TY - JOUR T1 - Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions JF - bioRxiv DO - 10.1101/2020.05.04.076299 SP - 2020.05.04.076299 AU - Georg Krainer AU - Timothy J. Welsh AU - Jerelle A. Joseph AU - Jorge R. Espinosa AU - Ella de Csilléry AU - Akshay Sridhar AU - Zenon Toprakcioglu AU - Giedre Gudiškytė AU - Magdalena A. Czekalska AU - William E. Arter AU - Peter St George-Hyslop AU - Rosana Collepardo-Guevara AU - Simon Alberti AU - Tuomas P.J. Knowles Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/05/07/2020.05.04.076299.abstract N2 - Many cellular proteins have the ability to demix spontaneously from solution to form liquid condensates. These phase-separated structures form membraneless compartments in living cells and have wide-ranging roles in health and disease. Elucidating the molecular driving forces underlying liquid–liquid phase separation (LLPS) of proteins has thus become a key objective for understanding biological function and malfunction. Here we show that proteins implicated in cellular phase separation, such as FUS, TDP-43, and Annexin A11, which form condensates at low salt concentrations via homotypic multivalent interactions, also have the ability to undergo LLPS at high salt concentrations by reentering into a phase-separated regime. Through a combination of experiments and simulations, we demonstrate that phase separation in the high-salt regime is mainly driven by hydrophobic and non-ionic interactions. As such, it is mechanistically distinct from the low-salt regime, where condensates are stabilized by a broad mix of electrostatic, hydrophobic, and non-ionic forces. Our work thus expands the molecular grammar of interactions governing LLPS of cellular proteins and provides a new view on hydrophobicity and non-ionic interactions as non-specific driving forces for the condensation process, with important implications for the aberrant function, druggability, and material properties of biomolecular condensates.One Sentence Summary Proteins implicated in cellular phase separation can undergo a salt-mediated reentrant liquid–liquid phase transition.Competing Interest StatementThe authors have declared no competing interest. ER -