Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
Department of Clinical Microbiology, Umeå University, 901 85 Umeå, Sweden.
Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2202295119. doi: 10.1073/pnas.2202295119. Epub 2022 Jun 13.
Caveolae are small plasma membrane invaginations, important for control of membrane tension, signaling cascades, and lipid sorting. The caveola coat protein Cavin1 is essential for shaping such high curvature membrane structures. Yet, a mechanistic understanding of how Cavin1 assembles at the membrane interface is lacking. Here, we used model membranes combined with biophysical dissection and computational modeling to show that Cavin1 inserts into membranes. We establish that initial phosphatidylinositol (4, 5) bisphosphate [PI(4,5)P]-dependent membrane adsorption of the trimeric helical region 1 (HR1) of Cavin1 mediates the subsequent partial separation and membrane insertion of the individual helices. Insertion kinetics of HR1 is further enhanced by the presence of flanking negatively charged disordered regions, which was found important for the coassembly of Cavin1 with Caveolin1 in living cells. We propose that this intricate mechanism potentiates membrane curvature generation and facilitates dynamic rounds of assembly and disassembly of Cavin1 at the membrane.
小窝是质膜向内凹陷的小窝，对于控制膜张力、信号级联和脂质分选非常重要。小窝衣蛋白 Cavin1 对于形成这种高曲率的膜结构是必不可少的。然而，对于 Cavin1 如何在膜界面上组装的机制理解还很缺乏。在这里，我们使用模型膜结合生物物理剖析和计算建模来表明 Cavin1 插入到膜中。我们确定 Cavin1 的三聚体螺旋区 1（HR1）最初与磷脂酰肌醇（4,5）二磷酸 [PI(4,5)P] 依赖性膜吸附介导随后的个别螺旋的部分分离和膜插入。HR1 的插入动力学通过侧翼带负电荷的无序区域进一步增强，这对于 Cavin1 与 Caveolin1 在活细胞中的共组装非常重要。我们提出，这种复杂的机制增强了膜曲率的产生，并促进了 Cavin1 在膜上的组装和拆卸的动态循环。
