Abstract
A perplexing feature of prion-based inheritance is that prions composed of the same polypeptide can evoke different phenotypes (such as distribution of brain lesions), even when propagated in genetically identical hosts1,2,3. The molecular basis of this strain diversity and the relationship between strains and barriers limiting transmission between species remain unclear. We have used the yeast prion phenomenon [PSI+]4 to investigate these issues and examine the role that conformational differences1,2,5 may have in prion strains. We have made a chimaeric fusion between the prion domains of two species (Saccharomyces cerevisae and Candida albicans) of Sup35, the protein responsible for [PSI+]4,6. Here we report that this chimaera forms alternate prion strains in vivo when initiated by transient overexpression of different Sup35 species. Similarly, in vitro the purified chimaera, when seeded with different species of Sup35 fibres, establishes and propagates distinct amyloid conformations. These fibre conformations dictate amyloid seeding specificity: a chimaera seeded by S. cerevisiae fibres efficiently catalyses conversion of S. cerevisiae Sup35 but not of C. albicans Sup35, and vice versa. These and other considerations1,2,5,7,8 argue that heritable prion strains result from self-propagating conformational differences within the prion protein itself. Moreover, these conformational differences seem to act in concert with the primary structure to determine a prion's propensity for transmission across a species barrier.
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Acknowledgements
We thank H. Bourne, H. Field, D. Julius, B. Panning, S. Lindquist, J. Reddy, S. Ribich, M. Scott and members of the Weissman and Lim lab for discussion and comments. This work was supported by the NIH, the Searle Scholars Program, the David and Lucile Packard Foundation, the Howard Hughes Medical Institute and a National Science Foundation Graduate Fellowship (P.C.).
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Chien, P., Weissman, J. Conformational diversity in a yeast prion dictates its seeding specificity. Nature 410, 223–227 (2001). https://doi.org/10.1038/35065632
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DOI: https://doi.org/10.1038/35065632
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