Rossetto, R. | bioRxiv Science

bioRxiv2025

Controlling the Formation of Multiple Condensates in the Synapse

The postsynaptic density (PSD) is a molecule rich structure that continuously adapts its organization controlling synaptic physiology and transmission. Experimental studies have shown that this organization is dominated by the formation of condensates or (nano)clusters and by the seamless transition in their numbers as response to synaptic plasticity. In this study, we utilize different computational modeling frameworks to show that variations in the level of local protein concentrations together with the modulation of protein binding strengths can be key molecular factors in controlling the formation and number of clusters in the synapse. Comparison to MINFLUX data of spatial localization of PSD95 in the postsynapse under different activity conditions allowed us to derive predictions about the correlation between these two factors across a population of synapses. Co-variations of the factors, to mimic a simple LTP protocol, shows that a PSD containing a single cluster can reorganize to form multiple clusters that persists for long periods of time, providing a potential explanation of recent experimental data of PSD reorganization.

molecular biology↗

bioRxiv2023

Optimized dimerization of the PAR-2 RING domain drives cooperative and selective membrane recruitment for robust feedback-driven cell polarization

The behavior of cell polarity networks is defined by the quantitative features of their constituent feedback circuits, which must be tuned to enable robust and stable polarization, while also ensuring that networks remain responsive to dynamically changing cellular states and/or spatial cues that arise during development. Using the PAR polarity network as a model, we demonstrate that these features are enabled by dimerisation of the polarity protein PAR-2 via ubiquitin-independent function of its N-terminal RING domain. Specifically, we combine theory and experiment to show that dimer affinity is optimized to achieve dynamic, selective, and cooperative recruitment of PAR-2 to the plasma membrane during polarization. Reducing dimerization results in loss of positive feedback and compromises robustness of symmetry-breaking, while enhanced dimerization renders the network less responsive due to kinetic trapping of PAR-2 on internal membranes and reduced sensitivity of PAR-2 to membrane displacement by the polarity kinase, aPKC/PKC-3. Thus, our data reveal how a dynamically oligomeric RING domain results in a cell polarity network that is both robust and responsive and highlight how tuning of oligomerization kinetics can serve as a general strategy for optimizing dynamic and cooperative intracellular targeting.

cell biology↗