The unique Alzheimer's β-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions.
The unique Alzheimer's β-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions.
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DOI：
10.1021/ja1100273
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发表时间：
2011-03-02
影响因子：
15
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Miller Y;Ma B;Nussinov R
阐明Aβ1-40原纤维的结构是阿尔茨海默病研究的兴趣所在，因为它是设计在疾病早期靶向Aβ1-40原纤维形成的治疗方法所必需的。M35是一个关键的残基，因为它的潜在氧化作用和它在Aβ原纤维中跨β链和跨β折叠的强相互作用。实验上，Aβ9-40原纤维的三重对称结构的数据表明，通过跨原纤维轴的M35相互作用和不同交叉β单元之间的强I31-V39相互作用形成紧密的疏水核心。在此，基于实验数据，我们探测全长Aβ1-40的具有三重对称性的构象。我们的全原子分子动力学模拟在显式溶剂的构象的基础上ssNMR数据再现实验观察到的M35-M35和I31-V39距离。我们对实验数据的解释表明，在原纤维三重对称结构中观察到的~5- 7 μ m M35-M35距离可能与沿着原纤维轴的M35相互作用有关，而不是跨越原纤维轴，因为我们测量的跨越原纤维轴的M35-M35距离始终高于15 μ m。因此，我们揭示了独特的Aβ1-40三角形结构具有沿原纤维轴的大空腔沿着，并且N末端可以通过与U形转弯结构域或C末端结构域相互作用来帮助原纤维的稳定。我们的研究结果以及最近对Aβ1-42纤维中空核心的cyroEM表征表明，在靶向寡聚体毒性时，应考虑Aβ1-40/1-42寡聚体中空腔的相关性。
Elucidating the structure of Aβ1–40 fibrils is of interest in Alzheimer's disease research because it is required for designing therapeutics that target Aβ1–40 fibril formation at an early stage of the disease. M35 is a crucial residue because of its potential oxidation and its strong interactions across β-strands and across β-sheets in Aβ fibrils. Experimentally, data for the three-fold symmetry structure of the Aβ9–40 fibril suggest formation of tight hydrophobic core through M35 interactions across the fibril axis and strong I31-V39 interactions between different cross-β units. Herein, based on experimental data, we probe conformers with three-fold symmetry of the full-length Aβ1–40. Our all-atom molecular dynamics simulations in explicit solvent of conformers based on the ssNMR data reproduced experimental observations of M35-M35 and I31-V39 distances. Our interpretation of the experimental data suggests that the observed ~5–7Å M35-M35 distance in the fibril three-fold symmetry structure is likely to relate to M35 interactions along the fibril axis, rather than across the fibril axis, since our measured M35-M35 distances across the fibril axis are consistently above 15Å. Consequently, we revealed that the unique Aβ1–40 triangular structure has a large cavity along the fibril axis and that the N-termini can assist in the stabilization of the fibril by interacting with the U-turn domains or with the C-termini domains. Our findings, together with the recent cyroEM characterization of the hollow core in Aβ1–42 fibrils, point to the relevance of a cavity in Aβ1–40/1–42 oligomers which should be considered when targeting oligomer toxicity.
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影响因子：
48
作者：
Wickramasinghe NP;Parthasarathy S;Jones CR;Bhardwaj C;Long F;Kotecha M;Mehboob S;Fung LW;Past J;Samoson A;Ishii Y
通讯作者：
Ishii Y
影响因子：
2.9
作者：
Petkova, AT;Yau, WM;Tycko, R
通讯作者：
Tycko, R
影响因子：
3.4
作者：
Miller, Yifat;Ma, Buyong;Nussinov, Ruth
通讯作者：
Nussinov, Ruth
影响因子：
4.4
作者：
Lee, MS;Salsbury, FR;Brooks, CL
通讯作者：
Brooks, CL
影响因子：
4.1
作者：
Kalé, L;Skeel, R;Schulten, K
通讯作者：
Schulten, K