Polymorphism of Alzheimer's Aβ17-42 (p3) Oligomers: The Importance of the Turn Location and Its Conformation
Polymorphism of Alzheimer's Aβ17-42 (p3) Oligomers: The Importance of the Turn Location and Its Conformation
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DOI：
10.1016/j.bpj.2009.05.042
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发表时间：
2009-08-19
影响因子：
3.4
通讯作者：
Nussinov, Ruth
中科院分区：
文献类型：
--
作者：
Miller, Yifat;Ma, Buyong;Nussinov, Ruth
在阿尔茨海默病或唐氏综合症患者的大脑中可检测到 β(17-42)（所谓的 p3）淀粉样蛋白。我们根据稳态 NMR 测量、电子显微镜、二维氢交换和突变研究的实验数据，使用显式溶剂的全原子分子动力学模拟，研究了 A beta(17-42) 寡聚物的多态性。我们评估了结构稳定性和人口。我们的结果表明，A beta(17-42) U 型转弯的构象差异导致 β-折叠登记的多态性以及在末端保留有序的 β-链组织。此外，虽然平行 A beta(17-42) 寡聚体组织是本文研究的构象异构体中最稳定的，但不同的反平行 A beta(17-42) 组织也是稳定的，并与平行结构竞争，呈现出多态性群体。在本研究中，我们提出：1) U 型转弯构象是导致 A beta(17-42) 寡聚物组装中多态性的主要因素，并且也与寡聚物的生长有关； 2) 平行的 A β(17-42) 寡聚物和包括平行和反平行组织的 A β(17-42) 寡聚物组装体都有助于淀粉样原纤维的形成。最后，由于 U 型转向基序通常出现在由完整蛋白质或长片段形成的淀粉样蛋白中，并且迄今为止这些已被证明仅存在于平行结构中，因此我们的结果适用于广泛的寡聚体和原纤维。
A beta(17-42) (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of A beta(17-42) oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom molecular-dynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of A beta(17-42) lead to polymorphism in beta-sheet registration and retention of an ordered beta-strand organization at the termini. Further, although the parallel A beta(17-42) oligomer organization is the most stable of the conformers investigated here, different antiparallel A beta(17-42) organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of A beta(17-42) Oligomers, and is also coupled to oligomer growth; and 2), both parallel A beta(17-42) Oligomers and an assembly of A beta(17-42) oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.