title: Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37.
abstract: LL-37 is an amphipathic, alpha-helical, antimicrobial peptide. (15)N chemical shift and (15)N dipolar-shift spectroscopy of site-specifically labeled LL-37 in oriented lipid bilayers indicate that the amphipathic helix is oriented parallel to the surface of the bilayer. This surface orientation is maintained in both anionic and zwitterionic bilayers and at different temperatures and peptide concentrations, ruling out a barrel-stave mechanism for bilayer disruption by LL-37. In contrast, electrostatic factors, the type of lipid, and the presence of cholesterol do affect the extent to which LL-37 perturbs the lipids in the bilayer as observed with (31)P NMR. The (31)P spectra also show that micelles or other small, rapidly tumbling membrane fragments are not formed in the presence of LL-37, excluding a detergent-like mechanism. LL-37 does increase the lamellar to inverted hexagonal phase transition temperature of both PE model lipid systems and Escherichia coli lipids, demonstrating that it induces positive curvature strain in these environments. These results support a toroidal pore mechanism of lipid bilayer disruption by LL-37.
authors.affiliation: Department of Chemistry and Biophysics Research Division, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Henzler Wildman
authors.forename: Dong-Kuk
authors.initials: DK
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Ramamoorthy
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry; D054804:Cathelicidins; D002784:Cholesterol / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D010452:Peptide Biosynthesis; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008051:Lipid Bilayers; D008055:Lipids; D008823:Micelles; D002784:Cholesterol