Ion-specific Effects on Prion Nucleation and Strain Formation

• Published in: The Journal of biological chemistry 2013-10, Vol.288 (42), p.30300-30308
• Main Authors: Rubin, Jonathan, Khosravi, Hasan, Bruce, Kathryn L., Lydon, Megan E., Behrens, Sven H., Chernoff, Yury O., Bommarius, Andreas S.
• Format: Article
• Language: English
• Subjects: Amyloid; Amyloid - chemistry; Amyloid - genetics; Amyloid - metabolism; Chaotrope; Hofmeister Series; Kosmotrope; Peptide Termination Factors - chemistry; Peptide Termination Factors - genetics; Peptide Termination Factors - metabolism; Prions - chemistry; Prions - genetics; Prions - metabolism; Protein Aggregation; Protein Conformation; Protein Structure and Folding; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Translation Release Factors; Yeast
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.467829

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. Background: 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. Conclusion: Both prion nucleation kinetics and prevailing strain patterns strongly depend on ionic composition of the aggregation mixture. Significance: Ionic composition is shown to be a critical determinant in the generation of prion strains.