Early stage β-amyloid-membrane interactions modulate lipid dynamics and influence structural interfaces and fibrillation.
Early stage β-amyloid-membrane interactions modulate lipid dynamics and influence structural interfaces and fibrillation.
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DOI：
10.1016/j.jbc.2022.102491
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Qiang, Wei
中科院分区：
文献类型：
--
作者：
Kenyaga, June M.;Cheng, Qinghui;Qiang, Wei
β-淀粉样蛋白(A-β)多肽和膜之间的分子相互作用有助于Aβ的神经元毒性和阿尔茨海默病的病理。神经细胞质膜是Aβ聚集过程的生物学相关环境，并影响Aβ聚集的结构多态。然而，这些相互作用的性质尚不清楚。在这里，我们利用固体核磁共振波谱来探索在膜相关成核阶段突触质膜中Aβ多肽和脂类之间的位置特异性相互作用。关键结果表明，Aβ疏水序列中的不同片段启动了膜结合和链间组装。我们证明了早期A期β-脂质相互作用调节脂质动力学，导致更快的脂质头群运动和减少的侧向扩散运动。这些早期事件影响了与水溶液中生长的纤维相比，产生的具有明显C-末端四元界面结构的膜相关Aβ纤维的结构多态。基于我们的结果，我们提出了Aβ-脂质相互作用驱动膜相关成核过程的示意性机制，为生物环境中纤颤的早期事件提供了分子见解。
Molecular interactions between β-amyloid (Aβ) peptide and membranes contribute to the neuronal toxicity of Aβ and the pathology of Alzheimer’s disease. Neuronal plasma membranes serve as biologically relevant environments for the Aβ aggregation process as well as affect the structural polymorphisms of Aβ aggregates. However, the nature of these interactions is unknown. Here, we utilized solid-state NMR spectroscopy to explore the site-specific interactions between Aβ peptides and lipids in synaptic plasma membranes at the membrane-associated nucleation stage. The key results show that different segments in the hydrophobic sequence of Aβ initiate membrane binding and interstrand assembling. We demonstrate early stage Aβ-lipid interactions modulate lipid dynamics, leading to more rapid lipid headgroup motion and reduced lateral diffusive motion. These early events influence the structural polymorphisms of yielded membrane-associated Aβ fibrils with distinct C-terminal quaternary interface structure compared to fibrils grown in aqueous solutions. Based on our results, we propose a schematic mechanism by which Aβ-lipid interactions drive membrane-associated nucleation processes, providing molecular insights into the early events of fibrillation in biological environments.
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作者：
Hu ZW;Au DF;Cruceta L;Vugmeyster L;Qiang W
通讯作者：
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Drabik D;Chodaczek G;Kraszewski S
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Kraszewski S
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通讯作者：
Fahr, Alfred
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Akinlolu, Rumonat D.;Nam, Mimi;Qiang, Wei
通讯作者：
Qiang, Wei