Effect of pathogenic mutations on the structure and dynamics of Alzheimer's Aβ42-amyloid oligomers
Effect of pathogenic mutations on the structure and dynamics of Alzheimer's Aβ42-amyloid oligomers
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DOI：
10.1007/s00894-009-0611-1
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发表时间：
2010-05-01
影响因子：
2.2
通讯作者：
Sticht, Heinrich
中科院分区：
文献类型：
--
作者：
Kassler, Kristin;Horn, Anselm H. C.;Sticht, Heinrich
越来越多的证据表明，可溶性Aβ-淀粉样蛋白寡聚体在阿尔茨海默病的发病机制中发挥着关键作用，是突触和认知功能障碍的直接效应者。三个病理性E22-Aβ-淀粉样点突变体(E22G、E22K、E22Q)和缺失突变体E22 Delta显示出形成前纤维聚集的增强趋势。本研究使用分子动力学模拟以及随后的结构和能量分析评估了这四种突变的影响。我们的数据表明，E22在野生型Aβ中发挥着独特的作用，因为它由于相邻E22侧链之间的静电排斥而对齐聚物结构产生了不稳定的影响。E22被不带电荷的残基取代的突变导致低聚物更高的稳定性。在E22K突变中也观察到了较小程度的这种影响，这与其与其他突变相比致病性较低是一致的。有趣的是，E22的缺失并不会破坏淀粉样折叠，而是通过主干几何结构的局部变化来补偿，这些变化允许保存一座具有重要结构意义的盐桥。所有研究的突变低聚物都表现出比野生型更高的内部稳定性，这一发现为实验观察到的增强低聚物的形成和稳定性提供了解释。
Converging lines of evidence suggest that soluble A beta-amyloid oligomers play a pivotal role in the pathogenesis of Alzheimer's disease, and present direct effectors of synaptic and cognitive dysfunction. Three pathological E22-A beta-amyloid point mutants (E22G, E22K, E22Q) and the deletion mutant E22 Delta exhibit an enhanced tendency to form prefibrillar aggregates. The present study assessed the effect of these four mutations using molecular dynamics simulations and subsequent structural and energetic analyses. Our data shows that E22 plays a unique role in wild type A beta, since it has a destabilising effect on the oligomer structure due to electrostatic repulsion between adjacent E22 side chains. Mutations in which E22 is replaced by an uncharged residue result in higher oligomer stability. This effect is also observed to a lesser extent for the E22K mutation and is consistent with its lower pathogenicity compared to other mutants. Interestingly, deletion of E22 does not destroy the amyloid fold but is compensated by local changes in the backbone geometry that allow the preservation of a structurally important salt bridge. The finding that all mutant oligomers investigated exhibit higher internal stability than the wild type offers an explanation for the experimentally observed enhanced oligomer formation and stability.