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

Published version
Peer-reviewed

Type

Article

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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.

Description

Keywords

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

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

12

Publisher

Springer Science and Business Media LLC
Sponsorship
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)
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