Membrane remodeling by the collective action of caveolin-1

Caveolin-1 proteins scaffold 50-100 nm large invaginations in the plasma membrane to mediate critical cellular processes. As revealed recently by cryo-electron microscopy, several caveolin-1 protomers can fold into a disk-like structure that embeds in the cytoplasmic leaflet. This 8S complex represents a basal component to drive membrane curvature via higher-order interactions. The biophysical mechanisms behind the membrane remodeling, however, are elusive. To address this shortcoming, we develop a bottom-up coarse-grained model to overcome the substantial computational limitations for this large system. During simulations with the coarse-grained model, the complexes increasingly coordinate as partially mediated by attractive electrostatic interactions between scaffolding domains. The coordination of complexes strongly correlates with membrane protrusion, as approaching complexes amplify localized stress in the exoplasmic leaflet. Thus, proximity of two CAV1-8S complexes induces dynamic curvature generation that can facilitate access for signaling partners. This mechanism is further explored through simulations of clusters of multiple CAV1-8S complexes that form large-scale membrane invaginations, suggesting that caveolin-mediated membrane remodeling arises collectively from the coordinated action of multiple complexes rather than from isolated complexes.