Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.
Location and Concentration of Aromatic-Rich Segments Dictates the Percolating Inter-Molecular Network and Viscoelastic Properties of Ageing Condensates.
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DOI：
10.1002/advs.202207742
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发表时间：
2023-09
期刊：
影响因子：
15.1
通讯作者：
Espinosa, Jorge R.
中科院分区：
文献类型：
--
作者：
Blazquez, Samuel;Sanchez-Burgos, Ignacio;Ramirez, Jorge;Higginbotham, Tim;Conde, Maria M.;Collepardo-Guevara, Rosana;Tejedor, Andres R.;Espinosa, Jorge R.
关键词：
功能性液体样生物分子缩合物成熟为固体样聚集体与几种神经退行性疾病的发作有关。许多RNA结合蛋白中含有的低复杂性富含芳香族的扭结片段（LARKS）可以通过形成随时间积累的蛋白质间β折叠原纤维来促进聚集，并最终驱动缩合物的液体到固体的转变。在这里，原子分子动力学模拟与各种分辨率的序列依赖性粗粒模型相结合，以研究LARKS丰度和氨基酸序列中的位置在冷凝物成熟中的作用。值得注意的是，随着时间的推移，具有尾部LARKS的蛋白质比那些LARKS朝向中心放置的蛋白质显示出更高的粘度。然而，在很长的时间尺度上，具有单个LARKS的蛋白质-与其位置无关-仍然可以松弛并形成高粘度的液体凝聚物。然而，含有两个或多个LARKS的蛋白质的相分离的缩合物由于形成显示凝胶样行为的折叠β折叠网络而被动力学捕获。此外，作为一个工作案例，他们证明了将FUS蛋白的含LARKS的低复杂性结构域的位置向其中心转移如何有效地阻止FUS-RNA缩合物中β折叠原纤维的积累，保持功能性液体样行为而不老化。生物分子凝聚物对细胞的时空组织有重要贡献。然而，冷凝物可以随着时间的推移而老化，转化为凝胶状病理性聚集体。在这里，通过结合原子和粗粒度模拟，作者研究了低复杂性富含芳香族的扭结片段的浓度和位置如何控制蛋白质缩合物的老化速率-易于发展蛋白质间β折叠转变。引人注目的是，作者发现这些片段在蛋白质序列中的重新定位可以严重调节冷凝物老化。
Maturation of functional liquid‐like biomolecular condensates into solid‐like aggregates has been linked to the onset of several neurodegenerative disorders. Low‐complexity aromatic‐rich kinked segments (LARKS) contained in numerous RNA‐binding proteins can promote aggregation by forming inter‐protein β‐sheet fibrils that accumulate over time and ultimately drive the liquid‐to‐solid transition of the condensates. Here, atomistic molecular dynamics simulations are combined with sequence‐dependent coarse‐grained models of various resolutions to investigate the role of LARKS abundance and position within the amino acid sequence in the maturation of condensates. Remarkably, proteins with tail‐located LARKS display much higher viscosity over time than those in which the LARKS are placed toward the center. Yet, at very long timescales, proteins with a single LARKS—independently of its location—can still relax and form high viscous liquid condensates. However, phase‐separated condensates of proteins containing two or more LARKS become kinetically trapped due to the formation of percolated β‐sheet networks that display gel‐like behavior. Furthermore, as a work case example, they demonstrate how shifting the location of the LARKS‐containing low‐complexity domain of FUS protein toward its center effectively precludes the accumulation of β‐sheet fibrils in FUS‐RNA condensates, maintaining functional liquid‐like behavior without ageing. Biomolecular condensates importantly contribute to the spatiotemporal organization of the cell. However, condensates can age over time transitioning into gel‐like pathological aggregates. Here, by combining atomistic and coarse‐grained simulations, the authors investigate how the concentration and location of low‐complexity aromatic‐rich kinked segments—susceptible of developing inter‐protein β‐sheet transitions—control the ageing rate of protein condensates. Strikingly, the authors find how just the reposition of these segments across the protein sequence can severely regulate condensate ageing.
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DOI：
10.1002/advs.202104247
发表时间：
2022-03
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
--
作者：
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影响因子：
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16.6
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Zweckstetter M
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影响因子：
19
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Boeynaems S;Alberti S;Fawzi NL;Mittag T;Polymenidou M;Rousseau F;Schymkowitz J;Shorter J;Wolozin B;Van Den Bosch L;Tompa P;Fuxreiter M
通讯作者：
Fuxreiter M