Intermembrane Molecular Contacts by Polymyxin B Mediate Exchange of Phospholipids

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Abstract
Direct intermembrane exchange of dimyristoylphosphatidylmethanol is mediated by polymyxin B (PxB), a cationic amphipathic cyclic decapeptide. The possibility that the phospholipid exchange is mediated by solubilization of phospholipids or by fusion of vesicles is ruled out. By kinetic and spectroscopic methods it is shown that the exchange occurs directly through vesicle−vesicle contacts formed by a few PxB molecules. The contact is stable on the time scale of several minutes such that neither PxB nor the vesicles in the pair forming a contact exchange with excess vesicles. Several contacts may be formed on a vesicle, which leads to the formation of a cluster of vesicles, and the lipid molecules on the outer monolayers of vesicles exchange throughout the cluster. Kinetics of substrate replenishment during processive interfacial catalysis suggests that the exchange of anionic lipids over the contact occurs at a rate considerably faster than 300 s-1. The exchange through the contact is specific for certain lipids, and phospholipids with a modified head group or phospholipase A2 bound to a vesicle are not transferred to the other vesicle in contact. Since this phenomenon has not been described before, possible implications of direct vesicle−vesicle exchange of phospholipids through peptide-mediated molecular contacts are discussed. Such a mechanism for intermembrane transfer of phospholipids could be responsible for intracellular trafficking and sorting of phospholipids; it could be a necessary first step for the sequence of events leading to budding, vesiculation, and secretion; and PxB-mediated transfer between the inner and outer membranes of Gram-negative bacteria could also account for its antibiotic action.

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