J proteins direct the processing of misfolded proteins within cellular protein quality control

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All proteins need to acquire their defined three-dimensional conformation in order to function properly, a process termed protein folding. Protein folding can be challenged by numerous environmental and genetic assaults resulting in misfolded proteins that are usually dysfunctional and often toxic to the cell. Cellular protein quality control, i.e. all mechanisms involved in protein synthesis, maintenance, and degradation, has thus evolved in all living cells to protect cells from the detrimental consequences of protein misfolding. Molecular chaperones of the J protein class are key players in cellular protein quality control as they facilitate proper protein synthesis, maintenance, and degradation. J proteins constitute the most diverse class of molecular chaperones as the number of different J proteins in all organism that have been analyzed so far exceeds the number of all other molecular chaperone. This perplexing diversity implies that J proteins evolved to selectively target client proteins and execute specialized functions within the cellular protein quality control network. Yet the molecular and cellular mechanisms underpinning this target specificity and the distinct cellular functions of individual J proteins remain unclear. Our research program proposed here aims to determine the target specificity and distinct cellular roles of J proteins by applying a combination of genetic, systems biology, cell biological and computational approaches using yeast (Saccharomyces cerevisiae) as a genetically tractable model organism. Our research will determine general biological principles by which J proteins specify the activity of cellular protein quality control and thus execute functionally distinct roles in living cells.