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Vol. 13, No. 24, pp. 3198-3208, December 15, 1999
1 University of California, San Diego (UCSD), Graduate
Student, Molecular Pathology Program, 2 Howard Hughes Medical
Institute (HHMI), 3 Department and School of Medicine,
4 Department of Cellular and Molecular Medicine,
5 Division of Endocrinology and Metabolism, UCSD, La Jolla,
California 92095-0648 USA; 6 Department of Structural
Chemistry, Glaxco Wellcome Inc., Research Triangle Park,
North Carolina 27709 USA
Retinoic acid and thyroid hormone receptors can act alternatively as
ligand-independent repressors or ligand-dependent activators, based on
an exchange of N-CoR or SMRT-containing corepressor complexes for
coactivator complexes 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 carboxyl 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 LXXLL helix, which is able to
interact with specific residues in the same receptor pocket required
for coactivator binding. We propose a model in which discrimination of
the different lengths of the coactivator and corepressor interaction
helices by the nuclear receptor AF2 motif provides the molecular basis for the exchange of coactivators for corepressors, with
ligand-dependent formation of the charge clamp that stabilizes LXXLL
binding sterically inhibiting interaction of the extended corepressor helix.
[Key Words: Transcription; nuclear receptors; corepressor-coactivator; N-CoR]
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