MOLECULAR CHAPERONES AND SIGNAL TRANSDUCTION

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DESCRIPTION (Adapted from the applicant's abstract): Steroid hormone receptors, among them the human androgen receptor, are maintained in an inactive state prior to hormone binding by association with hsp90 and other molecular chaperons. The studies proposed by Dr. Caplan will focus on the role of the molecular chaperon Ydj1p in this process, a DnaJ homolog that functions together with Hsp70 in protein assembly and disassembly events. Previous biochemical studies indicated that Hsp70 plays a direct role in the assembly of Hsp90 with the glucocorticoid receptor in a process requiring ATP, and a similar role of Ydj1p has been confirmed by genetic studies in vivo. Studies are proposed which will use a combination of genetic and biochemical approaches to dissect this process with a view to understanding the role of Ydj1p in receptor activation. These studies will be performed with yeast cells expressing human androgen receptor. The specific aims of this proposal are: 1). To define the domains of YDJ1 that function in human androgen receptor activation. 2). To determine where Ydj1p functions in the process of androgen receptor activation, and 3). To characterize how a DnaJ/Hsp70 chaperon pair functions in the activation of the androgen receptor in higher eukaryotes.