A β-barrel-like tetramer formed by a β-hairpin derived from Aβ.
A β-barrel-like tetramer formed by a β-hairpin derived from Aβ.
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DOI：
10.1039/d3sc05185d
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发表时间：
2023-12-20
期刊：
影响因子：
8.4
通讯作者：
Nowick, James S.
中科院分区：
文献类型：
--
作者：
Samdin, Tuan D.;Jones, Chelsea R.;Guaglianone, Gretchen;Kreutzer, Adam G.;Freites, J. Alfredo;Wierzbicki, Michal;Nowick, James S.
由β-淀粉样肽Aβ形成的β-发夹是Aβ寡聚体的结构单元。在Aβ寡聚体或原纤维的结构中观察到三种不同的β-发夹排列。β-发夹排列的差异可能导致Aβ寡聚体的异质性，从而阻碍其在高分辨率下的研究。在此，我们设计、合成并研究了一系列来源于Aβ12-40的β-发夹肽，并研究了它们的液相组装和折叠。这些试验揭示了四聚体和八聚体的形成，这些四聚体和八聚体通过Aβ残基12-14和38-40之间的分子间氢键相互作用（作为延伸的β-发夹构象的一部分）稳定。对该系列中的一种肽的X射线晶体学研究揭示了β-桶状四聚体和八聚体的形成，这些四聚体和八聚体通过边对边氢键和疏水堆积而稳定。使用来自该系列的四聚体和八聚体形成肽的染料渗漏和半胱天冬酶3/7活化测定揭示了膜损伤和凋亡特性。包埋在脂质双层中的β-桶状四聚体的分子动力学模拟显示膜破裂和水渗透。本文所述的四聚体和八聚体提供了Aβ如何组装成寡聚体的额外模型，并支持β-发夹对齐和拓扑结构可能直接导致寡聚体异质性的假设。由β-淀粉样肽Aβ形成的β-发夹是Aβ寡聚体的结构单元。
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 Aβ12–40 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. β-Hairpins formed by the β-amyloid peptide Aβ are building blocks of Aβ oligomers.
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影响因子：
21.8
作者：
通讯作者：
--
影响因子：
15
作者：
Do TD;LaPointe NE;Nelson R;Krotee P;Hayden EY;Ulrich B;Quan S;Feinstein SC;Teplow DB;Eisenberg D;Shea JE;Bowers MT
通讯作者：
Bowers MT
影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
5
作者：
Kreutzer AG;Samdin TD;Guaglianone G;Spencer RK;Nowick JS
通讯作者：
Nowick JS