TY - JOUR
T1 - Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions
AU - Krainer, Georg
AU - Welsh, Timothy J.
AU - Joseph, Jerelle A.
AU - Espinosa, Jorge R.
AU - Wittmann, Sina
AU - de Csilléry, Ella
AU - Sridhar, Akshay
AU - Toprakcioglu, Zenon
AU - Gudiškytė, Giedre
AU - Czekalska, Magdalena A.
AU - Arter, William E.
AU - Guillén-Boixet, Jordina
AU - Franzmann, Titus M.
AU - Qamar, Seema
AU - George-Hyslop, Peter St
AU - Hyman, Anthony A.
AU - Collepardo-Guevara, Rosana
AU - Alberti, Simon
AU - Knowles, Tuomas P.J.
N1 - Funding Information:
We thank Rohit V. Pappu for his helpful comments and stimulating discussions. We thank Jeetain Mittal and Gregory L. Dignon for invaluable help with the implementation of their sequence-dependent protein coarse-grained model in LAMMPS. The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) through the ERC grant PhysProt (agreement no. 337969) (T.P.J.K.), under the European Union’s Horizon 2020 Framework Programme through the Future and Emerging Technologies (FET) grant NanoPhlow (agreement no. 766972) (T.P.J.K. and G.K.), the Marie Skłodowska-Curie grant MicroSPARK (agreement no. 841466) (G.K.), the Marie Skłodowska-Curie grant StressGranule (agreement no. 791147) (S.W.), and the ERC grant InsideChromatin (agreement no. 803326) (R.C.-G.). We further thank the Newman Foundation (T.P.J.K.), the Biotechnology and Biological Sciences Research Council (T.P. J.K.), the Herchel Smith Funds (G.K.), the Wolfson College Junior Research Fellowship (G.K.), the Winston Churchill Foundation of the United States (T.J.W.), the Harding Distinguished Postgraduate Scholar Programme (T.J.W.), the Winton Advanced Research Fellowship (R.C.-G.), the King’s College Research Fellowship (J.A.J.), the Oppenheimer Research Fellowship (J.R.E.), and Emmanuel College Roger Ekins Fellowship (J.R.E). M.A.C. was supported by the Polish Ministry of Science and Higher Education within the Mobilność Plus V fellowship (decision number 1623/MOB/V/2017/0). We also acknowledge funding from the Canadian Institutes of Health Research (Foundation Grant and Canadian Consortium on Neurodegeneration in Aging Grant) (P.StG.-H.), the Wellcome Trust Collaborative Award 203249/Z/16/Z (P.StG.-H., T.P.J.K.), the ALS Canada Project Grant and the ALS Society of Canada/Brain Canada (grant no. 499553 (P.StG.-H.), the Alzheimer’s Research UK (ARUK) and the Alzheimer’s Society UK (P.StG.-H.), and the US Alzheimer Society Zenith Grant ZEN-18-529769 (P.StG.-H.). The simulations were performed using resources provided by the Cambridge Tier-2 system operated by the University of Cambridge Research Computing Service (http://www.hpc.cam.ac.uk) funded by EPSRC Tier-2 capital grant EP/P020259/1.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85100820646&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-21181-9
DO - 10.1038/s41467-021-21181-9
M3 - Article
C2 - 33597515
AN - SCOPUS:85100820646
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1085
ER -