Curvature sensing and generation by diverse membrane-tethered polymers can be explained by a unifying physical model
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Cell membranes are decorated by dense, polymeric macromolecules such as proteins with bulky intrinsically disordered regions, glycosylated proteins, and glycopolymers. Experiments have illustrated that the curvature of cellular membranes, which plays a role in diverse biological processes, can be regulated by the local density of these membrane-tethered polymers and their response to environmental changes. However, the mechanisms underlying the feedback between solution conditions, membrane curvature, and the local density and molecular weight of membrane-tethered polymers remain largely unexplored. In this work, using a combination of theory and experiment, we show that the ionic strength of the surrounding solution and the degree of ionization both play important roles in regulating the conformation of the membranetethered polymers, which in turn influences their membrane curvature generation capabilities. Specifically, we show that for negatively charged, disordered proteins and glycans, the thickness of the polymer brush decreases with ionic strength but increases with grafting density and degree of ionization, resulting in enhanced sensitivity to membrane curvature and an amplified ability to drive membrane curvature at lower ionic concentrations. Our findings reveal a mechanism by which membrane-tethered polymers generate membrane curvature to minimize free energy, with the extent of curvature generation modulated by the polymer grafting density and layer thickness, as well as by the ionic strength of the surrounding solution. The implications of these findings are broad, suggesting that perturbations to biopolymer charge, such as sialylation of glycans and phosphorylation of disordered proteins, could actively modulate membrane curvature induction in diverse cellular processes from endocytosis to cell motility.
Significance Statement
Cellular membranes are richly decorated by dense polymeric structures, including the glycocalyx and membrane-bound proteins with bulky intrinsically disordered domains. These biopolymers often have a high net-negative charge, such that they are sensitive to changes in the ionic landscape in the surrounding solution. They respond to such changes in their environment in multiple ways including by sensing local membrane curvature, changing their organization to shield the cell, and generating curvature to facilitate intra- and intercellular communication. However, a predictive framework that can relate solution conditions to the membrane-tethered polymer properties and in turn to their curvature generating abilities remains lacking. To address this gap, we present a unifying biophysical model that provides a physical explanation of how changes in the solution environment modulate interactions between polymer chains within the brush layer. Our findings predict that tuning the ionic strength of the extracellular space, along with the properties of the membrane-tethered polymers, can significantly modulate curvature sensing and curvature generation. These findings provide a predictive framework for understanding the role of self-avoiding biopolymers during diverse cellular processes from endocytosis to cell motility.
