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Open Access Dissertation
Doctor of Philosophy (PhD)
Molecular and Cellular Biology
Year Degree Awarded
Month Degree Awarded
Lila M. Gierasch
Biochemistry | Biophysics
The folded forms of most proteins are critical to their functions. Despite the complexity of the cellular milieu and the presence of high-risk deleterious interactions, there is a high level of fidelity observed in the folding process for entire proteomes. Two important reasons for this are the presence of the quality control machinery consisting of chaperones and degradation enzymes that work jointly to optimize the population of the folded state and interaction partners that re-enforce the functional state and add to the competitive advantage of an organism. While substantial effort has been directed to understand protein folding and interactions in vitro, comparatively little of these processes are explored inside the cell. This work examines two important aspects of protein folding inside the cell; first, the impact of small molecule ligands on protein folding; and second, the impact of the proteostasis network on the folding of an obligatory chaperone client. We deploy a combination of experiments and mathematical modeling based on the principle of kinetic partitioning to understand how these phenomena sculpt the protein folding landscape inside the cell. We find that ligands specifically deplete unfolded and aggregation- or degradation - prone protein populations by favoring the folded state and the chaperone and degradation proteins work to minimize off-pathway species thus reducing the population of aggregated protein inside the cell.
Hingorani, Karan, "Investigating the impact of small molecule ligands and the proteostasis network on protein folding inside the cell" (2016). Doctoral Dissertations. 717.