Mechanism of corepressor binding and release from nuclear hormone receptors
- Laszlo Nagy,
- Hung-Ying Kao,
- James D. Love,
- Chuan Li,
- Ester Banayo,
- John T. Gooch,
- V. Krishna,
- K. Chatterjee,
- Ronald M. Evans, and
- John W.R. Schwabe
- 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.
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Footnotes
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↵Present address: Department of Biochemistry and Molecular Biology, University Medical School of Debrecen, Debrecen, Hungary 4H-012.
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↵These authors contributed equally.
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↵Corresponding authors.
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E-MAIL evans{at}salk.edu; FAX (858) 455-1349.
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E-MAIL jws2{at}mrc-lmb.cam.ac.uk; FAX 44 1223 213 556.
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- Received September 27, 1999.
- Accepted November 4, 1999.
- Cold Spring Harbor Laboratory Press
