Amyloid β-Protein C-Terminal Fragments: Formation of Cylindrins and β-Barrels.
Amyloid β-Protein C-Terminal Fragments: Formation of Cylindrins and β-Barrels.
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DOI：
10.1021/jacs.5b09536
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发表时间：
2016-01-20
影响因子：
15
通讯作者：
Bowers MT
中科院分区：
文献类型：
--
作者：
Do TD;LaPointe NE;Nelson R;Krotee P;Hayden EY;Ulrich B;Quan S;Feinstein SC;Teplow DB;Eisenberg D;Shea JE;Bowers MT
为了评估治疗淀粉样变性如阿尔茨海默病（AD）的潜在治疗靶点，确定毒性淀粉样蛋白寡聚体的结构是必不可少的。然而，对于淀粉样β蛋白肽（Aβ），被认为是AD中的种子神经致病因子，其快速聚集动力学和不同大小的寡聚体之间的快速平衡动力学提出了重大的实验挑战。在这里，我们使用离子迁移率质谱，结合电子显微镜，原子力显微镜和计算建模，以测试假设，Aβ肽可以形成类似圆柱蛋白和β桶的寡聚体结构。假设这些结构通过扰乱质膜完整性而导致神经元损伤和死亡。我们发现，C端Aβ片段的六聚体，包括Aβ（24-34），Aβ（25-35）和Aβ（26-36），具有与圆柱蛋白相似的碰撞截面。我们还表明，连接两个相同的片段头到尾使用二甘氨酸增加的比例cylindrin大小的低聚物。此外，我们发现这些片段的较大低聚物可能采用β桶结构，并且β桶可以通过折叠不对齐的β折叠（淀粉样蛋白中常见的结构类型）形成。
In order to evaluate potential therapeutic targets for treatment of amyloidoses such as Alzheimer’s disease (AD), it is essential to determine the structures of toxic amyloid oligomers. However, for the amyloid β-protein peptide (Aβ), thought to be the seminal neuropathogenetic agent in AD, its fast aggregation kinetics and the rapid equilibrium dynamics among oligomers of different size pose significant experimental challenges. Here we use ion-mobility mass spectrometry, in combination with electron microscopy, atomic force microscopy, and computational modeling, to test the hypothesis that Aβ peptides can form oligomeric structures resembling cylindrins and β-barrels. These structures are hypothesized to cause neuronal injury and death through perturbation of plasma membrane integrity. We show that hexamers of C-terminal Aβ fragments, including Aβ(24-34), Aβ(25-35) and Aβ(26-36), have collision cross-sections similar to those of cylindrins. We also show that linking two identical fragments head-to-tail using di-glycine increases the proportion of cylindrin-sized oligomers. In addition, we find that larger oligomers of these fragments may adopt β-barrel structures and that β-barrels can be formed by folding an out-of-register β-sheet, a common type of structure found in amyloid proteins.