β-sheet constitution of prion proteins

Structural information regarding normal prion protein (PrPC) and the scrapie isoform (PrPSc) is of vital importance for elucidating the pathogenesis of prion diseases (PDs). Despite successful determination of the three-dimensional structures of PrPC, the structural details of PrPSc remain elusive. Nevertheless, accumulated evidence indicates that β-sheets comprise the basic building blocks of PrPSc. Consensus has been reached about the β-sheet constitution of the N-terminus of PrP, but the constitution of C-terminal β-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 β-sheet formation. This hypothesis also provides clues to explaining an intriguing phenomenon in prion biology—the lack of PDs in non-mammals.