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

Georg Krainer, Timothy J. Welsh, Jerelle A. Joseph, Jorge R. Espinosa, Sina Wittmann, Ella Csilléry, Akshay Sridhar, Zenon Toprakcioglu, Giedre Gudiškytė, Magdalena A. Czekalska, William E. Arter, Jordina Guillén-Boixet, Titus M. Franzmann, Seema Qamar, Peter St George-Hyslop (), Anthony A. Hyman (), Rosana Collepardo-Guevara (), Simon Alberti () and Tuomas P. J. Knowles ()
Additional contact information
Georg Krainer: University of Cambridge
Timothy J. Welsh: University of Cambridge
Jerelle A. Joseph: University of Cambridge, J J Thomson Avenue
Jorge R. Espinosa: University of Cambridge, J J Thomson Avenue
Sina Wittmann: Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)
Ella Csilléry: University of Cambridge
Akshay Sridhar: University of Cambridge, J J Thomson Avenue
Zenon Toprakcioglu: University of Cambridge
Giedre Gudiškytė: University of Cambridge
Magdalena A. Czekalska: University of Cambridge
William E. Arter: University of Cambridge
Jordina Guillén-Boixet: Technische Universität Dresden, Tatzberg 47/49
Titus M. Franzmann: Technische Universität Dresden, Tatzberg 47/49
Seema Qamar: University of Cambridge
Peter St George-Hyslop: University of Cambridge
Anthony A. Hyman: Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)
Rosana Collepardo-Guevara: University of Cambridge, J J Thomson Avenue
Simon Alberti: Technische Universität Dresden, Tatzberg 47/49
Tuomas P. J. Knowles: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21181-9

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