Chen Yujie, Sun Xun, Tang Yiming, Tan Yuan, Guo Cong, Pan Tong, Zhang Xuefeng, Luo Jinghui, Wei Guanghong
Department of Physics, State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai, 200438, P. R. China.
Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, 5232, Switzerland.
Small. 2025 Feb;21(6):e2406429. doi: 10.1002/smll.202406429. Epub 2024 Oct 18.
Liquid-liquid phase separation (LLPS) of tau protein can initiate its aggregation which is associated with Alzheimer's disease. The pathogenic mutation ΔK280 can enhance the aggregation of K18, a truncated tau variant comprising the microtubule-binding domain. However, the impact of ΔK280 on K18 LLPS and underlying mechanisms are largely unexplored. Herein, the conformational ensemble and LLPS of ΔK280 K18 through multiscale molecular simulations and microscopy experiments are investigated. All-atom molecular dynamic simulations reveal that ΔK280 significantly enhances the collapse degree and β-sheet content of the K18 monomer, indicating that ΔK280 mutation may promote K18 LLPS, validated by coarse-grained phase-coexistence simulations and microscopy experiments. Importantly, ΔK280 mutation promotes β-sheet formation of six motifs (especially PHF6), increases the hydrophobic solvent exposure of PHF6* and PHF6, and enhances hydrophobic, hydrogen bonding, and cation-π interactions involving most of the motifs, thus facilitating the phase separation of K18. Notably, ΔK280 alters the interaction network among the six motifs, inducing the formation of K18 conformations with high β-sheet contents and collapse degree. Coarse-grained simulations on full-length tau reveal that ΔK280 promotes tau LLPS by enhancing the hydrophobic interactions involving the microtubule-binding domain. These findings offer detailed mechanistic insights into ΔK280-induced tau pathogenesis, providing potential targets for therapeutic intervention.
tau蛋白的液-液相分离（LLPS）可引发其聚集，这与阿尔茨海默病相关。致病性突变ΔK280可增强K18的聚集，K18是一种包含微管结合结构域的截短tau变体。然而，ΔK280对K18 LLPS的影响及其潜在机制在很大程度上尚未得到探索。在此，通过多尺度分子模拟和显微镜实验研究了ΔK280 K18的构象集合和LLPS。全原子分子动力学模拟表明，ΔK280显著增强了K18单体的塌陷程度和β-折叠含量，表明ΔK280突变可能促进K18 LLPS，粗粒度相共存模拟和显微镜实验验证了这一点。重要的是，ΔK280突变促进了六个基序（尤其是PHF6）的β-折叠形成，增加了PHF6*和PHF6的疏水溶剂暴露，并增强了涉及大多数基序的疏水、氢键和阳离子-π相互作用，从而促进了K18的相分离。值得注意的是，ΔK280改变了六个基序之间的相互作用网络，诱导形成具有高β-折叠含量和塌陷程度的K18构象。对全长tau的粗粒度模拟表明，ΔK280通过增强涉及微管结合结构域的疏水相互作用来促进tau LLPS。这些发现为ΔK280诱导的tau发病机制提供了详细的机制见解，为治疗干预提供了潜在靶点。
