The Structural Basis of Yeast Prion Strain Variants

This study aimed to establish a better understanding of the structural basis of yeast prion strains. Prions are infectious agents that are comprised solely of protein, completely devoid of nucleic acid. This protein-only model, however, initially had its share of skeptics who pointed to disease phenomenon that could not be explained by a proteinaceous infectious agent. The existence of different strains was one such phenomenon that provided a formidable challenge to the protein-only prion hypothesis. How could a protein-only infectious agent cause different disease phenotypes in genetically identical animals? The explanation for this strain phenomenon was that there existed multiple infectious conformations of the prion protein, each of which corresponded to a specific disease manifestation. Although there was increasing evidence for multiple infectious conformations of the prion protein, the comprehensive connection from prion conformation to in vivo phenotype would most likely come from the more simple model yeast prion [PSI]. In these studies, I describe this yeast system and our structural studies that probed the conformational and physical differences between the aggregates responsible for two different strain phenotypes. Initial studies established that these two different prion strains, called Sc4 and Sc37, were indeed caused by two different conformations of aggregate. Our studies then established that these two conformations were physically distinct, the Sc4 conformation polymerizing slower but resulting in a physically weaker fiber and the Sc37 conformation polymerizing quickly into a strong and ridged structure. Our subsequent studies used hydrogen/deuterium exchange NMR and mutagenesis two map out in detail the conformational differences between Sc4 and Sc37 fibers. This study found that the Sc4 conformation represented a small core structure, while the Sc37 conformation represented an almost doubling of core structure. These data provided a structural rationale for the observed physical differences between Sc4 and Sc37 aggregates. Thus, a full explanation of how conformational heterogeneity can lead to distinct in vivo phenotypes is now possible