Prof. Jason Gestwicki, University of Michigan

Strategies for Targeting Protein-Protein Interactions in the Heat Shock Protein 70 (Hsp70) Complex

School Colloquia

Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein folding and quality control. In these tasks, Hsp70 is assisted by co-chaperones, including J proteins and nucleotide exchange factors, which associate with Hsp70 and help guide its activities. To better understand Hsp70’s cellular roles, our strategy is to identify drug-like small molecules that control the interactions between Hsp70 and its critical co-chaperones. More specifically, we have been exploring a ‘gray box” strategy in which defined Hsp70 complexes are re-constituted in vitro and their emergent activities are used to design chemical screening campaigns. Using this approach, we have screened >155,000 diverse compounds against a number of distinct Hsp70 complexes and identified candidates that interrupt protein-protein interactions with co-chaperones. We have shown that these compounds reduce the levels of some misfolded proteins, such as tau and huntingtin, in cell models. These results suggest that formation of specific Hsp70 complexes controls the fate of some misfolded proteins in disease. Using these chemical probes and additional screening efforts, our long-term goal is to understand how Hsp70’s substrates are selected and how multi-chaperone complexes guide triage decisions.

For more information contact Prof. Raquel Lieberman (404-385-3663).