The structure of melittin in the form I crystals and its implication for melittin's lytic and surface activities

Abstract

Melittin from bee venom is water-soluble, yet integrates into membranes and lyses cells. Each melittin chain consists of 26 amino acid residues and in aqueous salt solutions it exists as a tetramer. We have determined the molecular structure of the tetramer in two crystal forms grown from concentrated salt solutions. In both crystal forms the melittin polypeptide is a bent alpha-helical rod, with the "inner" surface largely consisting of hydrophobic sidechains and the "outer" surface consisting of hydrophilic side chains. Thus, the helix is strongly amphiphilic. In the tetramer, four such helices contribute their hydrophobic side chains to the center of the molecule. The packing of melittin tetramers is also very similar in the two crystal forms: they are packed in planar layers with the outsides forming hydrophilic surfaces and the insides (the centers of melittin tetramers) forming a hydrophobic surface. We suggest that the surface activity of melittin can be rationalized in terms of these surfaces. The lytic activity of melittin can also be interpreted in terms of the molecular structure observed in the crystals: the hydrophobic inner surface of a melittin helix may integrate into the apolar region of a bilayer with the helix axis approximately parallel to the plane of the bilayer, and with the hydrophilic surface exposed to the aqueous phase. This integration would be expected to disrupt the bilayer because of melittin helix would penetrate only a short distance into it. Additionally, the integration of melittin from one side of a bilayer would produce a surface area difference across the bilayer, perhaps leading to lysis. In this view, melittin is distinct from membrane proteins that penetrate evenly into both leaflets of a bilayer or exactly halfway through a bilayer, and hence we refer to melittin as a surface-active protein.

Defensins promote fusion and lysis of negatively charged membranes

“…This model is reminiscent of the wedge models proposed for a-helical peptides, such as melittin (Dawson et al, 1978;Terwilliger et al, 1982;Batenburg & de Kruiff, 1988) or SI (Fujii et al, 1992). If the defensin dimer is imagined to be an amphiphilic wedge, then Figure 7C illustrates the similarity of the defensins to the wedges formed by an a-helix.…”

A molecular model for membrane fusion based on solution studies of an amphiphilic peptide from HIV gp41

“…8A). The a-helical region of the peptide then embeds itself in the membrane surface, probably in a wedge type of interaction (Dawson et al, 1978;Terwilliger et al, 1982;Batenburg & de Kruiff, 1988). Fusion between liposomes occurs because some of the positively charged residues interact with other liposomes thus bringing them into close contact with one another (Fig.…”

Unusually stable helical kink in the antimicrobial peptide — A derivative of gaegurin

“…A few well-known examples are mellitin [3,4] in bees, cecropin [5] in moths and magainin [6] in frogs. These peptides respond to the infection of bacteria or fungi by destroying the foreign bodies to protect the host.…”