Molecular determinants of nuclear receptor-corepressor interaction

Retinoic acid and thyroid hormone receptors can act alternatively as ligand -independent repressors or ligand-dependent activators, based on an exchang e of N-CoR or SMRT-containing corepressor complexes for coactivator complex es in response to ligands. We provide evidence that the molecular basis of N-CoR recruitment is similar to that of coactivator recruitment, involving cooperative binding of two helical interaction motifs within the N-CoR carb oxyl terminus to both subunits of a RAR-RXR heterodimer. The N-CoR and SMRT nuclear receptor interaction motifs exhibit a consensus sequence of LXX I/ H I XXX I/L, representing an extended helix compared to the coactivator LXX LL helix, which is able to interact with specific residues in the same rece ptor pocket required for coactivator binding. We propose a model in which d iscrimination of the different lengths of the coactivator and corepressor i nteraction helices by the nuclear receptor AF2 motif provides the molecular basis for the exchange of coactivators for corepressors, with ligand-depen dent formation of the charge clamp that stabilizes LXXLL binding sterically inhibiting interaction of the extended corepressor helix.