Sarah A. Shelby1 and Sarah L. Veatch2 1Biochemistry & Cellular and Molecular Biology, University of Tennessee Knoxville, Knoxville, Tennessee 37996, USA 2Program in Biophysics, University of Michigan, Ann Arbor, Michigan 48109, USA Correspondences: sshelby4utk.edu; sveatchumich.edu

Several groups have recently reported evidence for the emergence of domains in cell plasma membranes when membrane proteins are organized by ligand binding or assembly of membrane proximal scaffolds. These domains recruit and retain components that favor the liquid-ordered phase, adding to a decades-old literature interrogating the contribution of membrane phase separation in plasma membrane organization and function. Here we propose that both past and present observations are consistent with a model in which membranes have a high compositional susceptibility, arising from their thermodynamic state in a single phase that is close to a miscibility phase transition. This rigorous framework naturally allows for both transient structure in the form of composition fluctuations and long-lived structure in the form of induced domains. In this way, the biological tuning of plasma membrane composition enables a responsive compositional landscape that facilitates and augments cellular biochemistry vital to plasma membrane functions.