Heterodimer formation between the antimicrobial peptides magainin 2 and PGLa in lipid bilayers: A cross-linking study

The antimicrobial peptides magainin 2 and PGLa, isolated from the skin of t he African clawed frog Xenopus laevis, show marked synergism [Westerhoff, H . V., Zasloff, M., Rosner, J. L., Hendler, R. W., de Waal, A., Vaz Gomes, A ., Jongsma, A. P. M., Riethorst, A., and Juretic, D. (1995) Eur. J. Biochem . 228, 257-264]. We suggested previously that these peptides form a potent heterodimer composed of either parallel or antiparallel helices in membrane s [Matsuzaki, K., Mitani, Y., Akada, K., Murase, O., Yoneyama, S., Zasloff, M., and Miyajima, K. (1998) Biochemistry 37, 15144-15153]. To detect the p utative heterodimer by chemical cross-linking, analogues of magainin 2 and PGLa with a Cys residue at either terminus were synthesized. These cross-li nking experiments suggested that both peptides form a parallel heterodimer in membranes composed of phosphatidylglycerol/phosphatidylcholine but not i n either buffer or a helix-promoting 2,2,2-trifluoroethano/buffer mixture. The isolated parallel heterodimers exhibited an order of magnitude higher m embrane permeabilization activity compared with the monomeric species, indi cating that the observed synergism is due to heterodimer formation.