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Molecular Endocrinology 16 (2): 271-286
Copyright © 2002 by The Endocrine Society

TR Surfaces and Conformations Required to Bind Nuclear Receptor Corepressor

Adhirai Marimuthu1, Weijun Feng, Tetsuya Tagami, Hoa Nguyen1, J. Larry Jameson, Robert J. Fletterick, John D. Baxter2 and Brian L. West1

Metabolic Research Unit (A.M., W.F., H.N., J.D.B., B.L.W.) and Departments of Biochemistry and Biophysics and Cellular and Molecular Pharmacology (R.J.F.), University of California San Francisco, San Francisco, California 94143; Center for Endocrinology, Metabolism, and Molecular Medicine (J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611; and Clinical Research Institute, Center for Endocrine and Metabolic Diseases (T.T.), Kyoto National Hospital, Kyoto 612-8555, Japan

Address all correspondence and requests for reprints to: Dr. Brian L. West, Molecular Biology Department, Plexxikon, Inc., 91 Bolivar Street, Berkeley, California 94710. E-mail: bwest{at}plexxikon.com

Residues of the TR that are critical for binding the nuclear receptor corepressor (N-CoR) were identified by testing more than 100 separate mutations of the full-length human TRß that scan the surface of its ligand binding domain. The primary inferred interaction surface overlaps the surface described for binding of p160 coactivators, but differs by extending to a novel site underneath which helix 12 rests in the liganded TR, rather than including residues of helix 12. Nonconservative mutations of this surface diminished binding similarly to three isolated N-CoR receptor interaction domains (RIDs), but conservative mutations affected binding variably, consistent with a role for this surface in RID selectivity. The commonality of this surface in binding N-CoR was confirmed for the RXRs and ERs. Deletion of helix 12 increased N-CoR binding by the TR modestly, and by the RXR and ER to a much greater extent, indicating a competition between this helix and the corepressor that regulates the extent of corepressor binding by nuclear receptors. When helix 12 was deleted, N-CoR binding by the ER was stimulated by tamoxifen, and binding by the TR was stimulated by Triac, indicating that helix 12 is not the only feature that regulates corepressor binding. Two additional mutationsensitive surfaces were found alongside helix 1, near the previously described CoR box, and above helix 11, nearby but separate from residues that help link receptor in dimers. Based on effects of selected mutations on T3 and coactivator binding, and on results of combined mutations of the three sites on corepressor binding, we propose that the second and third surfaces stabilize TR unliganded conformation(s) required for efficient N-CoR binding. In transfection assays mutations of all three surfaces impaired the corepressor-mediated functions of unliganded TR repression or activation. These detailed mapping results suggest approaches for selective modulation of corepressor interaction that include the shape of the molecular binding surface, the competitive occupancy by helix 12, pharmacological stimulation, and specific conformational stabilization.




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