Studies using low-resolution fiber diffraction, electron microscopy, and atomic force microscopy on various amyloid fibrils indicate that the misfolded conformers must be modular, compact, and adopt a cross-β structure. In an earlier study, we used electron crystallography to delineate molecular models of the N-terminally truncated, disease-causing isoform (PrPSc) of the prion protein, designated PrP 27–30, which polymerizes into amyloid fibrils, but we were unable to choose between a trimeric or hexameric arrangement of right- or left-handed β-helical models. From a study of 119 all-β folds observed in globular proteins, we have now determined that, if PrPSc follows a known protein fold, it adopts either a β-sandwich or parallel β-helical architecture. With increasing evidence arguing for a parallel β-sheet organization in amyloids, we contend that the sequence of PrP is compatible with a parallel left-handed β-helical fold. Left-handed β-helices readily form trimers, providing a natural template for a trimeric model of PrPSc. This trimeric model accommodates the PrP sequence from residues 89–175 in a β-helical conformation with the C terminus (residues 176–227), retaining the disulfide-linked α-helical conformation observed in the normal cellular isoform. In addition, the proposed model matches the structural constraints of the PrP 27–30 crystals, positioning residues 141–176 and the N-linked sugars appropriately. Our parallel left-handed β-helical model provides a coherent framework that is consistent with many structural, biochemical, immunological, and propagation features of prions. Moreover, the parallel left-handed β-helical model for PrPSc may provide important clues to the structure of filaments found in some other neurodegenerative diseases.
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