Understanding the Logic of Protein Triage Decisions

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Complexes formed between heat shock protein 70 (Hsp70) and tetratricopeptide repeat (TPR) co-chaperones direct Hsp70's various activities during quality control. However, the molecular mechanisms that influence which TPR co-chaperone will bind with Hsp70 remain uncharacterized. Our long term goal is to understand how the combinatorial assembly of TPR co-chaperones with Hsp70 drives protein quality control decisions. The objective of this proposal is to gain a molecular-level understanding of these protein-protein interactions using a suite of chemical and biochemical approaches. We hypothesize that each TPR co-chaperone maintains a unique set of interactions with Hsp70. In preliminary studies, we developed the first chemical inhibitors of an Hsp70-TPR co-chaperone complex, derivatives of the natural product spergualin. Accordingly, this proposal is innovative because these probes provide the unique opportunity to transiently perturb interactions between Hsp70 and TPR co-chaperones, thus facilitating studies on protein quality control complexes associated with human disease. With this promising preliminary data, we propose two specific aims to test our central hypothesis: (1) characterize interactions between Hsp70 and TPR co-chaperones and (2) characterize the inhibition of Hsp70-TPR co-chaperone complexes using spergualin analogs. Completion of these studies will help clarify the roles of individual Hsp70-TPR protein complexes implicated in diseases of protein misfolding.