Binding of LL-37 to model biomembranes: insight into target vs host cell recognition.
Pursuing the molecular mechanisms of the concentration dependent cytotoxic and hemolytic effects of the human antimicrobial peptide LL-37 on cells, we investigated the interactions of this peptide with lipids using different model membranes, together with fluorescence spectroscopy for the Trp-containing mutant LL-37(F27W). Minimum concentrations inhibiting bacterial growth and lipid interactions assessed by dynamic light scattering and monolayer penetration revealed the mutant to retain the characteristics of native LL-37. Although both LL-37 and the mutant intercalated effectively into zwitterionic phosphatidylcholine membranes the presence of acidic phospholipids caused augmented membrane binding. Interestingly, strongly attenuated intercalation of LL-37 into membranes containing both cholesterol and sphingomyelin (both at X=0.3) was observed. Accordingly, the distinction between target and host cells by LL-37 is likely to derive from i) acidic phospholipids causing enhanced association with the former cells as well as ii) from attenuated interactions with the outer surface of the plasma membrane of the peptide secreting host, imposed by its high content of cholesterol and sphingomyelin. Our results further suggest that LL-37 may exert its antimicrobial effects by compromising the membrane barrier properties of the target microbes by a mechanism involving cytotoxic oligomers, similarly to other peptides forming amyloid-like fibers in the presence of acidic phospholipids.
Sood
Rohit
R
Helsinki Biophysics and Biomembrane Group, Medical Biochemistry, Institute of Biomedicine, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Finland.
Domanov
Yegor
Y
Pietiäinen
Milla
M
Kontinen
Vesa P
VP
Kinnunen
Paavo K J
PK
D020106:Acrylamide; D000682:Amyloid; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D054804:Cathelicidins; D002942:Circular Dichroism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007700:Kinetics; D008051:Lipid Bilayers / Q000378:metabolism*; D008081:Liposomes; D008826:Microbial Sensitivity Tests; D010713:Phosphatidylcholines / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism
D000682:Amyloid; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D020106:Acrylamide; C027891:1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine; D014364:Tryptophan