Journal
SCIENCE
Volume 330, Issue 6004, Pages 680-683Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1197785
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Funding
- NIH [GM069802, GM085976, GM089049, AG034754, AG032818]
- NSF [0548311]
- Direct For Education and Human Resources
- Division Of Human Resource Development [0548311] Funding Source: National Science Foundation
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According to the prion hypothesis, atypical phenotypes arise when a prion protein adopts an alternative conformation and persist when that form assembles into self-replicating aggregates. Amyloid formation in vitro provides a model for this protein-misfolding pathway, but the mechanism by which this process interacts with the cellular environment to produce transmissible phenotypes is poorly understood. Using the yeast prion Sup35/[PSI+], we found that protein conformation determined the size distribution of aggregates through its interactions with a molecular chaperone. Shifts in this range created variations in aggregate abundance among cells because of a size threshold for transmission, and this heterogeneity, along with aggregate growth and fragmentation, induced age-dependent fluctuations in phenotype. Thus, prion conformations may specify phenotypes as population averages in a dynamic system.
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