Description
- Abstract:
- The prion hypothesis provides an explanation for a diverse collection of previously inexplicable phenomena, ranging from the appearance, progression and spread of neurodegenerative disease in mammals to the non-Mendelian inheritance of unique traits in fungi. According to this idea, prion-associated phenotypes arise when a prion protein adopts an alternative physical state and persist when that form self-replicates. This self-replication is mediated by the assembly of alternatively folded prion protein into aggregates, which template the conversion of other forms of the protein to a like state. The inherent ability of prion proteins to harness their conformational flexibility is a central event in establishing distinct phenotypes, but the extension of this process to practice becomes a multi-step endeavor within the context of a living cell. The goal of our work is to understand how protein quality control pathways, prion protein biogenesis, and cell biology all modify prion protein misfolding in vivo to create transmissible changes in physiology. To provide a window into this interplay, our studies have focused on the Sup35/[PSI+] prion of the budding yeast Saccharomyces cerevisiae. As is the case for the mammalian prion protein PrP, a number of mutations in Sup35 have been shown to dominantly inhibit prion propagation by wildtype Sup35 in vivo. The Sup35 mutations map to two regions of the protein that have been previously implicated in prion propagation, a Q/N rich tract and the adjacent oligopeptide repeat region. Through in vivo experiments, we report the mechanism by which two mutations, Q24R, located in the former element, and G58D, located in the latter element, dominantly eliminate the [PSI+] prion. These studies demonstrate that Q24R and G58D induce prion loss specifically by altering the outcome of the interaction between prion aggregates and the molecular chaperone Hsp104 in daughter cells. Remarkably, these mutations perturb different aspects of prion aggregate dynamics to induce these changes and are thus influenced by the conformation of the prion protein and by the cellular response to protein-folding stress. Together, our studies highlight the crucial importance of both protein misfolding pathways and their cellular context in establishing prion phenotypes.
- Notes:
- Thesis (Ph.D. -- Brown University (2012)
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Citation
DiSalvo, Susanne,
"The Mechanism of Dominant-Negative Prion Inhibition Reveals the Crucial Interplay between Protein Misfolding and its Cellular Environment"
(2012).
Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0862DR6
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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations
Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department....