{"title":"致病突变ΔK280促进了涉及微管结合域的疏水相互作用,并增强了Tau的液-液相分离能力","authors":"Yujie Chen, Xun Sun, Yiming Tang, Yuan Tan, Cong Guo, Tong Pan, Xuefeng Zhang, Jinghui Luo, Guanghong Wei","doi":"10.1002/smll.202406429","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":228,"journal":{"name":"Small","volume":null,"pages":null},"PeriodicalIF":13.0000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule-Binding Domain and Enhances Liquid-Liquid Phase Separation of Tau\",\"authors\":\"Yujie Chen, Xun Sun, Yiming Tang, Yuan Tan, Cong Guo, Tong Pan, Xuefeng Zhang, Jinghui Luo, Guanghong Wei\",\"doi\":\"10.1002/smll.202406429\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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.\",\"PeriodicalId\":228,\"journal\":{\"name\":\"Small\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":13.0000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Small\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1002/smll.202406429\",\"RegionNum\":2,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Small","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1002/smll.202406429","RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
tau蛋白的液-液相分离(LLPS)可导致其聚集,这与阿尔茨海默氏症有关。致病突变ΔK280能增强K18(一种包含微管结合结构域的截短tau变体)的聚集。然而,ΔK280对K18 LLPS的影响及其内在机制在很大程度上尚未被探索。本文通过多尺度分子模拟和显微镜实验研究了ΔK280 K18的构象组合和LLPS。全原子分子动力学模拟发现,ΔK280能显著提高K18单体的塌缩度和β片状含量,这表明ΔK280突变可能促进K18的LLPS,粗粒度相共存模拟和显微镜实验也验证了这一点。重要的是,ΔK280突变促进了六个基团(尤其是PHF6)的β片的形成,增加了PHF6*和PHF6的疏水溶剂暴露,增强了大部分基团的疏水、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 改变了六个基团之间的相互作用网络,诱导形成了具有高β片状含量和塌缩度的 K18 构象。对全长 tau 的粗粒度模拟显示,ΔK280 通过增强涉及微管结合域的疏水相互作用来促进 tau LLPS。这些发现提供了有关ΔK280诱导tau发病机制的详细机理见解,为治疗干预提供了潜在靶点。
Pathogenic Mutation ΔK280 Promotes Hydrophobic Interactions Involving Microtubule-Binding Domain and Enhances Liquid-Liquid Phase Separation of Tau
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.
期刊介绍:
Small serves as an exceptional platform for both experimental and theoretical studies in fundamental and applied interdisciplinary research at the nano- and microscale. The journal offers a compelling mix of peer-reviewed Research Articles, Reviews, Perspectives, and Comments.
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