Phases and Fluctuations in Biological Membranes

Abstract

Diverse cellular signaling events, including B cell receptor (BCR) activation, are hypothesized to be facilitated by domains enriched in specific plasma membrane lipids and proteins that resemble liquid-ordered phase separated domains in model membranes. However, this concept remains controversial due to the difficulty in directly observing these domains in intact cells. Here, we visualize ordered and disordered phase-like domains in intact B cell membranes using super-resolution fluorescence localization microscopy, demonstrate that clustered BCR resides within ordered phase-like domains capable of sorting key regulators of BCR activation, establish that ordered domains are local environments that favor tyrosine phosphorylation, and present a minimal and predictive model where clustering receptors leads to their collective activation by stabilizing an extended ordered domain. These results provide evidence for the role of membrane domains in BCR signaling as well as a plausible mechanism of BCR activation via receptor clustering. More generally, these studies demonstrate that lipid mediated forces can bias biochemical networks in ways that may broadly impact signal transduction.