Structural information regarding normal prion protein (PrP(C)) and the scrapie isoform (PrP(Sc)) is of vital importance for elucidating the pathogenesis of prion diseases (PDs). Despite successful determination of the three-dimensional structures of PrP(C), the structural details of PrP(Sc) remain elusive. Nevertheless, accumulated evidence indicates that beta-sheets comprise the basic building blocks of PrP(Sc). Consensus has been reached about the beta-sheet constitution of the N-terminus of PrP, but the constitution of C-terminal beta-sheets is heavily debated. By evaluating the most recent observations regarding the dynamics and structures of PrP, we propose that helix 2 is more likely than helices 1 and 3 to participate in beta-sheet formation. This hypothesis also provides clues to explaining an intriguing phenomenon in prion biology-the lack of PDs in non-mammals.
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