Analysis of the proteostasis network and the thermostability of the proteome

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Proteins are central components of our cells. Each protein typically folds or adopts a specific three-dimensional structure, also called native state, that is required for the protein to be functional and stable. The protein folding field witnessed tremendous advances in the past 50 years. Notably, it first became clear that the information required for folding is contained within the protein sequence. It was then discovered that folding is often assisted by chaperones that are specialized molecular machines. A major challenge is now to determine how the combination of these two actions leads to a stable proteome, which is the ensemble of all proteins in the cell. While chaperone proteins can be assessed on an individual basis, thanks to a myriad of elegant and sophisticated biochemical assays, it remains difficult to translate this knowledge into the cellular context, in which millions of different proteins cohabit in a very confined environment. We therefore need to develop new systems-wide approaches and tools to determine how the individual chaperones contribute to the overall stability of the proteome. ***In this research program, we propose to employ several complementary approaches to probe which proteins are destabilized upon stresses due to the loss of their three-dimensional structures. Our hypothesis is that destabilization is caused by both intrinsic features that make the proteins more vulnerable and the inability of specific chaperones to prevent their destabilization under the stress situations. To test this idea, we will employ the well characterized Saccharomyces cerevisiae yeast model organism that is less complex and more malleable than human cells. We will first determine which proteins in the proteome are more often destabilized and identify which characteristics are shared among those proteins using computational biology approaches. We will then selectively remove specific chaperones from cells to determine which proteins are further destabilized in these conditions. Our goal is to unveil some of the fundamental rules that govern proteome stability. A better knowledge of how the proteome can be maintained stable has wide implications from our understanding of cellular aging to industrial applications that rely on recombinant protein production. **