Prof. Jason Gestwicki
Title: Protein-Protein Interactions in Molecular Chaperone Networks Regulate Protein Homeostasis
Abstract:
Molecular chaperones, such as heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90), play an important role in the ubiquitin-proteasome system (UPS), by integrating information on client folding and recruiting the degradation machinery. This “triage” decision is made within the context of an inter-connected network of protein-protein interactions (PPIs) between chaperones, their clients and the E3 ubiquitin ligases. How do these networks make decisions? How is this network re-wired in the context of stress or disease? To address these questions, we have mapped the PPIs between Hsp70, Hsp90 and their critical co-chaperones using a suite of biophysical and structural assays. Recently, we have begun to integrate this information into biophysically-informed models that predict the percent occupancy for each PPI. This analysis has shown us that the chaperone network is remarkably robust across a range of concentrations, allowing it to make informed decisions about whether to retain or degrade clients. To illustrate these relationships, we have built a web interface that allows user-directed perturbations of the network to predict outcomes. We believe that this approach will be helpful in understanding the logic of protein quality control, while also being useful in identifying the most powerful drug targets.
Keywords: chemical biology, drug discovery, protein-protein interactions, proteostasis, protein folding
Bio:
Jason E. Gestwicki is a Professor in the Department of Pharmaceutical Chemistry and the Interim Director of the Institute for Neurodegenerative Diseases (IND) at the University of California San Francisco (UCSF). Professor Gestwicki earned a B.S. in Chemistry from the State University of New York at Fredonia and a Ph.D. in Biochemistry from University of Wisconsin-Madison before completing a postdoctoral fellowship at Stanford University. He began his independent group at the University of Michigan in 2005, where his laboratory developed chemical biology approaches to studying the roles of molecular chaperones in disease. His group developed special expertise in building drug-like small molecules that target protein-protein interactions between molecular chaperones. In 2013, he relocated to UCSF where his laboratory continues to study the mechanisms of protein homeostasis, with a focus on age-associated diseases of protein misfolding. Dr. Gestwicki has published 240+ manuscripts and is an inventor on 15+ patents. He has been active in biotechnology startups, including Amplyx (acquired by Pfizer; 2021) and Viewpoint (acquired by Visus; 2022), and is a consultant for venture capital, pharmaceutical and biotechnology firms. He is an elected Fellow of the American Association for the Advancement of Science (AAAS) and the Cell Stress Society International (CSSI). He was awarded the 2023 E. Thomas Kaiser Award from the Protein Society.
Host: Prof. Tina Wang