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Permanent link (DOI): https://doi.org/10.7939/R3988F

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Prions and regulation of prion variants in Saccharomyces cerevisiae Open Access

Descriptions

Other title
Subject/Keyword
[PSI+]
chaperone
prion variant
Rnq1
Prion
[PIN+]
Hsp90
Sup35
Riq1
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Lancaster, David L
Supervisor and department
Rachubinski, Richard (Cell Biology)
Examining committee member and department
Glover, John (Biochemistry)
LaPointe, Paul (Cell Biology)
Power, Christopher (Medicine)
Melancon, Paul (Cell Biology)
Westaway, David (Neurology)
Department
Department of Cell Biology
Specialization

Date accepted
2013-03-11T15:22:23Z
Graduation date
2013-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Prions are infectious proteins. In their prion conformation, they catalyze the transformation of non-prion isomers into prions. Another characteristic common to currently identified prions is that they form amyloid aggregates. They occur in several mammals and multiple species of yeast, acting in a variety of biological processes, and their numbers continue to grow. Prions can adopt different infectious conformations known as “strains” in mammals or “variants” in yeast, each with distinct, epigenetically inheritable phenotypes. Mechanisms by which prion variants are determined remain unclear. In this thesis, I describe the characterization of a potential novel prion in Saccharomyces cerevisiae, Riq1p. I show that Riq1p can form SDS/heat-resistant aggregates and is sufficient to maintain a reversibly curable, nonsense-suppression phenotype when it is used to replace Sup35p’s prion determining domain. These findings are significant because, unlike the majority of previously identified prion proteins, Riq1p is richer in glutamine (Q) than asparagine (N) and its prion-like behavior cannot be isolated to its Q/N rich domain. In this way, Riq1p provides an important exception to amino-acid composition trends proposed to govern prion behavior and suggests that such theories require revision. I also report the results of a targeted screen for genes affecting early stages of de novo conversion of the prion protein Sup35p into its [PSI+] conformation. From this screen, I identify several chaperone genes that affect the variant of the S. cerevisiae prion Rnq1p/[PIN+]. I show that the deletion of specific chaperone genes alters [PIN+] variant phenotypes, including [PSI+] induction efficiency, Rnq1p aggregate morphology/size, and variant dominance. Genetic analysis demonstrated that the deletion-induced phenotypic changes are stably inherited in a non-Mendelian manner even after restoration of the deleted gene, confirming that they are due to a bona fide change in the [PIN+] variant. Taken together, these results not only show that it is possible to alter an established prion variant in vivo, but also that molecular chaperones may play an important part in this mechanism for regulating prion variants.
Language
English
DOI
doi:10.7939/R3988F
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Lancaster, D.L., C.M. Dobson, and R.A. Rachubinski. 2013. Chaperone proteins select and maintain [PIN+] prion conformations in Saccharomyces cerevisiae. JBC. 228:1266-76.

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