Mechanism of membrane curvature generation and caveola formation by flat disc-like complexes of caveolin

Membrane sculpting by caveolin and accessory proteins is crucial for caveola formation. The discovery of the disc-like structure of caveolin oligomers has challenged earlier models for membrane shaping by caveolins. The flat shape of the caveolin discs apparently contradicts the large curvature of caveolar membranes these discs generate upon their predicted embedding into the cytoplasmic membrane leaflet. Here we have provided a mechanism for this phenomenon. We proposed that the central factor behind the membrane shaping by caveolin discs is a differential interaction of the membrane lipid monolayers with each other and with the hydrophobic faces of the caveolin discs. Based on this hypothesis we demonstrated by computations that the caveolin disc insertion causes elastic stresses of tilt and splay in the membrane monolayers, which, in turn, drive membrane kinking along the disc boundaries. The resulting membrane shapes are predicted to have a faceted appearance in agreement with observations and the estimated effective curvatures of these shapes are equal to those measured for caveolae in cells. We predicted and analysed the membrane-mediated repulsive forces developing between the inserted caveolin discs and discussed the strength of the counterforces needed to concentrate caveolin discs in the membrane plane. Besides recovering the major features of caveolar formation and morphology, our model provides a new mechanistic understanding of the role of cholesterol and other lipids with similar intrinsic curvature in the caveola assembly and control of caveolar size.