Structural Mechanism of Barriers to Interspecies Seeding Transmissibility of Full‐Length Prion Protein Amyloid

Abstract A puzzling feature of prion diseases is the cross‐species barriers. The detailed molecular mechanisms underlying these interspecies barriers remain poorly understood because of a lack of high‐resolution structural information on the scrapie isoform of the prion protein (PrPSc). In this study we identified the critical role of the residues 165/167 in the barrier to seeding mouse PrP (mPrP) fibril seeds to human cellular prion protein (PrPC). Solid‐state NMR revealed a C‐terminal β‐sheet core spanning residues 165–230 and the packing arrangement of mPrP fibrils. Residues 165/167 are located on one end of the fibril core. Molecular dynamics simulations demonstrated that the stabilities of the seeding‐induced β‐strand structures are significantly impacted by hydrogen bonds involving the side chain of residue 167 and steric resistance involving residue 165. These findings suggest that the α2–β2 loop containing residues 165/167 could be the initial site of seed–template conformational conversion.