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Effects of Cosolvents and Crowding Agents on the Stability and Phase Transition Kinetics of the SynGAP/PSD-95 Condensate Model of Postsynaptic Densities.

Authors:
Hasan Cinar Rosario Oliva Haowei Wu Mingjie Zhang Hue Sun Chan Roland Winter

J Phys Chem B 2022 03 16;126(8):1734-1741. Epub 2022 Feb 16.

Physical Chemistry I - Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany.

The SynGAP/PSD-95 binary protein system serves as a simple mimicry of postsynaptic densities (PSDs), which are protein assemblies based largely on liquid-liquid phase separation (LLPS), that are located underneath the plasma membrane of excitatory synapses. Surprisingly, the LLPS of the SynGAP/PSD-95 system is much more pressure sensitive than typical folded states of proteins or nucleic acids. It was found that phase-separated SynGAP/PSD-95 droplets dissolve into a homogeneous solution at a pressure of tens to hundred bar. Since organisms in the deep sea are exposed to pressures of up to ∼1000 bar, this observation suggests that deep-sea organisms must counteract the high pressure sensitivity of PSDs to avoid neurological impairment. We demonstrate here that the compatible osmolyte trimethylamine--oxide (TMAO) as well as macromolecular crowding agents at moderate concentrations can mitigate the deleterious effect of pressure on SynGAP/PSD-95 droplet stability, extending stable LLPS up to almost a kbar level. Moreover, the formation of SynGAP/PSD-95 droplets is a very rapid process that can be switched on and off in seconds. In contrast with the marked effects of the cosolutes on droplet stability, at the cosolutes' respective biologically relevant concentrations, their impact on the phase transformation kinetics is rather small. Only a high TMAO concentration results in a significant kinetic retardation of LLPS. Taken together, these findings offer new biophysical insights into the neurological effects of hydrostatic pressure. In particular, our results indicate how pressure-induced neurological disorders might be alleviated by upregulating certain cosolutes in the cellular milieu.

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http://dx.doi.org/10.1021/acs.jpcb.2c00794DOI Listing
March 2022

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Effects of Cosolvents and Crowding Agents on the Stability and Phase Transition Kinetics of the SynGAP/PSD-95 Condensate Model of Postsynaptic Densities.

Authors:
Hasan Cinar Rosario Oliva Haowei Wu Mingjie Zhang Hue Sun Chan Roland Winter

J Phys Chem B 2022 03 16;126(8):1734-1741. Epub 2022 Feb 16.

Physical Chemistry I - Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany.

The SynGAP/PSD-95 binary protein system serves as a simple mimicry of postsynaptic densities (PSDs), which are protein assemblies based largely on liquid-liquid phase separation (LLPS), that are located underneath the plasma membrane of excitatory synapses. Surprisingly, the LLPS of the SynGAP/PSD-95 system is much more pressure sensitive than typical folded states of proteins or nucleic acids. It was found that phase-separated SynGAP/PSD-95 droplets dissolve into a homogeneous solution at a pressure of tens to hundred bar. Read More

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Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Read More

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