Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers
Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers
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DOI：
10.1074/jbc.m114.569004
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发表时间：
2014-09-26
影响因子：
4.8
通讯作者：
Guo, Zhefeng
中科院分区：
文献类型：
--
作者：
Gu, Lei;Liu, Cong;Guo, Zhefeng
β 42 寡聚体在阿尔茨海默病的发病机制中发挥着关键作用，但其结构仍然难以捉摸，部分原因在于其短暂性。在这里，我们证明融合构建体中的 A beta 42 可以被捕获在稳定的寡聚体状态，这概括了前原纤维 A beta 42 寡聚体的特征，并使我们能够建立其详细结构。定点自旋标记和电子顺磁共振研究提供了所有 42 个残基位置的侧链迁移率和分子间距离方面的结构限制。利用这些限制和其他生物物理数据，我们提出了一种新颖的原子级低聚物模型。在我们的模型中，每个 A beta 42 蛋白形成一个 β-折叠层，其中三个 β-链呈反平行排列。每个 β-折叠层由四个头尾排列的 A beta 42 分子组成。四个 β-sheet 以面对面的方式包装在一起。寡聚物内不同β-折叠之间相同片段的堆叠表明，前原纤维寡聚物可以通过链旋转与原纤维相互转化，其中β-链沿链方向经历类似于90度的旋转。这项工作为针对有毒低聚物和无毒原纤维之间相互转化过程的疗法的合理设计提供了见解。
A beta 42 oligomers play key roles in the pathogenesis of Alzheimer disease, but their structures remain elusive partly due to their transient nature. Here, we show that A beta 42 in a fusion construct can be trapped in a stable oligomer state, which recapitulates characteristics of prefibrillar A beta 42 oligomers and enables us to establish their detailed structures. Site-directed spin labeling and electron paramagnetic resonance studies provide structural restraints in terms of side chain mobility and intermolecular distances at all 42 residue positions. Using these restraints and other biophysical data, we present a novel atomic-level oligomer model. In our model, each A beta 42 protein forms a single beta-sheet with three beta-strands in an antiparallel arrangement. Each beta-sheet consists of four A beta 42 molecules in a head-to-tail arrangement. Four beta-sheets are packed together in a face-to-back fashion. The stacking of identical segments between different beta-sheets within an oligomer suggests that prefibrillar oligomers may interconvert with fibrils via strand rotation, wherein beta-strands undergo an similar to 90 degrees rotation along the strand direction. This work provides insights into rational design of therapeutics targeting the process of interconversion between toxic oligomers and non-toxic fibrils.