Permeabilization of Raft-Containing Lipid Vesicles by δ-Lysin: A Mechanism for Cell Sensitivity to Cytotoxic Peptides

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Abstract
δ-Lysin is a linear, 26-residue peptide that adopts an α-helical, amphipathic structure upon binding to membranes. δ-Lysin preferentially binds to mammalian cell membranes, the outer leaflets of which are enriched in sphingomyelin, cholesterol, and unsaturated phosphatidylcholine. Mixtures including these lipids have been shown to exhibit separation between liquid-disordered (𝓁d) and liquid-ordered (𝓁o) domains. When rich in sphingomyelin and cholesterol, these ordered domains have been called lipid “rafts”. We found that δ-lysin binds poorly to the 𝓁o (raft) domains; therefore, in mixed-phase lipid vesicles, δ-lysin preferentially binds to the 𝓁d domains. This leads to the concentration of δ-lysin in 𝓁d domains, enhancing peptide aggregation and, consequently, the rate of peptide-induced dye efflux from lipid vesicles. The efficient lysis of eukaryotic cells by δ-lysin can thus be attributed not to specific δ-lysin−cholesterol or δ-lysin−sphingomyelin interactions but, rather, to the exclusion of δ-lysin from ordered rafts. The degree to which the kinetics of dye efflux are enhanced in mixed-phase vesicles over those observed in pure, unsaturated phosphatidylcholine vesicles directly reflects the amount of 𝓁d phase present in mixed-phase systems. This effect of lipid domains has broader consequences, beyond the hemolytic efficiency of δ-lysin. We discuss the hypothesis that bacterial sensitivity to antimicrobial peptides may be determined by a similar mechanism.

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