Physics-Biology interface seminar: Emmanuel Derivery


11:00 - 12:00

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Macromolecular condensation buffers intracellular water potential

Emmanuel Derivery (Cambridge U.)

Optimum protein function and biochemical activity critically depends on water availability inside cells. Macromolecules restrict the movement of “structured” water molecules in their hydration layers, reducing the available “free” bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Within concentrated macromolecular solutions like the cytosol, we found that modest changes in temperature greatly impact the water potential. We predicted that lower temperatures would reduce the available “free” intracellular water in a similar manner to external hyperosmotic conditions, and vice versa for higher temperatures and hypoosmotic conditions. We validated this duality of temperature and osmotic strength on cellular physiology: hypoosmotic conditions mimicked high temperature in thermosensitive yeast mutants, whereas cold temperatures induced chondrocyte Ca2+ signalling similar to hyperosmotic conditions. Most remarkably, simple manipulations of solvent thermodynamics were sufficient to prevent cell death upon extreme cold or heat shock. Physiologically, cells must sustain their activity in the face of fluctuating temperature, pressure and osmotic strength that impact water potential within seconds, but established mechanisms of water homeostasis act over much slower timescales, so we postulated the existence of a rapid compensatory response. We find this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically-disordered proteins, which is determined by the water potential rather than the concentration of any specific macromolecule. In cells, formation or dissolution of biomolecular condensates counteracted thermal or osmotic perturbations of water potential, which was robustly buffered in isolated cytoplasm. Our results indicate that biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

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