Pressure Sensitivity of SynGAP/PSD‐95 Condensates as a Model for Postsynaptic Densities and Its Biophysical and Neurological Ramifications

Biomolecular condensates consisting of proteins and nucleic acids can serve critical biological functions, so that some condensates are referred as membraneless organelles. They can also be disease‐causing, if their assembly is misregulated. A major physicochemical basis of the formation of biomolecular condensates is liquid–liquid phase separation (LLPS). In general, LLPS depends on environmental variables, such as temperature and hydrostatic pressure. The effects of pressure on the LLPS of a binary SynGAP/PSD‐95 protein system mimicking postsynaptic densities, which are protein assemblies underneath the plasma membrane of excitatory synapses, were investigated. Quite unexpectedly, the model system LLPS is much more sensitive to pressure than the folded states of typical globular proteins. Phase‐separated droplets of SynGAP/PSD‐95 were found to dissolve into a homogeneous solution already at ten‐to‐hundred bar levels. The pressure sensitivity of SynGAP/PSD‐95 is seen here as a consequence of both pressure‐dependent multivalent interaction strength and void volume effects. Considering that organisms in the deep sea are under pressures up to about 1 kbar, this implies that deep‐sea organisms have to devise means to counteract this high pressure sensitivity of biomolecular condensates to avoid harm. Intriguingly, these findings may shed light on the biophysical underpinning of pressure‐related neurological disorders in terrestrial vertebrates.