Letters to Nature

Nature 428, 319-323 (18 March 2004) | doi:10.1038/nature02391; Received 11 November 2003; Accepted 2 February 2004

Protein-only transmission of three yeast prion strains

Chih-Yen King & Ruben Diaz-Avalos

  1. Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306, USA

Correspondence to: Chih-Yen King Email: chihyen@sb.fsu.edu

Key questions regarding the molecular nature of prions are how different prion strains can be propagated by the same protein and whether they are only protein1, 2, 3. Here we demonstrate the protein-only nature of prion strains in a yeast model, the [PSI] genetic element that enhances the read-through of nonsense mutations in the yeast Saccharomyces cerevisiae 4, 5. Infectious fibrous aggregates containing a Sup35 prion-determining amino-terminal fragment labelled with green fluorescent protein were purified from yeast harbouring distinctive prion strains. Using the infectious aggregates as 'seeds', elongated fibres were generated in vitro from the bacterially expressed labelled prion protein. De novo generation of strain-specific [PSI] infectivity was demonstrated by introducing sheared fibres into uninfected yeast hosts. The cross-sectional morphology of the elongated fibres generated in vitro was indistinguishable from that of the short yeast seeds, as visualized by electron microscopy. Electron diffraction of the long fibres showed the 4.7 Å spacing characteristic of the cross-beta structure of amyloids. The fact that the amyloid fibres nucleated in vitro propagate the strain-specific infectivity of the yeast seeds implies that the heritable information of distinct prion strains must be encoded by different, self-propagating cross-beta folding patterns of the same prion protein.

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