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bioRxiv · 10.1101/2025.03.09.642159

Seeking the Membrane-Bound Structure of the Caveolin 8S Complex

Vasquez Rodriguez, S. Y.·Lazaridis, T.
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Abstract

The protein caveolin-1 (CAV1) is essential in the generation of caveolae, cup-like invaginations in the plasma membrane, but the mechanism of its action remains unclear. A recent cryo-EM structure showed an 11-mer of CAV1 (the 8S complex) forming a disk with a flat membrane-facing surface, raising the question of how a flat complex is able to generate membrane curvature. We previously conducted implicit-solvent molecular dynamics simulations, which showed the 8S complex adopting a conical shape, with its outer ridge deep inside the implicit membrane. These results suggested a scaffolding-type mechanism for curvature generation by the 8S complex. In this work we aimed to validate this proposal via all-atom simulations. To date, all simulations (other than in vacuum) show the complex taking a conical shape. The arrangement of lipids around the complex depends on the starting configuration. Starting on top of the bilayer leads to lipid extraction and water molecules trapped between the 8S complex and the bilayer, creating a protrusion on the distal leaflet. Starting deep inside the bilayer, displacing the proximal leaflet, leads to a more plausible configuration with the distal leaflet lipids adsorbed onto the 8S concave surface. Further work is needed to characterize the determinants of 8S shape and its membrane curvature generating capabilities, as well as the role of lipid composition.

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Vasquez Rodriguez, S. Y., Lazaridis, T.. 2025-03-12. Seeking the Membrane-Bound Structure of the Caveolin 8S Complex. https://doi.org/10.1101/2025.03.09.642159

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