Binding and pore-formation by actinoporins are determined by membrane physicochemical properties
Keywords:
actinoporinas, proteínas formadoras de poro, fluidez, membranas modelo, fases lipídicasAbstract
Introduction. Actinoporins (AP) are pore-forming proteins (PFPs) that readily bind to membranes leading to cell death. Sticholysins I and II (St, StI/II) are among the most potent AP described in nature. This proposal aimed to characterize the influence of lipid composition and dynamic properties of membranes on binding and pore-formation by StI/II and nigrelysin (Ngr), a novel AP here described. Methods. Binding and pore-formation were studied using model membranes such as liposomes and lipidic monolayers combined with fluorescence spectroscopy and microscopic techniques.Results and Discussion. St and Ngr bind and preferentially permeabilize membranes containing sphingomyelin (SM) over phosphatidylcholine (PC). This is explained by the presence of the PC phosphocholine unit plus a ceramide moiety (Cer) in SM. StI also recognizes Cer and gangliosides although to a lesser extent. In terms of dynamic properties, StI penetrates preferentially membranes with high lateral mobility and moderately enriched in SM. Also, StI permeabilizes more efficiently membranes containing sterols, in addition to SM. The appearance of borders resulting from lipidic domains coexistence is not a determining factor for binding or activity in membranes. Indeed, the activity is enhanced by membrane molecular heterogeneity beyond the presence of lipidic domains. As a conclusion these studies explain the relevance of SM and sterols for St, Ngr, and by extension, to APs binding to membrane and explain the contribution of other Cer-based lipids to their activity. In dynamic terms, a highly fluid phase, and moderately enriched in SM and sterols, is an ideal platform for the formation of pores in the membrane for AP.
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