Can cell penetrating peptides enter via membrane fusion?

Abstract

We aim at elucidating the molecular mechanism of passive membrane crossing of cell penetrating peptides, such as oligoarginines, using a combination of fluorescence and cryoelectron microscopies and molecular dynamics simulations. Recently, we have shown using atomistic simulations that calcium dicationscan induce membrane fusion in vesicles rich in phosphatidylethanolamine. Moreover, we have shown [1] that arginine-rich peptides are similarly fusogenic and have suggested that from mechanistic point of view the passive membrane penetration of arginine-rich peptides may be analogous to calcium-induced membrane fusion. Here, we employ fluorescence and cryo-electron microscopies on vesicles and cells to elucidate the molecular details of passive cell entrance of arginine-rich peptides. The experimental results point to a hitherto unexplored mechanism involving induction of membrane multilamellarity, potentially followed by a process analogous to calcium-induced membrane fusion. [1] Allolio C., Magarkar A., Jurkiewiczf P., Baxová K., Javanainen M., Mason P.E., Sachl R., Cbecauer M., Hof M., Horinek D., Heinz V., Rachel R., Zieglerg C.M., Schrofel A., Jungwirth P.: Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore. Proceedings of the National Academy of Sciences USA 115 (2018) 11923.