SUMMARY Heterogeneity in intact cell plasma membranes has been explained by analogy to coexisting liquid-ordered and liquid-disordered phases, although models based on this idea fall short of describing the rich structure within cell membranes. Here, a new framework of lipid-driven plasma membrane heterogeneity is presented, drawing on quantitative measurements of protein partitioning and dynamics within B cell receptor clusters in live B lymphocyte plasma membranes, compared to coexisting phases in isolated plasma membranes. We propose that membrane domains in cells integrate the thermodynamic state of the membrane and the magnitude of the applied stimulus to give rise to a tunable response. This framework is supported through functional observations of B cell receptor phosphorylation in perturbed systems.

Membrane phase separation drives organization at B cell receptor clusters