Krainer Georg, Welsh Timothy J, Joseph Jerelle A, Espinosa Jorge R, Wittmann Sina, de Csilléry Ella, Sridhar Akshay, Toprakcioglu Zenon, Gudiškytė Giedre, Czekalska Magdalena A, Arter William E, Guillén-Boixet Jordina, Franzmann Titus M, Qamar Seema, George-Hyslop Peter St, Hyman Anthony A, Collepardo-Guevara Rosana, Alberti Simon, Knowles Tuomas P J
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, UK.
Nat Commun. 2021 Feb 17;12(1):1085. doi: 10.1038/s41467-021-21181-9.
Liquid-liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition 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 sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.
蛋白质的液-液相分离是活细胞中无膜区室形成的基础。因此，阐明蛋白质相变背后的分子驱动力是理解生物功能正常和异常的关键目标。在这里，我们表明，在低盐浓度下形成凝聚物的细胞蛋白，包括FUS、TDP-43、Brd4、Sox2和膜联蛋白A11，在高盐浓度下可以重新进入相分离状态。通过结合实验和模拟，我们证明高盐状态下的这种折返相变是由疏水和非离子相互作用驱动的，其机制与低盐状态不同，在低盐状态下，凝聚物还通过静电力得到稳定。因此，我们的工作揭示了疏水和非离子相互作用作为凝聚过程中的一般驱动力的协同作用，这对生物分子凝聚物的异常功能、可药物性和材料特性具有重要意义。
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