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Bending of a lipid membrane edge by annexin A5 trimers
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Edité par CCSD ; Biophysical Society -
International audience. 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 and Annexin A5 (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 Annexin A6, leads to membrane repair. The molecular details and mechanisms of repair remain unknown, in part because the membrane edge is a transient structure which is difficult to investigate both experimentally and computationally. For the first time, we investigate the impact of ANXA5 near a membrane edge, which is modelled by a bicelle under periodic boundary conditions. ANXA5 trimers induce both 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 can change the overall shape of a free standing membrane. We also demonstrate that ANXA5 trimers reduce the rate of phosphatidylserine (PS) 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 PS 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. SIGNIFICANCE Cell membrane repair is vital for cellular survival for both healthy and cancer cells, and is mediated by the Annexin family of Ca +2 -dependant membrane-binding proteins. ANXA5 forms trimers at the bilayer surface, and induces high negative curvature on a flat bilayer, which is deemed essential for the repair process. However, investigation of molecular processes occurring at a membrane damage site is challenging owing to the transient nature of a membrane hole. We use a bicelle edge as a model for a membrane edge, and demonstrate that ANXA5 trimers induce both local and global curvature on the bicelle. Our study provides new physical insights into ANXA5-mediated membrane repair mechanisms, interfering with which can lead to novel cancer treatments.
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