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Updated: Feb 22, 2026
Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy
Published on: September 17, 2017
Species-dependent structural polymorphism of Y145Stop prion protein amyloid revealed by solid-state NMR spectroscopy
Theint Theint1, Philippe S Nadaud1, Darryl Aucoin1
1Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.
Abstract:
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.
Insights
Two amino acids control prion protein amyloid structure and species barriers. This finding in human, mouse, and hamster prion diseases offers insights into prion propagation and strain diversity.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Prion diseases exhibit complex strain variations and interspecies transmission barriers.
- Prion protein (PrP) strain phenomena and species barriers can be modeled in vitro using seeded fibrillization of the Y145Stop PrP variant.
Purpose of the Study:
- To investigate the atomic-level structural differences in Y145Stop prion protein amyloids across species.
- To identify the key molecular determinants governing prion strain structure and interspecies transmissibility.
Main Methods:
- Solid-state nuclear magnetic resonance (ssNMR) spectroscopy was employed.
- Comparative structural analysis of Y145Stop prion protein amyloids from human, mouse, and Syrian hamster.
Main Results:
- Structural variations in Y145Stop PrP amyloids are primarily dictated by two amino acid residues at positions 112 and 139.
- These specific residues function as conformational switches, influencing amyloid strain formation.
- A model for human Y145Stop PrP amyloid was developed, explaining cross-seeding specificity.
Conclusions:
- Two key amino acid residues are critical for determining prion protein amyloid structure and interspecies transmissibility.
- Understanding these residue roles provides a molecular basis for prion strain diversity and cross-species propagation.
- This research lays the groundwork for comprehending prion disease mechanisms and developing targeted interventions.
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