Structure, location, and lipid perturbations of melittin at the membrane interface.
Melittin is arguably the most widely studied amphipathic, membrane-lytic alpha-helical peptide. Although several lines of evidence suggest an interfacial membrane location at low concentrations, melittin's exact position and depth of penetration into the hydrocarbon core are unknown. Furthermore, the structural basis for its lytic action remains largely a matter of conjecture. Using a novel x-ray absolute-scale refinement method, we have now determined the location, orientation, and likely conformation of monomeric melittin in oriented phosphocholine lipid multilayers. Its helical axis is aligned parallel to the bilayer plane at the depth of the glycerol groups, but its average conformation differs from the crystallographic structure. As observed earlier for another amphipathic alpha-helical peptide, the lipid perturbations induced by melittin are remarkably modest. Small bilayer perturbations thus appear to be a general feature of amphipathic helices at low concentrations. In contrast, a dimeric form of melittin causes larger structural perturbations under otherwise identical conditions. These results provide direct structural evidence that self-association of amphipathic helices may be the crucial initial step toward membrane lysis.
Hristova
K
K
Department of Physiology and Biophysics and the Program in Macromolecular Structure, University of California at Irvine, Irvine, California 92697-4560, USA.
Dempsey
C E
CE
White
S H
SH
D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002942:Circular Dichroism; D019281:Dimerization; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000737:chemistry; D008555:Melitten / Q000737:chemistry*; D008563:Membrane Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000737:chemistry; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D014961:X-Ray Diffraction
D008051:Lipid Bilayers; D008563:Membrane Lipids; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D008555:Melitten; C017251:1,2-oleoylphosphatidylcholine