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J. Biol. Chem., Vol. 279, Issue 26, 27584-27590, June 25, 2004

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Quantitative Proteomics of the Thyroid Hormone Receptor-Coregulator Interactions^*

Jamie M. R. Moore, Sarah J. Galicia, Andrea C. McReynolds, Ngoc-Ha Nguyen, Thomas S. Scanlan¶, and R. Kiplin Guy¶||

From the Departments of Pharmaceutical Chemistry and ^¶Molecular & Cellular Pharmacology, University of California at San Francisco, San Francisco, California 94143-2280

The thyroid hormone receptor regulates a diverse set of genes that control processes from embryonic development to adult homeostasis. Upon binding of thyroid hormone, the thyroid receptor releases corepressor proteins and undergoes a conformational change that allows for the interaction of coactivating proteins necessary for gene transcription. This interaction is mediated by a conserved motif, termed the NR box, found in many coregulators. Recent work has demonstrated that differentially assembled coregulator complexes can elicit specific biological responses. However, the mechanism for the selective assembly of these coregulator complexes has yet to be elucidated. To further understand the principles underlying thyroid receptor-coregulator selectivity, we designed a high-throughput in vitro binding assay to measure the equilibrium affinity of thyroid receptor to a library of potential coregulators in the presence of different ligands including the endogenous thyroid hormone T3, synthetic thyroid receptor -selective agonist GC-1, and antagonist NH-3. Using this homogenous method several coregulator NR boxes capable of associating with thyroid receptor at physiologically relevant concentrations were identified including ones found in traditional coactivating proteins such as SRC1, SRC2, TRAP220, TRBP, p300, and ARA70; and those in coregulators known to repress gene activation including RIP140 and DAX-1. In addition, it was discovered that the thyroid receptor-coregulator binding patterns vary with ligand and that this differential binding can be used to predict biological responses. Finally, it is demonstrated that this is a general method that can be applied to other nuclear receptors and can be used to establish rules for nuclear receptor-coregulator selectivity.

Received for publication, March 29, 2004 , and in revised form, April 19, 2004.

^* This work was supported by Department of Defense Grant DAMD17-01-1-0188, the Sandler Research Foundation, National Institutes of Health Grants DK-52798 and DK-58390, the Center for Advanced Technology, and the Genomics and Proteomics Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Data.

Current Address: 600 University Ave., Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto, Ontario M5G 1X5, Canada.

^|| To whom correspondence should be addressed. E-mail: rguy{at}cgl.ucsf.edu.

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