1. Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California 94143, USA
2. Graduate Group in Biophysics, University of California-San Francisco, San Francisco, California 94143, USA
3. Department of Biochemistry and Biophysics, University of California-San Francisco, San Francisco, California 94143, USA

Correspondence to: Jonathan S. Weissman^1,2 Email: jsw1@itsa.ucsf.edu

Abstract

A remarkable feature of prion biology is the strain phenomenon wherein prion particles apparently composed of the same protein lead to phenotypically distinct transmissible states^{1, 2, 3, 4}. To reconcile the existence of strains with the 'protein-only' hypothesis of prion transmission, it has been proposed that a single protein can misfold into multiple distinct infectious forms, one for each different strain^{1, 2, 3, 5}. Several studies have found correlations between strain phenotypes and conformations of prion particles^{6, 7, 8, 9, 10}; however, whether such differences cause or are simply a secondary manifestation of prion strains remains unclear, largely due to the difficulty of creating infectious material from pure protein^{3, 5}. Here we report a high-efficiency protocol for infecting yeast with the [PSI⁺] prion using amyloids composed of a recombinant Sup35 fragment (Sup-NM). Using thermal stability and electron paramagnetic resonance spectroscopy, we demonstrate that Sup-NM amyloids formed at different temperatures adopt distinct, stably propagating conformations. Infection of yeast with these different amyloid conformations leads to different [PSI⁺] strains. These results establish that Sup-NM adopts an infectious conformation before entering the cell—fulfilling a key prediction of the prion hypothesis⁵—and directly demonstrate that differences in the conformation of the infectious protein determine prion strain variation.

1. Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California 94143, USA
2. Graduate Group in Biophysics, University of California-San Francisco, San Francisco, California 94143, USA
3. Department of Biochemistry and Biophysics, University of California-San Francisco, San Francisco, California 94143, USA

Correspondence to: Jonathan S. Weissman^1,2 Email: jsw1@itsa.ucsf.edu

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