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

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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.



Animals, Annexins, Cell Cycle Proteins, DNA-Binding Proteins, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Dynamics Simulation, Phase Transition, Proteins, RNA-Binding Protein FUS, SOXB1 Transcription Factors, Sf9 Cells, Spodoptera, Static Electricity, Transcription Factors

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Nat Commun

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Springer Science and Business Media LLC
European Research Council (337969)
Wellcome Trust (203249/Z/16/Z)
European Research Council (803326)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (841466)
European Commission Horizon 2020 (H2020) Future and Emerging Technologies (FET) (766972)
Engineering and Physical Sciences Research Council (EP/P020259/1)