Extracellular environment modulates the formation and propagation of particular amyloid structures

Summary Amyloidogenic proteins, including prions, assemble into multiple forms of structurally distinct fibres. The [ PSI + ] prion, endogenous to the yeast S accharomyces cerevisiae , is a dominantly inherited, epigenetic modifier of phenotypes. [ PSI + ] formation relies on the coexistence of another prion, [ RNQ + ]. Here, in order to better define the role of amyloid diversity on cellular phenotypes, we investigated how physiological and environmental changes impact the generation and propagation of diverse protein conformations from a single polypeptide. Utilizing the yeast model system, we defined extracellular factors that influence the formation of a spectrum of alternative self‐propagating amyloid structures of the Sup 35 protein, called [ PSI + ] variants. Strikingly, exposure to specific stressful environments dramatically altered the variants of [ PSI + ] that formed de novo . Additionally, we found that stress also influenced the association between the [ PSI + ] and [ RNQ + ] prions in a way that it superceded their typical relationship. Furthermore, changing the growth environment modified both the biochemical properties and [ PSI + ]‐inducing capabilities of the [ RNQ + ] template. These data suggest that the cellular environment contributes to both the generation and the selective propagation of specific amyloid structures, providing insight into a key feature that impacts phenotypic diversity in yeast and the cross‐species transmission barriers characteristic of prion diseases.