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

Abstract

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.

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Cited by papers we hold 6

• Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases · 2024
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• Biomolecular condensates formed by designer minimalistic peptides · 2023
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• Intermolecular interactions underlie protein/peptide phase separation irrespective of sequence and structure at crowded milieu · 2023
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• Hydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins · 2022
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• Protein condensation diseases: therapeutic opportunities · 2022
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• A multi-step nucleation process determines the kinetics of prion-like domain phase separation · 2021
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