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The structural basis of yeast prion strain variants


Among the many surprises to arise from studies of prion biology, perhaps the most unexpected is the strain phenomenon whereby a single protein can misfold into structurally distinct, infectious states that cause distinguishable phenotypes1,2,3. Similarly, proteins can adopt a spectrum of conformations in non-infectious diseases of protein folding; some are toxic and others are well tolerated4. However, our understanding of the structural differences underlying prion strains and how these differences alter their physiological impact remains limited. Here we use a combination of solution NMR, amide hydrogen/deuterium (H/D) exchange and mutagenesis to study the structural differences between two strain conformations, termed Sc4 and Sc37 (ref. 5), of the yeast Sup35 prion. We find that these two strains have an overlapping amyloid core spanning most of the Gln/Asn-rich first 40 amino acids that is highly protected from H/D exchange and very sensitive to mutation. These features indicate that the cores are composed of tightly packed β-sheets possibly resembling ‘steric zipper’ structures revealed by X-ray crystallography of Sup35-derived peptides6,7. The stable structure is greatly expanded in the Sc37 conformation to encompass the first 70 amino acids, revealing why this strain shows increased fibre stability and decreased ability to undergo chaperone-mediated replication8. Our findings establish that prion strains involve large-scale conformational differences and provide a structural basis for understanding a broad range of functional studies, including how conformational changes alter the physiological impact of prion strains.

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Figure 1: Solution NMR of SupNM fibres.
Figure 2: H/D exchange of Sc4 and Sc37 fibres.
Figure 3: Mutational analysis of SupNM fibres.

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We thank M. Tanaka, C. Ritter, M. Hoshino, W. Bermel and R. Riek for experimental advice; and D. Breslow, D. Cameron, S. Collins, V. Denic, K. Filaski, C. Foo, C. Gross, J. Hollien, N. Ingolia, E. Quan, E. Rodriguez and K. Tipton and other members of the Weissman laboratory for helpful discussion and critical reading of the manuscript. This research was funded by the NIH and the Howard Hughes Medical Institute.

Backbone assignments of SupNM have been deposited in the Biological Magnetic Resonance Data Bank, accession number 15379.

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Correspondence to Jonathan S. Weissman.

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Toyama, B., Kelly, M., Gross, J. et al. The structural basis of yeast prion strain variants. Nature 449, 233–237 (2007).

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