Plasma membrane damage occurs in healthy cells and more frequently in cancer cells where high growth rates and metastasis result in frequent membrane damage. The annexin family of proteins plays a key role in membrane repair. Annexins are recruited at the membrane injury site by Ca and repair the damaged membrane in concert with several other proteins. Annexin A4 (ANXA4) and ANXA5 form trimers at the bilayer surface, and previous simulations show that the trimers induce high local negative membrane curvature on a flat bilayer. The membrane-curvature-inducing property of ANXA5 is presumed to be vital to the membrane repair mechanism. A previously proposed descriptive model hypothesizes that ANXA5-mediated curvature force is utilized at the free edge of the membrane at a wound site to pull the wound edges together, resulting in the formation of a “neck”-shaped structure, which, when combined with a constriction force exerted by ANXA6, leads to membrane repair. The molecular details and mechanisms of repair remain unknown, in part because the membrane edge is a transient structure that is difficult to investigate both experimentally and computationally. For the first time, we investigate the impact of ANXA5 near a membrane edge, which is modeled by a bicelle under periodic boundary conditions. ANXA5 trimers induce local curvature on the membrane leading to global bending of the bicelle. The global curvature depends on the density of annexins on the bicelle, and the curvature increases with the ANXA5 concentration until it reaches a plateau. The simulations suggest that not only do annexins induce local membrane curvature, but they can change the overall shape of a free-standing membrane. We also demonstrate that ANXA5 trimers reduce the rate of phosphatidylserine lipid diffusion from the cytoplasmic to the exoplasmic leaflet along the edge of the bicelle. In this way, membrane-bound annexins can potentially delay the apoptotic signal triggered by the presence of phosphatidylserine lipids in the outer leaflet, thus biding time for repair of the membrane hole. Our findings provide new insights into the role of ANXA5 at the edges of the membrane (the injury site) and support the curvature-constriction model of membrane repair.

中文翻译：

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膜联蛋白 A5 三聚体导致脂质膜边缘弯曲

质膜损伤发生在健康细胞中，更频繁地发生在癌细胞中，癌细胞的高生长率和转移导致频繁的膜损伤。膜联蛋白家族在膜修复中发挥着关键作用。膜联蛋白被 Ca 招募到膜损伤部位，并与其他几种蛋白质一起修复受损的膜。膜联蛋白 A4 (ANXA4) 和 ANXA5 在双层表面形成三聚体，之前的模拟表明，三聚体在平坦的双层上诱导高局部负膜曲率。 ANXA5 的膜曲率诱导特性被认为对膜修复机制至关重要。先前提出的描述性模型假设，ANXA5 介导的曲率力被利用在伤口部位膜的自由边缘，将伤口边缘拉到一起，从而形成“颈”形结构，当与ANXA6 施加的收缩力导致膜修复。修复的分子细节和机制仍然未知，部分原因是膜边缘是一种瞬态结构，很难通过实验和计算进行研究。我们首次研究了 ANXA5 在膜边缘附近的影响，该膜边缘通过周期边界条件下的 bicelle 进行建模。 ANXA5 三聚体诱导膜上的局部弯曲，导致 bicelle 的整体弯曲。整体曲率取决于 bicelle 上膜联蛋白的密度，曲率随着 ANXA5 浓度的增加而增加，直至达到稳定水平。模拟表明，膜联蛋白不仅会引起局部膜弯曲，而且还可以改变独立膜的整体形状。我们还证明，ANXA5 三聚体降低了磷脂酰丝氨酸脂质沿着 bicelle 边缘从细胞质到外质小叶的扩散速率。通过这种方式，膜结合的膜联蛋白可以潜在地延迟由外叶中磷脂酰丝氨酸脂质的存在引发的细胞凋亡信号，从而为膜孔的修复等待时间。我们的研究结果为ANXA5在膜边缘（损伤部位）的作用提供了新的见解，并支持膜修复的曲率收缩模型。