Amyloid degeneracy in yeast prion strains and specificity

One of the fundamental features of prion diseases is the existence of prion strains in which multiple phenotypes are associated with a single polypeptide sequence. While conventional viral strains are attributed to either host or pathogen genome variation, the protein-only nature of prions requires another mode of encoding. A second hallmark of prion biology is the presence of a species barrier that limits infectivity between even closely related species of prion proteins. This work centers on defining and exploring the origin of the species barrier and the existence of prion strains using the yeast prion [PSI+], a self-propagating amyloid aggregate of the translation termination factor Sup35p. [PSI +] has proven invaluable as both a genetically tractable and biochemically accessible system for understanding fundamental questions of prion biology. Using this yeast prion system we have shown that (i) yeast prions are subject to a species barrier, where prion proteins isolated from one species of yeast do not interact with others, (ii) changes in the conformation of a chimeric prion domain can dictate the species-specificity of the resulting infectious particle, and (iii) the spectrum of preferred conformations of a prion particle is intimately dependent on sequence and environment. We find that prion strains can arise directly from the ability of a prion protein to adopt multiple amyloid conformations and that these conformations can determine which polypeptide sequences can add onto the growing aggregate. The existence of these multiple conformations are shown both in vitro , through formation of amyloid fibers, and in vivo, through the use of transgenic yeast harbouring different species of prion domains. Furthermore, by biasing conformational preference through point mutations or environment, we can generate a de novo species barrier between prion domains. Thus, our data suggests that prion strains and species barriers are intimately connected: changes in sequence can influence conformational choice that in turn directly affects its ability to recruit a particular sequence. As amyloid fibers in general can form multiple morphologies and display a measure of sequence specificity, the degeneracy inherent in amyloid formation can explain the origin of prion strains and species barriers.