Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

G Krainer and TJ Welsh and JA Joseph and JR Espinosa and S Wittmann and E de Csillery and A Sridhar and Z Toprakcioglu and G Gudiskyte and MA Czekalska and WE Arter and J Guillen-Boixet and TM Franzmann and S Qamar and P St George-Hyslop and AA Hyman and R Collepardo-Guevara and S Alberti and TPJ Knowles, NATURE COMMUNICATIONS, 12, 1085 (2021).

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. Elucidating the molecular driving forces underlying liquid-liquid phase separation is a key objective for understanding biological function and malfunction. Here the authors show that a wide range of cellular proteins, 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.

Return to Publications page