Interaction of a magainin-PGLa hybrid peptide with membranes: insight into the mechanism of synergism.
The antimicrobial peptides magainin 2 and PGLa isolated from the skin of the African clawed frog Xenopus laevis show marked functional synergism. We have proposed that the two peptides form a heterodimer composed of parallel helices with strong membrane permeabilizing activity [Hara, T., Mitani, Y., Tanaka, K., Uematsu, N., Takakura, A., Tachi, T., Kodama, H., Kondo, M., Mori, H., Otaka, A., Fujii, N., and Matsuzaki, K. (2001) Biochemistry 40, 12395-12399]. In this study, to elucidate the molecular mechanism of the synergy, we synthesized a chemically fixed heterodimer and investigated in detail the interaction of the hybrid peptide with bacteria, erythrocytes, and lipid bilayers. The hybrid peptide showed antimicrobial activity and membrane permeabilizing activity against negatively charged membranes, similar to or even stronger than those of a physical equimolar mixture of magainin and PGLa, indicating that the synergy is due to the formation of a parallel heterodimer. The heterodimer assumed a more oblique orientation than the component peptides. In contrast, the cross-linking of the two peptides significantly strengthened the action against erythrocytes and zwitterionic lipid bilayers by enhancing the affinity for membranes without changing the basic mode of action. Thus, the separate production of mutually recognizing peptides without cross-linking appears to be a good way to increase selective toxicity.
Nishida
Minoru
M
Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Imura
Yuichi
Y
Yamamoto
Megumi
M
Kobayashi
Satoe
S
Yano
Yoshiaki
Y
Matsuzaki
Katsumi
K
D000328:Adult; D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D002463:Cell Membrane Permeability / Q000187:drug effects; D019281:Dimerization; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D054806:Magainins; D008297:Male; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011498:Protein Precursors / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013212:Staphylococcus epidermidis / Q000187:drug effects; D053835:Unilamellar Liposomes; D029867:Xenopus Proteins / Q000737:chemistry*
D023181:Antimicrobial Cationic Peptides; D054806:Magainins; C088254:PGLa prepropeptide; D010455:Peptides; D011498:Protein Precursors; D053835:Unilamellar Liposomes; D029867:Xenopus Proteins; C526465:magainin-PGLa hybrid peptide; C053301:magainin 2 peptide, Xenopus