Abstract
Ordered, fibrous, self-seeding aggregates of misfolded proteins known as amyloids are associated with important diseases in mammals and control phenotypic traits in fungi. A given protein may adopt multiple amyloid conformations, known as variants or strains, each of which leads to a distinct disease pattern or phenotype. Here, we study the effect of Hofmeister ions on amyloid nucleation and strain generation by the prion domain-containing fragment (Sup35NM) of a yeast protein Sup35p. Strongly hydrated anions (kosmotropes) initiate nucleation quickly and cause rapid fiber elongation, whereas poorly hydrated anions (chaotropes) delay nucleation and mildly affect the elongation rate. For the first time, we demonstrate that kosmotropes favor formation of amyloid strains that are characterized by lower thermostability and higher frangibility in vitro and stronger phenotypic and proliferation patterns effectively in vivo as compared with amyloids formed in chaotropes. These phenomena point to inherent differences in the biochemistry of Hofmeister ions. Our work shows that the ionic composition of a solution not only influences the kinetics of amyloid nucleation but also determines the amyloid strain that is preferentially formed.
Highlights
Prion proteins may adopt multiple aggregate conformations, known as strains
We demonstrate that kosmotropes favor formation of amyloid strains that are characterized by lower thermostability and higher frangibility in vitro and stronger phenotypic and proliferation patterns effectively in vivo as compared with amyloids formed in chaotropes
Ion Specificity and Sup35NM Aggregation Kinetics—We first examined the effects of salt type and salt concentration on Sup35NM amyloid formation in vitro via a fluorescence assay using the amyloid-binding dye thioflavin T [49]
Summary
Prion proteins may adopt multiple aggregate conformations, known as strains. Results: Kosmotropic and chaotropic anions exhibit opposite effects on aggregation kinetics and favor different strains. We demonstrate that kosmotropes favor formation of amyloid strains that are characterized by lower thermostability and higher frangibility in vitro and stronger phenotypic and proliferation patterns effectively in vivo as compared with amyloids formed in chaotropes. These phenomena point to inherent differences in the biochemistry of Hofmeister ions. Phenotypically strong strains are characterized by less stable physical structure and shorter amyloid core region; the opposite is true of phenotypically weak strains This is due to the fact that efficient prion propagation in vivo occurs via a chaperone-mediated fragmentation of aggregates that generates new seeds. Our data show for the first time that the ionic composition of the solution modulates the structural patterns of nucleated amyloids
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