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Vol. 13, No. 24, pp. 3209-3216, December 15, 1999
1 Medical Research Council (MRC), Laboratory of Molecular
Biology, Cambridge, CB2 2QH, UK; 2 Howard Hughes Medical
Institute (HHMI), 3 The Salk Institute for Biological Studies,
Gene Expression Laboratory, La Jolla, California 92037 USA;
4 Department of Medicine, University of Cambridge,
Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
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 (
xx) 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.
[Key Words: Transcription corepressors; SMRT; coactivator binding; corepressor binding; nuclear hormone receptors]
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