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

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.