Structural basis of caveolin-driven membrane bending

Caveolins are monotopic membrane proteins essential for caveolae formation and have key roles in signaling and lipid regulation. Caveolins assemble into amphipathic discs with a central {beta}-barrel, an architecture distinct from other membrane-remodeling proteins. These discs embed in the membrane 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 curve membranes despite their conserved architecture. Through computational and theoretical analyses, we demonstrate that patterning of hydrophobic residues along the rim of the disc of human Caveolin-1 induces the deformation of the surrounding leaflet, dictating membrane bending. Finally, we determine a 4.1[A] resolution structure of Caveolin-1 within heterologous caveolae in situ, showing 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.