Grant: Discovery Grants Program - Individual

The holdase functions of molecular chaperones in cellular protein quality control All proteins in our cells need to acquire their specific three-dimensional structure to function properly in a process termed protein folding. Cellular protein quality control, or proteostasis, has evolved to guarantee efficient protein folding and to prevent the misfolding of proteins, which can have detrimental effects on cellular function and survival. Cellular proteostasis safeguards the production, maintenance, and degradation of proteins. Molecular chaperones are key elements of proteostasis as they are involved in each stage of protein quality control. Hsp90 and Hsp70 are highly conserved, essential molecular chaperones in eukaryotic cells. Hsp90 and Hsp70 functions rely on multiple co-chaperones. Previous research has almost exclusively focused on how Hsp90 and Hsp70 regulate protein folding by an ATP hydrolysis-dependent mechanism. Here, ATP hydrolysis elicits a large conformational change in Hsp90 and Hsp70, which imparts the mechanical force to fold proteins, i.e., they can act as foldases. Moreover, co-chaperones are mostly described to participate in protein folding by merely regulating Hsp90 and Hsp70 ATP-hydrolysis thereby supporting their foldase functions. As our long-term goal, we seek to decrypt a poorly understood yet key feature of cellular protein quality control, which is the holdase function of molecular chaperones. As short-term goals for the next five years, our research program focuses on two major molecular chaperones, Hsp90 and Hsp70, and their co-chaperones to explore how they regulate cellular protein quality control as holdases in the cytoplasm using yeast (S. cerevisiae) as a genetically and biochemically tractable model system combined with in vitro approaches exploring underlying molecular mechanisms. Our research will test our central hypothesis that the holdase function of molecular chaperones is essential for cellular survival under stress. We will thus fill a critical knowledge gap by advancing our basic understanding of a crucial but hitherto mostly unexplored aspects of cellular protein quality control, which will have a significant impact on multiple stakeholders in protein engineering, protein production, the industrial use of microbes (e.g. brewing and bakeries), biomedical research (e.g. for age-depdent neurodegenerative diseases), and plant molecular biology and plant breeding (e.g., to optimize growth and yields under stress conditions). Our research program builds on our expertise in the field of proteostasis and the research tools we developed to explore the functions of molecular chaperones in vitro and in living eukaryotic cells. Our research program will give trainees with diverse backgrounds, at different experience levels, and with different time commitments the opportunity to employ biochemical, cell biological, and genetic research approaches to solve a fundamental biological problem.