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Originally published In Press as doi:10.1074/jbc.M010195200 on January 5, 2001

J. Biol. Chem., Vol. 276, Issue 18, 14987-14995, May 4, 2001
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Definition of the Surface in the Thyroid Hormone Receptor Ligand Binding Domain for Association as Homodimers and Heterodimers with Retinoid X Receptor*

Ralff C. J. RibeiroDagger §, Weijun FengDagger ||, Richard L. Wagner**, Cláudia H. R. M. CostaDagger , Alexandre C. PereiraDagger , James W. AprilettiDagger , Robert J. Fletterick**, and John D. BaxterDagger Dagger Dagger

From the Dagger  Metabolic Research Unit Department of Medicine and the ** Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143 and the § Department of Pharmaceutical Sciences, University of Brasilia, DF 70910-900, Brazil

Thyroid hormone receptors (TRs) bind as homodimers or heterodimers with retinoid X receptors (RXRs) to DNA elements with diverse orientations of AGGTCA half-sites. We performed a comprehensive x-ray crystal structure-guided mutation analysis of the TR ligand binding domain (TR LBD) surface to map the functional interface for TR homodimers and heterodimers with RXR in the absence and/or in the presence of DNA. We also identified the molecular contacts in TR LBDs crystallized as dimers. The results show that crystal dimer contacts differ from those found in the functional studies. We found that identical TR LBD residues found in helices 10 and 11 are involved in TR homodimerization and heterodimerization with RXR. Moreover, the same TR LBD surface is operative for dimerization with direct repeats spaced by 4 base pairs (DR-4) and with the inverted palindrome spaced by 6 base pairs (F2), but not with TREpal (unspaced palindrome), where homodimers appear to be simply two monomers binding independently to DNA. We also demonstrate that interactions between the TR and RXR DNA binding domains stabilize TR-RXR heterodimers on DR-4. The dimer interface can be functional in the cell, because disruption of key residues impairs transcriptional activity of TRs mediated through association with RXR LBD linked to GAL4 DNA-binding domain.

* This work was supported by National Institutes of Health Grants DK41842 (to R. J. K.) and DK09516 (to J. D. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from the Brazilian Research Council (CNPq). To whom correspondence should be addressed: Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasília, UnB, Brasilia, DF 70910-900 Brazil. Tel.: 55-61-307-2098; Fax: 55-61-347-4622; E-mail: ralff@unb.br.

|| Recipient of a postdoctoral fellowship from the National Institutes of Health.

Dagger Dagger Proprietary interests in and serves as a consultant and Deputy Director to Karo Bio AB, which has commercial interests in this area of research.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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