Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Thursday Speaker Abstracts

CURVATURE GENERATION BY THE CAVEOLIN 8S COMPLEX Sayyid Y Vasquez Rodriguez 1 ; Themis Lazaridis 1 ; 1 City College of New York, Chemistry, New York, NY, USA

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. We then conducted all-atom simulations, which also showed the complex taking a conical shape. Starting deep inside the bilayer, displacing the proximal leaflet, led to the distal leaflet lipids adsorbed onto the 8S concave surface. To measure the ability of the 8S complex to generate global curvature, we here simulated the complex in a discontinuous circular membrane patch of 290 Å diameter. In a 2- μ s simulation on the Anton 3 supercomputer, the flat membrane patch acquired pronounced positive curvature (curved away from the complex), converting into a hemisphere of 130-Å inner and 175-Å outer diameter. However, when the complex was constrained to prevent the conversion into a conical shape, the membrane patch acquired negative curvature. These results differ sharply from those with coarse-grained force fields and show that the conical shape of the 8S complex is essential for positive curvature generation. Similar simulations are conducted on disease-associated mutants, other human caveolin family members, and nonvertebrate caveolins.

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