Mechanism of corepressor binding and release from nuclear hormone receptors

The association of transcription corepressors SMRT and N-CoR with retinoid and thyroid receptors results in suppression of basal transcriptional activ ity. A key event in nuclear receptor signaling is the hormone-dependent rel ease of corepressor and the recruitment of coactivator. Biochemical and str uctural studies have identified a universal motif in coactivator proteins t hat mediates association with receptor LBDs. We report here the identity of complementary acting signature motifs in SMRT and N-CoR that are sufficien t for receptor binding and ligand-induced release. Interestingly, the motif contains a hydrophobic core (Phi xx Phi Phi) similar to that found in NR c oactivators. Surprisingly, mutations in the amino acids that directly parti cipate in coactivator binding disrupt the corepressor association. These re sults indicate a direct mechanistic link between activation and repression via competition for a common or at least partially overlapping binding site .