Signal transduction through nonequilibrium nucleation of prewet surface condensates

An early stage of many eukaryotic signaling cascades is the formation of a signaling cluster, enriched in membrane bound receptors and signaling components and coated by a condensate of bulk proteins. These surface condensates variously integrate information through formation processes that are inherently far from equilibrium. In this work, we ask whether nonequilibrium nucleation of a prewet domain can act as a computational step, integrating information from binding events at surface receptors and transducing them into a reaction environment for chemical modification of downstream molecules. We address this question by combining theoretical analysis with Monte Carlo simulations. In our model, signaling components act as recruiters to signaling domains, by covalently modifying other components so as to have a propensity to partition into a marginally stable prewet domain held together by membrane mediated forces and protein-protein interactions. By tuning the switching rate of the recruiter which represents the ligand–receptor affinity, we show that the nucleation rate for a stable domain can be made exquisitely sensitive to ligand-receptor affinity, as needed for immune cell signaling. More broadly, we argue that nucleation, driven by a combination of kinetic sorting by localized recruiters and thermodynamic forces driven by membrane mediated forces and protein-protein interactions can serve as a signal integration and processing step in diverse signaling cascades.