Macromolecular condensation buffers intracellular water potential

• Published in: Nature (London) Vol. 623; no. 7988; pp. 842 - 852
• Main Authors: Watson, Joseph L., Seinkmane, Estere, Styles, Christine T., Mihut, Andrei, Krüger, Lara K., McNally, Kerrie E., Planelles-Herrero, Vicente Jose, Dudek, Michal, McCall, Patrick M., Barbiero, Silvia, Vanden Oever, Michael, Peak-Chew, Sew Yeu, Porebski, Benjamin T., Zeng, Aiwei, Rzechorzek, Nina M., Wong, David C. S., Beale, Andrew D., Stangherlin, Alessandra, Riggi, Margot, Iwasa, Janet, Morf, Jörg, Miliotis, Christos, Guna, Alina, Inglis, Alison J., Brugués, Jan, Voorhees, Rebecca M., Chambers, Joseph E., Meng, Qing-Jun, O’Neill, John S., Edgar, Rachel S., Derivery, Emmanuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.11.2023; Nature Publishing Group
• Subjects: 13; 13/62; 14; 14/19; 631/45/470; 631/57/2269; 631/80; 631/80/458; Cell Death; Cytosol - chemistry; Cytosol - metabolism; Denaturation; Homeostasis; Humanities and Social Sciences; Hydration; Hydrogen; Intracellular; Kinases; Low temperature; Macromolecular Substances - chemistry; Macromolecular Substances - metabolism; Macromolecules; Molecular dynamics; multidisciplinary; Osmolar Concentration; Pressure; Protein denaturation; Protein folding; Proteins; Proteins - chemistry; Proteins - metabolism; Science; Science (multidisciplinary); Solvents; Solvents - chemistry; Solvents - metabolism; Temperature; Temperature dependence; Thermodynamics; Time Factors; Water - chemistry; Water - metabolism; Water availability; Water content; Water potential
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06626-z

Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive protein folding and macromolecular interactions 1 . 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 timescales 2 , 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. Water thermodynamics drive changes in macromolecular assembly that rapidly restore intracellular water availability in response to physiological fluctuations in temperature, pressure and osmotic strength.