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bioRxiv · 10.1101/2022.05.17.492259

A structural basis for prion strain diversity

Manka, S. W.·Wenborn, A.·Betts, J.·Joiner, S.·Saibil, H. R.·Collinge, J.·Wadsworth, J. D.
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Abstract

Recent cryo-EM studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a comparable, parallel in-register intermolecular {beta}-sheet (PIRIBS) amyloid architecture. Rungs of the fibrils are composed of individual prion protein (PrP) monomers that fold to create distinct N- and C-terminal lobes. However, disparity in the hamster/mouse PrP sequence precludes understanding how divergent prion strains emerge from an identical PrP substrate. Here, we determined the near-atomic resolution cryo-EM structure of infectious, ex vivo mouse prion fibrils from the ME7 prion strain and have compared this with the RML fibril structure. This structural comparison of two biologically distinct mouse-adapted prion strains suggests defined folding sub-domains of PrP rungs and the way in which they are interrelated, providing the first structural definition of intra-species prion strain-specific conformations.

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Manka, S. W., Wenborn, A., Betts, J., Joiner, S., Saibil, H. R., Collinge, J., Wadsworth, J. D.. 2022-05-17. A structural basis for prion strain diversity. https://doi.org/10.1101/2022.05.17.492259

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