Dynamic mechanisms for membrane skeleton transitions

Abstract The plasma membrane and the underlying skeleton form a protective barrier for eukaryotic cells. The molecules forming this complex composite material constantly rearrange under mechanical stress to confer this protective capacity. One of those molecules, spectrin, is ubiquitous in the membrane skeleton and primarily located proximal to the inner leaflet of the plasma membrane and engages in protein-lipid interactions via a set of membrane-anchoring domains. Spectrin is linked by short actin filaments and its conformation varies in different types of cells. In this work, we developed a generalized network model for the membrane skeleton integrated with myosin contractility and membrane mechanics to investigate the response of the spectrin meshwork to mechanical loading. We observed that the force generated by membrane bending is important to maintain a smooth skeletal structure. This suggests that the membrane is not just supported by the skeleton, but has an active contribution to the stability of the cell structure. We found that spectrin and myosin turnover are necessary for the transition between stress and rest states in the skeleton. Our model reveals that the actin-spectrin meshwork dynamics are balanced by the membrane forces with area constraint and volume restriction promoting the stability of the membrane skeleton. Furthermore, we showed that cell attachment to the substrate promotes shape stabilization. Thus, our proposed model gives insight into the shared mechanisms of the membrane skeleton associated with myosin and membrane that can be tested in different types of cells. Significance Statement Spectrin was first observed in red blood cells, as a result of which, many theoretical models focused on understanding its function in this cell type. However, recently, experiments have shown that spectrin is an important skeletal component for many different cell types and that it can form different configurations with actin. In this work, we proposed a model to study the shared mechanisms behind the function of the actin-spectrin meshwork in different types of cells. We found that membrane dynamics in addition to spectrin and myosin turnover are necessary to achieve conformational changes when stresses are applied and to guarantee shape stability when the stresses are removed. We observed that membrane bending is important to support skeletal structure. Furthermore, our model gives insight into how cell shape is maintained despite constant spectrin turnover and myosin contraction.