TY - JOUR

T1 - Bending of a lipid membrane edge by annexin A5 trimers

AU - Pandey, Mayank Prakash

AU - Telles de Souza, Paulo Cesar

AU - Pezeshkian, Weria

AU - Khandelia, Himanshu

N1 - Funding Information: Support from the Novo Nordisk Fonden (grant no. NNF18OC0034936 ) is acknowledged. Simulations were performed on ROBUST Resource for Biomolecular Simulations (supported by the Novo Nordisk Foundation ) and Vega supercomputer, Slovenia (supported by EUROHPC grant #EHPC-REG-2021R0060 ). P.C.T.d.S. acknowledges the support of the French National Center for Scientific Research (CNRS) and the research collaboration with PharmCADD . We thank Siewert-Jan Marrink for useful discussions and feedback on the manuscript. W.P. acknowledges funding from the Novo Nordisk Foundation (grant no. NNF18SA0035142 ) and the Independent Research Fund Denmark (grant no. 10.46540/2064-00032B ). W.P. thanks the Skłodowska-Curie Fellowship (grant no. 101104867 ). P.C.T.d.S. also acknowledges the support of the Centre Blaise Pascal’s IT test platform at ENS de Lyon (Lyon, France) for the computer facilities. The platform operates the SIDUS solution developed by Emmanuel Quemener ( 48 ). Publisher Copyright: © 2024 Biophysical Society

PY - 2024/4/16

Y1 - 2024/4/16

N2 - 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.

AB - 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.

U2 - 10.1016/j.bpj.2024.03.019

DO - 10.1016/j.bpj.2024.03.019

M3 - Journal article

C2 - 38486451

AN - SCOPUS:85189069562

VL - 123

SP - 1006

EP - 1014

JO - Biophysical Society. Annual Meeting. Abstracts

JF - Biophysical Society. Annual Meeting. Abstracts

SN - 0523-6800

IS - 8

ER -