Strategies for Modulating the Diverse Activities of Heat Shock Protein 70.

[摘要] Heat shock protein 70 (Hsp70) is an essential regulator of protein homeostasis. Dysfunction of protein homeostasis is directly linked to many diseases, including cancer and neurodegeneration. Thus, an understanding of Hsp70’s roles in this process is expected to provide insights into the mechanisms of disease and, potentially, provide new opportunities for therapies. However, Hsp70 is also involved in essential cellular functions, so it is not clear how to safely target it. In this thesis, I first review how Hsp70 cooperates with co-chaperones to enable its many activities. Hsp70 binds to distinct co-chaperones to form complexes that have individual functions in protein folding, degradation and trafficking, suggesting that inhibition of the protein-protein interactions (PPIs) between Hsp70 and its co-chaperones might be one promising way to safely modulate this system. In Chapter 2, I performed a comprehensive, comparative study on how five TPR domain-containing co-chaperones bind to Hsp70 in vitro. These experiments highlighted the opportunities and challenges of targeting this PPI. In Chapter 3, I demonstrate how allosteric networks in Hsp70 can be manipulated, using both chemical and genetic approaches, in order to regulate binding to co-chaperones and tune chaperone activity in unexpected ways. Taking all this information together, I show in Chapter 4 that allosteric inhibitors of Hsp70 have surprisingly potent antibiotic activity in drug-resistant bacteria, which seem to rely on robust protein homeostasis. By better understanding allostery and PPIs in the Hsp70 network, I made new insights into Hsp70 biology and also discovered new lead compounds for therapeutic development.

[发布机构] University of Michigan

[效力级别] protein-protein interactions

[关键词] Heat shock protein 70;protein-protein interactions;co-chaperones;allostery;drug-resistant bacteria;protein homeostasis;Biological Chemistry;Science;Chemical Biology