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. 2021 Nov 4;81(21):4540-4551.e6.
doi: 10.1016/j.molcel.2021.08.011. Epub 2021 Aug 25.

High-resolution structure and strain comparison of infectious mammalian prions

Allison Kraus  1 , Forrest Hoyt  2 , Cindi L Schwartz  2 , Bryan Hansen  2 , Efrosini Artikis  3 , Andrew G Hughson  3 , Gregory J Raymond  3 , Brent Race  3 , Gerald S Baron  3 , Byron Caughey  4
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Free article

High-resolution structure and strain comparison of infectious mammalian prions

Allison Kraus et al. Mol Cell. .
Free article

Abstract

Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g., ∼109 lethal doses per milligram). The structures of such lethal assemblies of PrP molecules have been poorly understood. Here we report a near-atomic core structure of a brain-derived, fully infectious prion (263K strain). Cryo-electron microscopy showed amyloid fibrils assembled with parallel in-register intermolecular β sheets. Each monomer provides one rung of the ordered fibril core, with N-linked glycans and glycolipid anchors projecting outward. Thus, single monomers form the templating surface for incoming monomers at fibril ends, where prion growth occurs. Comparison to another prion strain (aRML) revealed major differences in fibril morphology but, like 263K, an asymmetric fibril cross-section without paired protofilaments. These findings provide structural insights into prion propagation, strains, species barriers, and membrane pathogenesis. This structure also helps frame considerations of factors influencing the relative transmissibility of other pathologic amyloids.

Keywords: amyloid; cryo-electron microscopy; glycan; glycophosphatidylinositol anchor; infectious; membrane; parallel in-register β sheet; prion; species barrier; strain.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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