXR-tetramer interface is as sembled from amino acids that are conserved across several closely related receptors, including the HNF4s and COUP transcription factors, and may ther efore provide a model for understanding structure and regulation of this su bfamily of nuclear receptors.