1.C.16 The Magainin (Magainin) Family
Many organisms synthesize proteins (or peptides) which are degraded to relatively small hydrophobic or amphipathic, bioactive peptides. These peptides exhibit antibiotic, fungicidal, virucidal, hemolytic and/or tumoricidal activities by interacting with membranes and forming transmembrane channels that allow the free flow of electrolytes, metabolites and water across the phospholipid bilayers. Most of these peptides appear to function in biological warfare. There are many designations given to these bioactive peptides. They include the magainins, cecropins, melittins, defensins, bacteriocidins, etc. The proteins in each family within this functional superfamily are homologous, but they exhibit little or no significant sequence similarity with members of the other families. Thus, each family may have evolved independently. However, certain common structural features observed between members of distinct families suggest that at least some of these families share a common ancestry.
Magainins are a group of amphipathic peptides (21-26 amino acyl residues in length) from the skin and intestines of frogs. They form right-handed α-helical structures in membranes and serve bactericidal, fungicidal and virucidal functions. They thereby provide defense against infectious agents. As revealed by their synergistic behavior, they can form homo- or heterooligomeric transmembrane channels. One distant member of the magainin family, 'peptide between glycine and leucine amide' (PGLa) (GMASKAGAIAGKIAKVALKAL-NH2) is not hemolytic but acts on Gram-negative and Gram-positive bacteria as well as fungi and protozoa. PGLa is positively charged, adopts a random coil configuration in water and folds into an amphipathic α-helix when it inserts into the membrane, parallel to the membrane surface at low peptide concentrations but perpendicular to the membrane surface at higher concentrations when it forms a peptide/lipid pore. Pore formation depends on anionic phospholipids. PGLa and magainin2 amide exhibit synergism when forming transmembrane pores. The synergism of magainin 2 amide and PGLa in forming transmembrane pores results from formation of a heterodimer composed of parallel helices with strong membrane permeabilizing activity (Hara et al., 2001; Nishida et al., 2007). While magainin 1 is anion-selective, magainin 2 is cation-selective (Kourie and Shorthouse, 2000).
The antimicrobial peptides magainin 2 and the PGLa (PYLa) precursor (TC# 1.C.16.1.5) show marked synergism. These two peptides form a heterodimer composed of parallel helices with strong membrane permeabilizing activity (Hara et al., 2001). The synergy observed for the two peptides is due to the formation of a parallel heterodimer (Nishida et al., 2007). Magainin disruption of cells is concentration-dependent and a highly stochastic process (Han et al., 2009). Based on NMR and other analyses, Han et al., 2009 concluded that magainin-induced pores in lipid vesicles have a mean diameter of approximately 80 A.
Model membranes have been used to elucidate how peptides permeabilize membranes. The interaction of F5W-magainin 2 (GIGKWLHSAKKFGKAFVGEIMNS), an equipotent analogue of magainin 2 isolated from the African clawed frog Xenopus laevis was studied with unfixed Bacillus megaterium and Chinese hamster ovary (CHO)-K1 cells by Imura et al. (2008). The influx of fluorescent markers of various sizes into the cytosol revealed that magainin 2 permeabilizes bacterial and mammalian membranes in significantly different ways. The peptide formed pores with a diameter of approximately 2.8 nm (<6.6 nm) in B. megaterium. In contrast, the peptide perturbed the membrane of CHO-K1 cells, permitting the entry of large molecules (diameter, >23 nm) into the cytosol.
The generalized transport reaction catalyzed by channel-forming amphipathic peptides is:
small solutes, electrolytes and water (in) 
small solutes, electrolytes and water (out).
