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bioRxiv · 10.1101/2020.05.04.076299

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

Krainer, G.·Welsh, T. J.·Joseph, J. A.·Espinosa, J. R.·de Csillery, E.·Sridhar, A.·Toprakcioglu, Z.·Gudiskyte, G.·Czekalska, M. A.·Arter, W. E.·St George-Hyslop, P.·Collepardo-Guevara, R.·Alberti, S.·Knowles, T. P.
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Abstract

Many cellular proteins demix spontaneously from solution to form liquid condensates. These phase-separated systems have wide-ranging roles in health and disease. Elucidating the molecular driving forces underlying liquid-liquid phase separation (LLPS) is therefore a key objective for understanding biological function and malfunction. Here we show that proteins implicated in cellular LLPS, 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. By bringing together experiments and simulations, we demonstrate that phase separation 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 provides a new view on the cooperation of hydrophobicity and non-ionic interactions as non-specific driving forces for the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

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Krainer, G., Welsh, T. J., Joseph, J. A., Espinosa, J. R., de Csillery, E., Sridhar, A., Toprakcioglu, Z., Gudiskyte, G., Czekalska, M. A., Arter, W. E., St George-Hyslop, P., Collepardo-Guevara, R., Alberti, S., Knowles, T. P.. 2020-05-07. Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions. https://doi.org/10.1101/2020.05.04.076299

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