A structural basis for prion strain diversity

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.