Rodriguez Sayyid Yobhel Vasquez, Lazaridis Themis
CCNY Undergraduate Program, Biology Senior.
Department of Chemistry, City College of New York/CUNY, 160 Convent Ave, New York, NY 10031, USA; Graduate Programs in Chemistry, Biochemistry, and Physics, The Graduate Center, City University of New York,365 Fifth Ave., New York, NY 10016, USA.
bioRxiv. 2025 Mar 12:2025.03.09.642159. doi: 10.1101/2025.03.09.642159.
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.
蛋白质小窝蛋白-1（CAV1）在小窝（质膜中杯状内陷结构）的形成过程中至关重要，但其作用机制仍不清楚。最近的冷冻电镜结构显示，CAV1的11聚体（8S复合物）形成了一个面向膜的表面平坦的盘状物，这就引发了一个问题：一个表面平坦的复合物是如何产生膜曲率的。我们之前进行了隐式溶剂分子动力学模拟，结果显示8S复合物呈圆锥形，其外脊深入隐式膜内部。这些结果提示了8S复合物产生曲率的一种支架型机制。在这项工作中，我们旨在通过全原子模拟来验证这一推测。迄今为止，所有模拟（除了在真空中进行的模拟）都显示该复合物呈圆锥形。复合物周围脂质的排列取决于起始构型。从双层膜顶部开始会导致脂质提取以及水分子被困在8S复合物和双层膜之间，从而在远端小叶上形成一个突起。从双层膜内部深处开始，使近端小叶移位，会导致一种更合理的构型，即远端小叶脂质吸附在8S凹面上。需要进一步开展工作来表征8S形状的决定因素及其产生膜曲率的能力，以及脂质组成的作用。
