title: Extensive diversity of prion strains is defined by differential chaperone interactions and distinct amyloidogenic regions.
abstract: Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Stein
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Heather L
authors.initials: HL
authors.lastname: True
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D018832:Molecular Chaperones / Q000378:metabolism*; D011328:Prions / Q000145:classification / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D018832:Molecular Chaperones; D011328:Prions