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Generation of prion transmission barriers by mutational control of amyloid conformations


Self-propagating β-sheet-rich protein aggregates are implicated in a wide range of protein-misfolding phenomena, including amyloid diseases and prion-based inheritance1. Two properties have emerged as common features of amyloids. Amyloid formation is ubiquitous: many unrelated proteins form such aggregates and even a single polypeptide can misfold into multiple forms2,3,4,5,6 — a process that is thought to underlie prion strain variation7. Despite this promiscuity, amyloid propagation can be highly sequence specific: amyloid fibres often fail to catalyse the aggregation of other amyloidogenic proteins8,9. In prions, this specificity leads to barriers that limit transmission between species7,8,10,11,12. Using the yeast prion [PSI+]13, we show in vitro that point mutations in Sup35p, the protein determinant of [PSI+], alter the range of ‘infectious’ conformations, which in turn changes amyloid seeding specificity. We generate a new transmission barrier in vivo by using these mutations to specifically disfavour subsets of prion strains. The ability of mutations to alter the conformations of amyloid states without preventing amyloid formation altogether provides a general mechanism for the generation of prion transmission barriers and may help to explain how mutations alter toxicity in conformational diseases.

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Figure 1: Conformation of chimaeric prion fibres is sensitive to polymerization conditions.
Figure 2: Mutations create a transmission barrier in vitro.
Figure 3: Mutations create a transmission barrier in vivo by shifting strain preference of chimaeric prion.
Figure 4: Effects of mutations on the natural S. cerevisiae Sup35 prion domain.


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We thank H. Wille, J. Hood-DeGrenier and members of the Weissman and Lim lab for discussion and critical reading of the manuscript. P.C. and S.R.C. were supported by National Science Foundation Graduate Fellowships and the ARCS (Achievement Rewards for College Scientists) foundation (P.C.). A.H.D. was supported by a Howard Hughes Medical Institute predoctoral fellowship. Funding was also provided by Howard Hughes Medical Institute, The David and Lucile Packard Foundation and the National Institutes of Health.

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Correspondence to Jonathan S. Weissman.

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Chien, P., DePace, A., Collins, S. et al. Generation of prion transmission barriers by mutational control of amyloid conformations. Nature 424, 948–951 (2003).

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