Abstract
Caveolins are monotopic membrane proteins essential for caveolae formation and play a key role in signaling and lipid regulation. Recent structural studies show that caveolins assemble into amphipathic disc-shaped oligomers with a central β-barrel, an architecture conserved across species and distinct from other membrane-remodeling proteins. These discs embed in the membrane by displacing lipids from a single leaflet, inducing membrane curvature. However, the mechanism of disc-driven bending remains unresolved. Using cryo-electron tomography, structure-guided mutagenesis, and mammalian cell studies, we show that evolutionarily distinct caveolins differ dramatically in their ability to induce membrane curvature despite sharing a conserved global architecture. Through computational and theoretical analyses, we further demonstrate that patterning of hydrophobic residues along the outer rim of the disc of human Caveolin-1 induces the deformation of the surrounding leaflet, which, in turn, dictates membrane bending. Finally, we determine a 4.1 A resolution structure of human Caveolin-1 within heterologous caveolae in situ, revealing that the disc adopts a funnel-like conformation, further shaping membrane architecture. Together, these findings reveal fundamental structural principles that empower caveolins to sculpt and remodel cellular membranes.
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