Retinoic Acid Receptors: Dynamics, Stability and Folding

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DESCRIPTION (provided by applicant): Retinoid X receptors (RXR) act as homodimers or heterodimers with retinoic acid receptors (RAR) or other nuclear hormone receptors to regulate gene expression. Among the genes regulated by retinoids are those that mediate apoptosis, cholesterol absorption and efflux, expression of xenobiotic metabolizing enzymes and the oncogene v-Erb A. Because of the important roles that RXR and RAR play in growth, development and cellular differentiation retinoids are of interest as chemopreventative and chemotherapeutic agents. They are also used in the treatment of acne, psoriasis and precancerous lesions. Although X-ray structures of several receptors for retinoids have been determined, information concerning the dynamics and stability of these proteins and the effects of ligands on these properties is lacking. This proposal will use mass spectrometry in conjunction with hydrogen/deuterium exchange to (1) examine the dynamics of the RARgamma and RXRalpha ligand binding domains and the effects of ligands and protein quaternary structure on solvent accessibility of structural elements, (2) probe the kinetic mechanism by which these proteins fold and (3) analyze conformational changes by differential protease sensitivity. Thermodynamic and kinetic studies are also proposed to examine the energetics and mechanisms of folding. These studies give information that complements the static, structural data, forms the foundation for future work to characterize the interactions of these proteins with other components of their signal transduction pathways and provides new data that may aid in the design of more effective drugs that act on receptors for retinoids.