ISOLATION AND CHARACTERIZATION OF PROGESTERONE RECEPTOR

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When in its inactive form in cytosol extracts, the avian progesterone receptor, like most steroid receptors, is complexed with the heat shock protein hsp90. This complex does not form through a simple association, but through a process that requires ATP hydrolysis and several additional proteins. other proteins in the receptor complex are hsp70 and three peptidylprolyl isomerases or immunophilins. Two of these, FKBP52 and FKBP54, bind the immunosuppressant drug FK506 and the third, CyP-40, binds cyclosporin A. A final protein in the receptor complex is p23 which is a unique phosphoprotein. We have made much progress in the description of receptor complexes and in the development of cell-free systems for their study. The objective of the proposed studies is to further our understanding on the assembly of receptor complexes, their dissociation upon hormone binding, and the functional significance of the receptor- associated proteins. This will be accomplished through the development and manipulation of chemically defined systems for receptor complex formation using purified proteins and specific antibody probes. Sub-complexes will also be analyzed to describe intermediates in complex formation and the various protein:protein interactions that occur. Finally, a yeast system with progesterone receptor will be used to identify the homologs of receptor-associated proteins in yeast and to test the biological significance of specific proteins of the complex by mutagenesis. These studies should provide new and valuable information on the earliest events in progesterone action and the axillary proteins that are needed for these events.