In prion diseases, the mammalian prion protein PrP is converted from a monomeric, mainly α-helical state into β-rich amyloid fibrils. To examine the structure of the misfolded state, amyloid fibrils were grown from a β form of recombinant mouse PrP (residues 91–231). The β-PrP precursors assembled slowly into amyloid fibrils with an overall helical twist. The fibrils exhibit immunological reactivity similar to that of ex vivo PrPSc. Using electron microscopy and image processing, we obtained three-dimensional density maps of two forms of PrP fibrils with slightly different twists. They reveal two intertwined protofilaments with a subunit repeat of not, vert, similar60 Å. The repeating unit along each protofilament can be accounted for by elongated oligomers of PrP, suggesting a hierarchical assembly mechanism for the fibrils. The structure reveals flexible crossbridges between the two protofilaments, and subunit contacts along the protofilaments that are likely to reflect specific features of the PrP sequence, in addition to the generic, cross-β amyloid fold
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