Paravastu Anant K, Leapman Richard D, Yau Wai-Ming, Tycko Robert
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18349-54. doi: 10.1073/pnas.0806270105. Epub 2008 Nov 17.
We describe a full structural model for amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)), based on numerous constraints from solid state NMR and electron microscopy. This model applies specifically to fibrils with a periodically twisted morphology, with twist period equal to 120 +/- 20 nm (defined as the distance between apparent minima in fibril width in negatively stained transmission electron microscope images). The structure has threefold symmetry about the fibril growth axis, implied by mass-per-length data and the observation of a single set of (13)C NMR signals. Comparison with a previously reported model for Abeta(1-40) fibrils with a qualitatively different, striated ribbon morphology reveals the molecular basis for polymorphism. At the molecular level, the 2 Abeta(1-40) fibril morphologies differ in overall symmetry (twofold vs. threefold), the conformation of non-beta-strand segments, and certain quaternary contacts. Both morphologies contain in-register parallel beta-sheets, constructed from nearly the same beta-strand segments. Because twisted and striated ribbon morphologies are also observed for amyloid fibrils formed by other polypeptides, such as the amylin peptide associated with type 2 diabetes, these structural variations may have general implications.
基于来自固态核磁共振和电子显微镜的大量限制条件，我们描述了一种由与阿尔茨海默病相关的40个残基的β-淀粉样肽（Abeta(1-40)）形成的淀粉样纤维的完整结构模型。该模型特别适用于具有周期性扭曲形态的纤维，其扭曲周期等于120±20纳米（定义为负染透射电子显微镜图像中纤维宽度表观最小值之间的距离）。该结构围绕纤维生长轴具有三重对称性，这由每长度质量数据和一组(13)C NMR信号的观察结果所暗示。与先前报道的具有定性不同的条纹状带状形态的Abeta(1-40)纤维模型进行比较，揭示了多态性的分子基础。在分子水平上，这两种Abeta(1-40)纤维形态在整体对称性（二重与三重）、非β链段的构象以及某些四级接触方面存在差异。两种形态都包含由几乎相同的β链段构成的对齐平行β折叠片。由于在由其他多肽（如与2型糖尿病相关的胰岛淀粉样多肽）形成的淀粉样纤维中也观察到扭曲和条纹状带状形态，这些结构变化可能具有普遍意义。
