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The physical basis of how prion conformations determine strain phenotypes


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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Figure 1: An analytical model describing prion strains.
Figure 2: Effects of strain conformation on fibre growth rate.
Figure 3: Effects of strain conformation on fibre fragmentation.
Figure 4: Analysis of distinct [ PSI + ] strain phenotypes.


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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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Correspondence to Jonathan S. Weissman.

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Supplementary information

Supplementary Data

This file contains additional Methods, data and references. (DOC 295 kb)

Supplementary Figure 1

Supplementary Figure 1 nature04922-s2.pdf Introduction of a single prion fibre is sufficient to allow induction of a stable [PSI+] state. (PDF 47 kb)

Supplementary Figure 2

Ade1-14 read-through phenotype of typical [PSI+] strains produced by infection of [psi−] with in vitro produced Sc4, Sc37 and SCS Sup-NM amyloid fibres as well as a [psi−] control. (PDF 430 kb)

Supplementary Figure 3

Supplementary Figure 3 nature04922-s4.pdf Frequency of Sup-NM fibre length after physical shearing of fibres for 60 minutes. (PDF 32 kb)

Supplementary Figure 4

Effects of strains conformation on prion growth and division in vivo. (PDF 76 kb)

Supplementary Figure 5

Separation of in vivo prion particles of distinct strains by sucrose gradient. (PDF 111 kb)

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Tanaka, M., Collins, S., Toyama, B. et al. The physical basis of how prion conformations determine strain phenotypes. Nature 442, 585–589 (2006).

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