Many cellular proteins demix spontaneously from solution to form liquid condensates. These phase-separated systems have wide-ranging roles in health and disease. Elucidating the molecular driving forces underlying liquid-liquid phase separation (LLPS) is therefore a key objective for understanding biological function and malfunction. Here we show that proteins implicated in cellular LLPS, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, which form condensates at low salt concentrations, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that phase separation in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus provides a new view on the cooperation of hydrophobicity and non-ionic interactions as non-specific driving forces for the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

中文翻译：

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蛋白质的折返液体冷凝相通过疏水和非离子相互作用稳定

许多细胞蛋白从溶液中自发分解，形成液体冷凝物。这些相分离的系统在健康和疾病中具有广泛的作用。因此，阐明液相-液相分离（LLPS）背后的分子驱动力是理解生物学功能和故障的关键目标。在这里，我们显示了与细胞LLPS有关的蛋白质，包括FUS，TDP-43，Brd4，Sox2和Annexin A11，它们在低盐浓度下会形成冷凝物，在高盐浓度下会重新进入相​​分离状态。通过综合实验和模拟，我们证明了高盐体系中的相分离是由疏水和非离子相互作用驱动的，并且在机械上不同于低盐体系，在低盐体系中，冷凝物还通过静电力得到稳定。