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1.C.18 The Melittin (Melittin) 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.  The process of pore formation for mellitin in lipid bilayers has been studied in some detail (Lee et al. 2013).

How antimicrobial peptides form pores in membranes is of interest as a fundamental membrane process. The time-dependent process of pore formation has been studied in individual giant unilamellar vesicles exposed to a melittin solution (Lee et al., 2008). An individual vescile first expanded its surface area at constant volume and then suddenly reversed expansion of its volume at constant area. The area expansion, the volume expansion, and the point of reversal all match the results of equilibrium measurements performed on peptide%u2013lipid mixtures. The mechanism includes negative feedback that makes peptide-induced pores stable with a well defined size, contrary to the suggestion that peptides disintegrate the membrane in a detergent-like manner.  Melittin creates transient pores in lipid bilayers (Santo et al. 2013).

A large variety of antimicrobial peptides have been shown to act, at least in vitro, by poration of the lipid membrane. The nanometer size of these pores, however, complicates their structural characterization by experimental techniques. Sengupta et al. (2008) used molecular dynamics simulation to study the interaction of a specific class of melittin with a dipalmitoylphosphatidylcholine bilayer in atomic detail. Transmembrane pores spontaneously formed above a critical peptide to lipid ratio (Sengupta et al., 2008). The lipid molecules bent inwards to form a toroidally shaped pore but with only one or two peptides lining the pore, in contrast to the traditional models of toroidal pores in which the peptides are assumed to adopt a transmembrane orientation. Sengupta et al., 2008 reported that peptide aggregation, either prior to or after binding to the membrane surface, is a prerequisite to pore formation. The presence of a stable helical secondary structure of the peptide, however is not. Electrostatic interactions are important in the poration process; removing charges of the basic amino-acid residues of melittin prevents pore formation. In the absence of counter ions, pores not only form more rapidly, but lead to membrane rupture via a novel recursive poration pathway.  Melittin has been reported to form transient pores (Wiedman et al. 2013).

The generalized transport reaction catalyzed by channel-forming amphipathic peptides is:


small solutes, electrolytes and water (in) small solutes, electrolytes and water (out).


Several families of eukaryotic channel-forming amphipathic peptide, each from a different group of organisms, are recognized. These families will be listed below and briefly described.

Melittin (26 residues) is the best studied of the insect peptide toxins. It is found in the venom of the European honey bee, Apis mellifera. Three-dimensional structures of melittin have been elucidated.

This family belongs to the: Cecropin Superfamily.

References associated with 1.C.18 family:

Bechinger, B. (1997). Structure and functions of channel-forming peptides: magainins, cecropins, melittin and alamethicin. J. Membr. Biol. 156: 197-211. 9096062
Bechinger, B., M. Zasloff and S.J. Opella (1993). Structure and orientation of the antibiotic peptide magainin in membrane by solid-state nuclear magnetic resonance spectroscopy. Prot. Sci. 2: 2077-2084. 8298457
Ganz, T., J.R. Rayner, E.V. Valore, A. Tumolo, K. Talmadge and F. Fuller (1989). The structure of the rabbit macrophage defensin genes and their organ-specific expression. J. Immunol. 143: 1358-1365. 2745983
Gudmundsson, G.H., D.A. Lidholm, B. Asling, R.B. Gan and H.G. Boman (1991). The cecropin locus–cloning and expression of a gene cluster encoding 3 antibacterial peptides in Hyalophora cecropia. J. Biol. Chem. 266: 11510-11517. 1711035
Hill, C.P., J. Yee, M.E. Selsted and D. Eisenberg (1991). Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science 251: 1481-1485. 2006422
Kourie, J.I. and A.A. Shorthouse (2000). Properties of cytotoxic peptide-formed ion channels. Am. J. Physiol. Cell Physiol. 278: C1063-C1087. 10837335
Lee, M.T., T.L. Sun, W.C. Hung, and H.W. Huang. (2013). Process of inducing pores in membranes by melittin. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print] 23940362
Lee, M.T., W.C. Hung, F.Y. Chen, and H.W. Huang. (2008). Mechanism and kinetics of pore formation in membranes by water-soluble amphipathic peptides. Proc. Natl. Acad. Sci. USA 105: 5087-5092. 18375755
Matsuzaki, K. (1998). Magainins as paradigm for the mode of action of pore forming polypeptides. Biochim. Biophys. Acta 1376: 391-400. 9804997
Nagaoka, I., A. Someya, K. Iwabuchi and T. Yamashita (1991). Characterization of cDNA clones encoding guinea pig neutrophil cationic peptides. FEBS Lett. 280: 287-291. 2013325
Pardi, A., X.L. Zhang, M.E. Selsted, J.J. Skalicky and P.F. Yip (1992). NMR studies of defensin antimicrobial peptides. 2. Three-dimensional structures of rabbit NP-2 and human HNP-1. Biochemistry 31: 11357-11364. 1445873
Santo, K.P., S.J. Irudayam, and M.L. Berkowitz. (2013). Melittin Creates Transient Pores in a Lipid Bilayer: Results from Computer Simulations. J Phys Chem B. [Epub: Ahead of Print] 23534858
Sengupta, D., H. Leontiadou, A.E. Mark, and S.J. Marrink. (2008). Toroidal pores formed by antimicrobial peptides show significant disorder. Biochim. Biophys. Acta. 1778: 2308-2317. 18602889
Terwilliger, T.C. and D. Eisenberg (1982). The structure of melittin. II. Interpretation of the structure. J. Biol. Chem. 257: 6016-6022.
Vlasak, R., C. Unger-Ullmann, G. Kreil and A.M. Frischauf (1983). Nucleotide sequence of cloned cDNA coding for honeybee prepromelittin. Eur. J. Biochem. 135: 123-126. 6309516
Wiedman, G., K. Herman, P. Searson, W.C. Wimley, and K. Hristova. (2013). The electrical response of bilayers to the bee venom toxin melittin: evidence for transient bilayer permeabilization. Biochim. Biophys. Acta. 1828: 1357-1364. 23384418
Zhang, X.L., M.E. Selsted and A. Pardi (1992). NMR studies of defensin antimicrobial peptides. 1. Resonance assignment and secondary structure determination of rabbit NP-2 and human HNP-1. Biochemistry 31: 11348-11356. 1445872