Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast

Jia-Jia Liu and Susan Lindquist ()
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Jia-Jia Liu: Howard Hughes Medical Institute, University of Chicago
Susan Lindquist: Howard Hughes Medical Institute, University of Chicago

Nature, 1999, vol. 400, issue 6744, 573-576

Abstract: 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.

Date: 1999
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DOI: 10.1038/23048

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