Structural and biochemical studies of the hsp90 chaperone proteins
Seidler, Paul M.
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The hsp90 family of proteins is a highly conserved class of ATP-dependent macromolecular chaperones which aid in the late-stage folding and/or stabilization of a diverse group of nascent proteins, which are referred to as clients. In mammals there are four hsp90 paralogs, two in the cytosol (Hsp90 alpha and beta), one in the mitochondrion (TRAP1), and one in the ER (Grp94). The hsp90 chaperones are central to a number of cellular processes, as evidenced by the fact that Hsp90 comprises 1-2% of the cytosolic protein pool, and Grp94 is the most abundant ER glycoprotein. Remarkably however, despite the prevalence of these chaperones in the cell and their ubiquitous involvement in cellular pathways, we have only recently begun to uncover details concerning their mechanism of action. Although a complete molecular picture of how hsp90 paralogs mediate client maturation remains elusive, the process is driven by conformational changes associated with ATP binding and hydrolysis. Hsp90 has garnered a great deal of attention as a pharmaceutical target, and inhibitors may be useful for treating a host of diseases including cancer, infection, and neurological disorders. The goals of the studies presented in this dissertation were to elucidate (i) how paralog-specific inhibitors target the ER paralog, Grp94, (ii) how ATP lid dynamics differ between the Hsp90 and Grp94 paralogs, and finally (iii) how Grp94 interacts with cellular partner proteins.