Insights into Prion Biology: Mechanistic Contributions and Phenotypic Consequences of Oligopeptide Repeats

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Title
Insights into Prion Biology: Mechanistic Contributions and Phenotypic Consequences of Oligopeptide Repeats
Contributors
Langlois, Christine Ricalo (creator)
Serio, Tricia (Director)
Bender, Judith (Reader)
Hart, Anne (Reader)
Salomon, Arthur (Reader)
Hines, Justin (Reader)
Brown University. BIOMED: Molecular Biology, Cell Biology, and Biochemistry (sponsor)
Doi
10.7301/Z0MS3R4M
Copyright Date
2015
Abstract
Prions are proteins that can adopt multiple distinct and stable conformations, a properly folded form and a collection of misfolded or prion forms that are each associated with a unique phenotype. For the prion phenotypes to remain stable, the misfolded form must template the conversion of the native form to a like state, an event that occurs within the context of ordered amyloid aggregates. These complexes must then be fragmented by molecular chaperones to generate new templates for conversion. These processes are dictated by the sequence of the prion protein. Here, we use the Sup35 prion protein of S. cerevisaie as a model to determine the contribution of specific elements to prion propagation. The Sup35 prion domain contains a glutamine and asparagine-rich tract and five and a half imperfect oligopeptide repeats, both of which are required for prion propagation. The glutamine and asparagine-rich element mediates templating of the prion form, but the precise function of the repeat region remains unknown. Deletion of repeats has previously been shown to impair prion propagation, while expansion of this region has been shown to increase the spontaneous appearance of the prion state. Our work shows that repeat expansion results in a decrease in steady-state aggregate size, a decrease in soluble Sup35, and an increase in the number of heritable prion aggregates, and together, these results are consistent with enhanced prion aggregate fragmentation. Repeat deletions, in the combination with deletion of a downstream element results in increased soluble Sup35 and a decrease in the number of heritable prion aggregates, suggesting deletion of these elements inhibits fragmentation. Importantly, the repeat variants did not change the physical properties of aggregates, suggesting the fragmentation effects occur through interactions with cellular chaperones. Indeed, we propose that the repeat region alters the ability of Sup35 to be processed by molecular chaperones, with repeat number being inversely correlated to processing efficiency. Taken together, our studies suggest that both the repeat and proximal regions fine-tune the process of self-replication through a change in the ability of these aggregates to be fragmented by molecular chaperones.
Keywords
Prion propagation
Sup35
oligopeptide repeats
Notes
Thesis (Ph.D. -- Brown University (2015)
Extent
xiv, 177 p.

Citation

Langlois, Christine Ricalo, "Insights into Prion Biology: Mechanistic Contributions and Phenotypic Consequences of Oligopeptide Repeats" (2015). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0MS3R4M

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