<br>由 Aβ 衍生的 β 发夹形成的 β 桶状四聚体,Chemical Science

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由 Aβ 衍生的 β 发夹形成的 β 桶状四聚体
Chemical Science ( IF 7.6 ) Pub Date : 2023-11-28 , DOI: 10.1039/d3sc05185d
Tuan D Samdin ₁ , Chelsea R Jones ₁ , Gretchen Guaglianone ₁ , Adam G Kreutzer ₁ , J Alfredo Freites ₁ , Michał Wierzbicki ₁ , James S Nowick _{1,

2}

Affiliation

β-淀粉样肽 Aβ 形成的 β-发夹是 Aβ 寡聚体的组成部分。在 Aβ 寡聚体或原纤维的结构中观察到 β-发夹的三种不同排列。β-发夹比对的差异可能导致 Aβ 寡聚体的异质性，从而阻碍它们在高分辨率下的研究。在这里，我们设计、合成和研究了一系列源自 Aβ_12-40 的 β 发夹肽，并以这三种比对方式之一，并研究了它们的液相组装和折叠。这些分析揭示了四聚体和八聚体的形成，它们通过 Aβ 残基 12-14 和 38-40 之间的分子间氢键相互作用而稳定，作为延伸的 β 发夹构象的一部分。该系列中一种肽的 X 射线晶体学研究揭示了β桶状四聚体和八聚体的形成，它们通过边对边氢键和疏水堆积来稳定。使用该系列的四聚体和八聚体形成肽进行的染料泄漏和 caspase 3/7 激活测定揭示了膜损伤和凋亡特性。嵌入脂质双层中的β桶状四聚体的分子动力学模拟显示了膜破裂和水渗透。本文描述的四聚体和八聚体提供了 Aβ 如何组装成低聚体的额外模型，并支持β发夹比对和拓扑结构可能直接导致低聚物异质性的假设。

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A β-barrel-like tetramer formed by a β-hairpin derived from Aβ

β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers. Three different alignments of β-hairpins have been observed in the structures of Aβ oligomers or fibrils. Differences in β-hairpin alignment likely contribute to the heterogeneity of Aβ oligomers and thus impede their study at high-resolution. Here, we designed, synthesized, and studied a series of β-hairpin peptides derived from Aβ_12–40 in one of these three alignments and investigated their solution-phase assembly and folding. These assays reveal the formation of tetramers and octamers that are stabilized by intermolecular hydrogen bonding interactions between Aβ residues 12–14 and 38–40 as part of an extended β-hairpin conformation. X-ray crystallographic studies of one peptide from this series reveal the formation of β-barrel-like tetramers and octamers that are stabilized by edge-to-edge hydrogen bonding and hydrophobic packing. Dye-leakage and caspase 3/7 activation assays using tetramer and octamer forming peptides from this series reveal membrane-damaging and apoptotic properties. A molecular dynamics simulation of the β-barrel-like tetramer embedded in a lipid bilayer shows membrane disruption and water permeation. The tetramers and octamers described herein provide additional models of how Aβ may assemble into oligomers and supports the hypothesis that β-hairpin alignment and topology may contribute directly to oligomer heterogeneity.

更新日期：2023-11-28

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