Abstract
The misfolding and aggregation of the prion protein (PrP) is the primary cause of a group of infectious neurodegenerative diseases including Creutzfeldt-Jacob disease in humans and Bovine Spongiform Encephalopathy in cows. A single disease can exhibit different infectious strains distinguishable by incubation time and morphology or distribution of the aggregates. Infected brain tissue from one species can be used to infect other species, but with different efficiencies, suggesting a spectrum of species compatibility. If PrP is, as widely believed, the sole component of infection, then the species and strain differences must be accounted for by the structure of the aggregates, likely influenced by each species’ PrP sequence. As there are no high-resolution data exploring this hypothesis, we performed molecular dynamics simulations of PrP for human, bovine, hamster, and D147N mutant hamster sequences at low pH to induce misfolding of the protein. We selected representative converted structures from each of the four sequences and, with the guidance of experimental data, constructed models of the infectious aggregates. Both hamster monomers showed high flexibility during conversion, suggesting hamster may more easily adopt altered conformations, which in turn may explain why it is more easily infected by some other species. Human and bovine aggregates were similar, with monomers docking in P31 symmetry to form a left-handed spiral. In contrast, hamster aggregates formed a P31 right-handed spiral. We detail the differences in the converted monomers that give rise to this difference and show that our results compare favorably with experimental data.
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This paper is part of the special Journal of Materials Science issue Nano- and micromechanical properties of hierarchical biological materials: Linking mechanics, chemistry and biology; Guest Editor: Markus J. Buehler that appeared in Journal of Materials Science volume 42, issue 21, November 2007. This paper was delayed for nonscientific reasons.
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Scouras, A.D., Daggett, V. Species variation in PrPSc protofibril models. J Mater Sci 43, 3625–3637 (2008). https://doi.org/10.1007/s10853-008-2578-1
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DOI: https://doi.org/10.1007/s10853-008-2578-1