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J Biol Chem. 2018 Nov 30;293(48):18494-18503. doi: 10.1074/jbc.RA118.005622. Epub 2018 Oct 1.

Structural attributes of mammalian prion infectivity: Insights from studies with synthetic prions.

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From the Departments of Physiology and Biophysics and.
the Center for Neurodegenerative Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503.
Pathology and.
Centers for Synchrotron Biosciences and.
Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106 and.
From the Departments of Physiology and Biophysics and


Prion diseases are neurodegenerative disorders that affect many mammalian species. Mammalian prion proteins (PrPs) can misfold into many different aggregates. However, only a small subpopulation of these structures is infectious. One of the major unresolved questions in prion research is identifying which specific structural features of these misfolded protein aggregates are important for prion infectivity in vivo Previously, two types of proteinase K-resistant, self-propagating aggregates were generated from the recombinant mouse prion protein in the presence of identical cofactors. Although these two aggregates appear biochemically very similar, they have dramatically different biological properties, with one of them being highly infectious and the other one lacking any infectivity. Here, we used several MS-based structural methods, including hydrogen-deuterium exchange and hydroxyl radical footprinting, to gain insight into the nature of structural differences between these two PrP aggregate types. Our experiments revealed a number of specific differences in the structure of infectious and noninfectious aggregates, both at the level of the polypeptide backbone and quaternary packing arrangement. In particular, we observed that a high degree of order and stability of β-sheet structure within the entire region between residues ∼89 and 227 is a primary attribute of infectious PrP aggregates examined in this study. By contrast, noninfectious PrP aggregates are characterized by markedly less ordered structure up to residue ∼167. The structural constraints reported here should facilitate development of experimentally based high-resolution structural models of infectiosus mammalian prions.


infectious disease; mass spectrometry (MS); neurodegenerative disease; prion; prion disease; protein aggregation; protein conformation; structural biology

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