Abstract
The yeast [PSI +] element represents a new type of genetic inheritance, in which changes in phenotype are transmitted by a ‘protein only’ mechanism1,2,3 reminiscent of the ‘protein-only’ transmission of mammalian prion diseases1,4. The underlying molecular mechanisms for both are poorly understood and it isnot clear how similar they might be. Sup35, the [PSI +] protein determinant, and PrP, the mammalian prion determinant, have different functions, different cellular locations and no sequence similarity; however, each contains five imperfect oligopeptide repeats—PQGGYQQYN in Sup35 and PHGGGWGQ in PrP5,6. Repeat expansions in PrP produce spontaneous prion diseases7,8. Here we show that replacing the wild-type SUP35 gene with a repeat-expansion mutation induces new [PSI +] elements, the first mutation of its type among these newly described elements of inheritance. In vitro, fully denatured repeat-expansion peptides can adopt conformations rich in β-sheets and form higher-order structures much more rapidly than wild-type peptides. Our results provide insight into the nature of the conformational changes underlying protein-based mechanisms of inheritance and suggest a link between this process and those producing neurodegenerative prion diseases in mammals.
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Acknowledgements
We thank A. Kowal for technical assistance on electron microscopy, A. Cashikar for assistance with the circular dichroism study, and H. True, T. Serio, S. Uptain, T. Scheibel, L. Li and J. Ma for comments on the manuscript. This work was supported by a grant from the National Institutes of Health and the Howard Hughes Medical Institute.
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Liu, JJ., Lindquist, S. Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast. Nature 400, 573–576 (1999). https://doi.org/10.1038/23048
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DOI: https://doi.org/10.1038/23048
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