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Nat Commun. 2017 Sep 29;8(1):753. doi: 10.1038/s41467-017-00794-z.

Species-dependent structural polymorphism of Y145Stop prion protein amyloid revealed by solid-state NMR spectroscopy.

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Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.


One of the most puzzling aspects of the prion diseases is the intricate relationship between prion strains and interspecies transmissibility barriers. Previously we have shown that certain fundamental aspects of mammalian prion propagation, including the strain phenomenon and species barriers, can be reproduced in vitro in seeded fibrillization of the Y145Stop prion protein variant. Here, we use solid-state nuclear magnetic resonance spectroscopy to gain atomic level insight into the structural differences between Y145Stop prion protein amyloids from three species: human, mouse, and Syrian hamster. Remarkably, we find that these structural differences are largely controlled by only two amino acids at positions 112 and 139, and that the same residues appear to be key to the emergence of structurally distinct amyloid strains within the same protein sequence. The role of these residues as conformational switches can be rationalized based on a model for human Y145Stop prion protein amyloid, providing a foundation for understanding cross-seeding specificity.Prion diseases can be transmitted across species. Here the authors use solid-state NMR to study prion protein (PrP) amyloids from human, mouse and Syrian hamster and show that their structural differences are mainly governed by two residues, which helps to understand interspecies PrP propagation on a molecular level.

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