Macromolecular condensation buffers intracellular water potential

Joseph L. Watson, Estere Seinkmane, Christine T. Styles, Andrei Mihut, Lara K. Krüger, Kerrie E. McNally, Vicente Jose Planelles-Herrero, Michal Dudek, Patrick M. McCall, Silvia Barbiero, Michael Vanden Oever, Sew Yeu Peak-Chew, Benjamin T. Porebski, Aiwei Zeng, Nina M. Rzechorzek, David C. S. Wong, Andrew D. Beale, Alessandra Stangherlin, Margot Riggi, Janet Iwasa, Jörg Morf, Christos Miliotis, Alina Guna, Alison J. Inglis, Jan Brugués, Rebecca M. Voorhees, Joseph E. Chambers, Qing-Jun Meng, John S. O’Neill (), Rachel S. Edgar () and Emmanuel Derivery ()
Additional contact information
Joseph L. Watson: MRC Laboratory of Molecular Biology
Estere Seinkmane: MRC Laboratory of Molecular Biology
Christine T. Styles: Imperial College London
Andrei Mihut: MRC Laboratory of Molecular Biology
Lara K. Krüger: MRC Laboratory of Molecular Biology
Kerrie E. McNally: MRC Laboratory of Molecular Biology
Vicente Jose Planelles-Herrero: MRC Laboratory of Molecular Biology
Michal Dudek: University of Manchester
Patrick M. McCall: TU Dresden
Silvia Barbiero: MRC Laboratory of Molecular Biology
Michael Vanden Oever: Imperial College London
Sew Yeu Peak-Chew: MRC Laboratory of Molecular Biology
Benjamin T. Porebski: MRC Laboratory of Molecular Biology
Aiwei Zeng: MRC Laboratory of Molecular Biology
Nina M. Rzechorzek: MRC Laboratory of Molecular Biology
David C. S. Wong: MRC Laboratory of Molecular Biology
Andrew D. Beale: MRC Laboratory of Molecular Biology
Alessandra Stangherlin: MRC Laboratory of Molecular Biology
Margot Riggi: University of Utah
Janet Iwasa: University of Utah
Jörg Morf: Babraham Institute
Christos Miliotis: Babraham Institute
Alina Guna: California Institute of Technology
Alison J. Inglis: California Institute of Technology
Jan Brugués: TU Dresden
Rebecca M. Voorhees: California Institute of Technology
Joseph E. Chambers: Cambridge Institute for Medical Research
Qing-Jun Meng: University of Manchester
John S. O’Neill: MRC Laboratory of Molecular Biology
Rachel S. Edgar: Imperial College London
Emmanuel Derivery: MRC Laboratory of Molecular Biology

Nature, 2023, vol. 623, issue 7988, 842-852

Abstract: Abstract Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive protein folding and macromolecular interactions1. Reciprocally, macromolecules restrict the movement of ‘structured’ water molecules within their hydration layers, reducing the available ‘free’ bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Here, within concentrated macromolecular solutions such as the cytosol, we found that modest changes in temperature greatly affect the water potential, and are counteracted by opposing changes in osmotic strength. This duality of temperature and osmotic strength enables simple manipulations of solvent thermodynamics to prevent cell death after extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength, which impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales2,3; we therefore postulated the existence of a rapid compensatory response. We find that this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically disordered proteins. The formation and dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which is consequently robustly buffered in the cytoplasm. Our results indicate that biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest that preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

Date: 2023
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DOI: 10.1038/s41586-023-06626-z

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