Yeast Prions Are Pathogenic, In-Register Parallel Amyloids

Abstract

Most yeast prions are self-propagating amyloids of normally non-amyloid proteins. The prion domains of Ure2p, Sup35p, and Rnq1p each form highly infectious in-register parallel β-sheet amyloids. This architecture can explain perhaps the most mysterious prion phenomenon: the stable propagation of any of several prion variants (“strains”) by a single amino acid sequence. We have thus proposed a detailed model for the mechanism of templating of protein conformation by amyloid filaments. The yeast prions [URE3] and [PSI+] are diseases of yeast, with different variants differing in the degree to which they deter cell growth or viability, but even the most mild forms not being found in wild strains. Sequence conservation of the prion domains reflects the important non-prion function of these domains, not conservation of prion-forming ability, which does not require sequence conservation and is, in fact, not conserved. Upon infection with a prion, cells undergo induction of Hsp70s and Hsp104, indicative of a stress response: the cells know that prion infection is not a good thing.