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

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 can 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 the generation of curvature
by the 8S complex. In this work, we aimed to validate this proposal
via all-atom simulations. To date, all simulations (other than in
a vacuum) show the complex taking a conical shape. The arrangement
of the lipids around the complex depends on the starting configuration.
Starting on top of the bilayer leads to lipid extraction and trapped
water molecules 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.