The liquid-to-solid transition of FUS is promoted by the condensate surface.
The liquid-to-solid transition of FUS is promoted by the condensate surface.
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FUS 的液-固转变是由冷凝表面促进的。
DOI：
10.1073/pnas.2301366120
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发表时间：
2023
影响因子：
11.1
通讯作者：
Knowles,Tuom
中科院分区：
文献类型：
--
作者：
Shen,Yi;Chen,Anqi;Wang,Wenyun;Shen,Yinan;Ruggeri,FrancescoSimone;Aime,Stefano;Wang,Zizhao;Qamar,Seema;Espinosa,JorgeR;Garaizar,Adiran;StGeorge-Hyslop,Peter;Collepardo-Guevara,Rosana;Weitz,DavidA;Vigolo,Daniele;Knowles,Tuom
大范围的大分子可以经历相分离，在活细胞中形成生物分子凝聚物。这些无膜细胞器通常是高度动态的，可逆地形成，并在生物系统中执行基本功能。然而，至关重要的是，冷凝物的进一步液体到固体的转变可导致与神经退行性疾病的发作和发展相关的不可逆的病理性聚集和细胞功能障碍。尽管蛋白质的这种液体到固体的转变很重要，但在正常功能的缩合物中引发这种转变的机制尚不清楚。在这里，我们表明，通过测量在时间和空间中的结构，动力学和力学的变化，单组分FUS冷凝物不均匀地转化为固体凝胶，而是液体和凝胶相同时共存于同一冷凝物中，导致高度不均匀的结构。此外，我们的研究结果表明，这种转变起源于冷凝物和稀连续相之间的界面，一旦启动，凝胶化过程向冷凝物的中心传播。为了探测冷凝物老化过程中这种空间不均匀的流变学，我们使用了两种光学技术，空间动态映射和反射共聚焦动态散斑显微镜的组合，建立微量吸管抽吸实验。这些结果揭示了液体到固体的转变的时空维度的重要性，并突出了生物分子凝聚物的界面作为驱动病理性蛋白质聚集的关键要素。
A wide range of macromolecules can undergo phase separation, forming biomolecular condensates in living cells. These membraneless organelles are typically highly dynamic, formed reversibly, and carry out essential functions in biological systems. Crucially, however, a further liquid-to-solid transition of the condensates can lead to irreversible pathological aggregation and cellular dysfunction associated with the onset and development of neurodegenerative diseases. Despite the importance of this liquid-to-solid transition of proteins, the mechanism by which it is initiated in normally functional condensates is unknown. Here we show, by measuring the changes in structure, dynamics, and mechanics in time and space, that single-component FUS condensates do not uniformly convert to a solid gel, but rather that liquid and gel phases coexist simultaneously within the same condensate, resulting in highly inhomogeneous structures. Furthermore, our results show that this transition originates at the interface between the condensate and the dilute continuous phase, and once initiated, the gelation process propagates toward the center of the condensate. To probe such spatially inhomogeneous rheology during condensate aging, we use a combination of established micropipette aspiration experiments together with two optical techniques, spatial dynamic mapping and reflective confocal dynamic speckle microscopy. These results reveal the importance of the spatiotemporal dimension of the liquid-to-solid transition and highlight the interface of biomolecular condensates as a critical element in driving pathological protein aggregation.