In the intensely crowded environment of living cells, proteins have difficulty folding into their proper structures and in maintaining these structures in face of the normal wear and tear of their existence. Misfolded proteins are responsible for some of the most devastating diseases of mankind. But the folding problem is as old as life itself. Not surprisingly, the mechanisms that cells use to cope with it (proteins chaperones, remodeling factors, osmolytes, and sophisticated degradation machineries) are universally employed and highly conserved. Moreover, it now appears that the same types of misfolded states that can be terribly toxic in some circumstances can be beneficial in others. This allows us to use tractable model organisms to study deeply complex protein folding problems that are of interest to human biology and medicine. This application aims to take advantage of yeast cells, and proteins derived from them, to investigate a particularly important type of fold, the self-templating amyloids, and the protein chaperones and remodeling factors that govern their conformational states. We will focus on two such proteins from the yeast Saccharomyces cerevisiae, Sup35, Rnq1, and one from Aplysia californica, CPEB. Using an array of biochemical and genetic methods in our own laboratory, and collaborating with others who have biophysical expertise far beyond our own, we will a) determine the basic structural framework of amyloids formed by the three proteins, b) investigate the effects of chaperones and synthetic compounds on prion nucleation and propagation in vivo and in vitro, and c) examine why some amyloidogenic conformers are toxic and others are not. Relevance: Amyloids are responsible for some of the most devastating diseases of mankind, including Alzheimers, Parkinsons, and Huntingtins Diseases. Yet we still have little understanding of the nature of the toxic species, much less a clear route to therapeutic intervention. Yeast amyloids undergo remarkably similar conformational conversions and are much more amenable to investigation, offering the hope of more rapid progress on the very difficult problems of amyloid structure, conformational change, and the nature of toxic states.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM025874-31
Application #
7791449
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Wehrle, Janna P
Project Start
1978-12-01
Project End
2013-08-31
Budget Start
2010-04-01
Budget End
2013-08-31
Support Year
31
Fiscal Year
2010
Total Cost
$548,679
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Bryan Jr, Allen W; Starner-Kreinbrink, Jennifer L; Hosur, Raghavendra et al. (2011) Structure-based prediction reveals capping motifs that inhibit ?-helix aggregation. Proc Natl Acad Sci U S A 108:11099-104

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