A principle that has emerged from studies of protein aggregation is that proteins typically can misfold into a range of different aggregated forms. Moreover, the phenotypic and pathological consequences of protein aggregation depend critically on the specific misfolded form1,2. A striking example of this is the prion strain phenomenon, in which prion particles composed of the same protein cause distinct heritable states3. Accumulating evidence from yeast prions such as [PSI+] and mammalian prions argues that differences in the prion conformation underlie prion strain variants3,4,5,6,7. Nonetheless, it remains poorly understood why changes in the conformation of misfolded proteins alter their physiological effects. Here we present and experimentally validate an analytical model describing how [PSI+] strain phenotypes arise from the dynamic interaction among the effects of prion dilution, competition for a limited pool of soluble protein, and conformation-dependent differences in prion growth and division rates. Analysis of three distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids.
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We thank G. Legname and S. Prusiner for communicating their results before publication, B. Cox and T. Serio for personal communication, and T. C. Keller III for providing us with chicken pectoralis extracts. We also thank C. Cunningham, J. Newman, L. Osherovich, M. Schuldiner, K. Tipton and members of the Weissman laboratory for helpful discussion and critical reading of the manuscript. M.T. was partly supported by JSPS and Uehara Memorial postdoctoral fellowships for research abroad. S.R.C. was supported by predoctoral fellowships from the Burroughs Wellcome Fund. Funding was also provided by the Howard Hughes Medical Institute, The David and Lucile Packard Foundation and the National Institutes of Health (J.S.W.). Author Contributions S.R.C. led the development of the analytical model. M.T. was responsible for the execution of the experiments, with the exception of the fibre growth studies, which were conducted by B.H.T. and M.T. M.T., S.R.C. and J.S.W. were primarily responsible for the design, interpretation and written description of the results.
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Scientific Reports (2017)