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首页> 外文期刊>Journal of Molecular Biology >Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation
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Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation

机译：形成形成支架蛋白质促进淀粉样蛋白β聚集的延迟

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摘要

Peptidic nanodiscs are useful membrane mimetic tools for structural and functional studies of membrane proteins, and membrane interacting peptides including amyloids. Here, we demonstrate anti-amyloidogenic activities of a nanodisc-forming 18-residue peptide (denoted as 4F), both in lipid-bound and lipid-free states by using Alzheimer's amyloid-beta (Aβ40) peptide as an example. Fluorescence-based amyloid fibrillation kinetic assays showed a significant delay in Aβ40 amyloid aggregation by the 4F peptide. In addition, 4F-encased lipid nanodiscs, at an optimal concentration of 4F (>20?μM) and nanodisc size (<10?nm), significantly affect amyloid fibrillation. A comparison of experimental results obtained from nanodiscs with that obtained from liposomes revealed a substantial inhibitory efficacy of 4F-lipid nanodiscs against Aβ40 aggregation and were also found to be suitable to trap Aβ40 intermediates. A combination of atomistic molecular dynamics simulations with NMR and circular dichroism experimental results exhibited a substantial change in Aβ40 conformation upon 4F binding through electrostatic and π–π interactions. Specifically, the 4F peptide was found to interfere with the central β-sheet-forming residues of Aβ40 through substantial hydrogen, π–π, and π–alkyl interactions. Fluorescence experiments and coarse-grained molecular dynamics simulations showed the formation of a ternary complex, where Aβ40 binds to the proximity of peptidic belt and membrane surface that deaccelerate amyloid fibrillation. Electron microscopy images revealed short and thick amyloid fibers of Aβ40 formed in the presence of 4F or 4F-lipid nanodsics. These findings could aid in the development of amyloid inhibitors as well as in stabilizing Aβ40 intermediates for high-resolution structural and neurobiological studies.
机译：肽纳米肽是用于膜蛋白的结构和功能性研究的有用膜模拟工具，以及包括淀粉样蛋白的膜相互作用肽。在此，我们通过使用阿尔茨海默蛋白的淀粉样蛋白 - β（Aβ40）肽作为实例，证明了纳米蛋白形成的18-残基肽（表示为4F）的抗淀粉样活性。荧光基淀粉样蛋白原纤化动力学测定显示出4F肽的Aβ40淀粉样蛋白聚集的显着延迟。另外，4F包装的脂质纳米DISC，以最佳的4F（> 20μm）和纳米芯片尺寸（<10？NM），显着影响淀粉样蛋白纤维化。从脂质体获得的纳米乳头获得的实验结果的比较揭示了4F-脂质纳米对Aβ40聚集的显着抑制效果，并且还发现适合捕获Aβ40中间体。具有NMR和圆形二色性实验结果的原子分子动力学模拟的组合表现出通过静电和π-π相互作用的4F结合的Aβ40构象的显着变化。具体地，发现4F肽通过大致氢，π-π和π-烷基相互作用干扰Aβ40的中央β-片状残留物。荧光实验和粗粒分子动力学模拟显示了三元复合物的形成，其中Aβ40与肽带和膜表面的接近结合，使得淀粉样蛋白纤维化纤维化纤维化。电子显微镜图像显示在4F或4F-脂质纳米型存在下形成的Aβ40的短且厚的淀粉样纤维。这些发现可以有助于淀粉样蛋白抑制剂的发育，以及稳定Aβ40中间体以进行高分辨率结构和神经生物学研究。

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