PDF(Pubmed)
Abstract：
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+2 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.
摘要：
质膜损伤发生在健康细胞中,并且更频繁地发生在癌细胞中,其中高生长速率和转移导致频繁的膜损伤。膜联蛋白家族蛋白在膜修复中起关键作用。膜联蛋白在膜损伤部位被Ca+2募集,并与其他几种蛋白质协同修复受损的膜。膜联蛋白A4（ANXA4）和ANXA5在双层表面形成三聚体，和先前的模拟表明，三聚体在平坦的双层上诱导高的局部负膜曲率。推测ANXA5的膜曲率诱导特性对膜修复机制至关重要。先前提出的描述性模型假设，在伤口部位的膜的自由边缘处利用ANXA5介导的曲率力来将伤口边缘拉在一起，导致形成“颈状”结构，which,当与ANXA6施加的收缩力结合时,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，难以通过实验和计算进行研究。第一次,我们研究了ANXA5在膜边缘附近的影响，这是在周期性边界条件下由双管箱建模的。ANXA5三聚体在膜上诱导局部弯曲,导致二节的整体弯曲。整体曲率取决于双节上膜联蛋白的密度，曲率随着ANXA5浓度的增加而增加，直到达到平稳状态。模拟表明，膜联蛋白不仅会引起局部膜弯曲，但是它们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从细胞质扩散到沿二节边缘的外质小叶的速率。这样,膜结合膜联蛋白可能会延迟由磷脂酰丝氨酸脂质在外小叶中的存在触发的凋亡信号，从而争取时间修复膜孔。我们的发现为ANXA5在膜边缘（损伤部位）的作用提供了新的见解，并支持了膜修复的曲率收缩模型。
