Neuroscience Department, Trinity University, San Antonio, TX 78212, USA.
Physics Department, Trinity University, San Antonio, TX 78212, USA.
Molecules. 2024 Feb 5;29(3):740. doi: 10.3390/molecules29030740.
The molecular events of protein misfolding and self-aggregation of tau and amylin are associated with the progression of Alzheimer's and diabetes, respectively. Recent studies suggest that tau and amylin can form hetero-tau-amylin oligomers. Those hetero-oligomers are more neurotoxic than homo-tau oligomers. So far, the detailed interactions between the hetero-oligomers and the neuronal membrane are unknown. Using multiscale MD simulations, the lipid binding and protein folding behaviors of hetero-oligomers on asymmetric lipid nanodomains or raft membranes were examined. Our raft membranes contain phase-separated phosphatidylcholine (PC), cholesterol, and anionic phosphatidylserine (PS) or ganglioside (GM1) in one leaflet of the lipid bilayer. The hetero-oligomers bound more strongly to the PS and GM1 than other lipids via the hydrophobic and hydrophilic interactions, respectively, in the raft membranes. The hetero-tetramer disrupted the acyl chain orders of both PC and PS in the PS-containing raft membrane, but only the GM1 in the GM1-containing raft membrane as effectively as the homo-tau-tetramer. We discovered that the alpha-helical content in the heterodimer was greater than the sum of alpha-helical contents from isolated tau and amylin monomers on both raft membranes, indicative of a synergetic effect of tau-amylin interactions in surface-induced protein folding. Our results provide new molecular insights into understanding the cross-talk between Alzheimer's and diabetes.
tau 和淀粉样蛋白的错误折叠和自聚集的分子事件分别与阿尔茨海默病和糖尿病的进展有关。最近的研究表明，tau 和淀粉样蛋白可以形成异源 tau-淀粉样蛋白寡聚物。这些异源寡聚物比同源 tau 寡聚物具有更高的神经毒性。到目前为止，异源寡聚物与神经元膜之间的详细相互作用尚不清楚。本研究使用多尺度 MD 模拟，研究了异源寡聚物在不对称脂质纳米域或筏状膜上的脂质结合和蛋白折叠行为。我们的筏状膜在脂质双层的一个叶状层中包含相分离的磷脂酰胆碱（PC）、胆固醇和阴离子磷脂酰丝氨酸（PS）或神经节苷脂（GM1）。与其他脂质相比，异源寡聚物通过疏水和亲水相互作用分别更强烈地结合到 PS 和 GM1 上。异源四聚体破坏了 PS 含有筏状膜中 PC 和 PS 的酰链顺序，但在 GM1 含有筏状膜中，其破坏效果仅与同源 tau 四聚体一样有效。我们发现，在两种筏状膜上，异源二聚体中的α-螺旋含量大于孤立的 tau 和淀粉样蛋白单体的α-螺旋含量之和，表明 tau-淀粉样蛋白相互作用在表面诱导蛋白折叠中具有协同效应。我们的结果为理解阿尔茨海默病和糖尿病之间的串扰提供了新的分子见解。
