Mechanism of corepressor binding and release from nuclear hormone receptors (original) (raw)

  1. Laszlo Nagy,
  2. Hung-Ying Kao,
  3. James D. Love,
  4. Chuan Li,
  5. Ester Banayo,
  6. John T. Gooch,
  7. V. Krishna,
  8. K. Chatterjee,
  9. Ronald M. Evans, and
  10. John W.R. Schwabe
  11. Medical Research Council (MRC), Laboratory of Molecular Biology, Cambridge, CB2 2QH, UK; Howard Hughes Medical Institute (HHMI), The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037 USA; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK

Abstract

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

Footnotes