Coupling signaling cascades to membrane criticality

Cellular biology has long understood spatial organization to be a crucial feature for determining function. Recent evidence suggests that thermodynamic phase separation may explain a range of structures in Eukaryotic cells. In particular, proximity to a liquid-liquid critical point may underlie membrane domains that are often termed lipid rafts. Such domains have been implicated in the functioning of many signaling cascades by localizing components to particular domains. Addition of ligand may lead to the formation of signaling platforms, and perturbations to membrane criticality often modify signaling outcomes. In order to create a theory that explains the interplay between signaling cascades and membrane criticality, here we present a model and Monte-Carlo simulation framework for proteins coupled to their surrounding lipid membrane using a 2D Ising model. We have additionally developed schematic diagrams that predict the effects of domain size on the outcome of various simple signaling cascade motifs. Our model naturally explains how changes in domain size arising from perturbations to membrane criticality can lead to changes in the rates of interaction amongst signaling components, eventually leading to altered signaling outcomes.