文章基本信息

标题：Evidence for assembly of prions with left-handed β-helices into trimers
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作者：Cédric Govaerts ; Holger Wille ; Stanley B. Prusiner 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：22
页码：8342-8347
DOI：10.1073/pnas.0402254101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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-{beta} 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 {beta}-helical models. From a study of 119 all-{beta} folds observed in globular proteins, we have now determined that, if PrPSc follows a known protein fold, it adopts either a {beta}-sandwich or parallel {beta}-helical architecture. With increasing evidence arguing for a parallel {beta}-sheet organization in amyloids, we contend that the sequence of PrP is compatible with a parallel left-handed {beta}-helical fold. Left-handed {beta}-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 {beta}-helical conformation with the C terminus (residues 176-227), retaining the disulfide-linked {alpha}-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 {beta}-helical model provides a coherent framework that is consistent with many structural, biochemical, immunological, and propagation features of prions. Moreover, the parallel left-handed {beta}-helical model for PrPSc may provide important clues to the structure of filaments found in some other neurodegenerative diseases.