How lipids influence the mode of action of membrane-active peptides.
The human, multifunctional peptide LL-37 causes membrane disruption by distinctly different mechanisms strongly dependent on the nature of the membrane lipid composition, varying not only with lipid headgroup charge but also with hydrocarbon chain length. Specifically, LL-37 induces a peptide-associated quasi-interdigitated phase in negatively charged phosphatidylglycerol (PG) model membranes, where the hydrocarbon chains are shielded from water by the peptide. In turn, LL-37 leads to a disintegration of the lamellar organization of zwitterionic dipalmitoyl-phosphatidylcholine (DPPC) into disk-like micelles. Interestingly, interdigitation was also observed for the longer-chain C18 and C20 PCs. This dual behavior of LL-37 can be attributed to a balance between electrostatic interactions reflected in different penetration depths of the peptide and hydrocarbon chain length. Thus, our observations indicate that there is a tight coupling between the peptide properties and those of the lipid bilayer, which needs to be considered in studies of lipid/peptide interaction. Very similar effects were also observed for melittin and the frog skin peptide PGLa. Therefore, we propose a phase diagram showing different lipid/peptide arrangements as a function of hydrocarbon chain length and LL-37 concentration and suggest that this phase diagram is generally applicable to membrane-active peptides localized parallel to the membrane surface.
Institute of Biophysics and Nanosystems Research, Austrian Academy of Sciences, Schmiedlstrasse 6, 8042 Graz, Austria.
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Sevcsik
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Pabst
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Jilek
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Lohner
D000731:Androstanes / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002152:Calorimetry, Differential Scanning; D002462:Cell Membrane / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D008051:Lipid Bilayers / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry*; D008854:Microscopy, Electron; D010715:Phosphatidylglycerols; D012542:Scattering, Radiation; D054804:Cathelicidins
C415601:3-oxo-androstan-17-yl-(2'',2'',6'',6''-tetramethyl-N-oxyl)piperidyl butan-1',4'-dioate; D000731:Androstanes; D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010715:Phosphatidylglycerols; C030345:1,2-dipalmitoylphosphatidylglycerol; D054804:Cathelicidins