The Barrel Stave Model

The barrel-stave model was first proposed to describe the formation of transmembrane channels/pores by bundles of amphipatic a-helical peptides (Ehrenstein and Lecar 1977; Sansom 1993,1998). Peptides which act via this mechanism are inserted into the membrane such that their hydrophobic surfaces interact with the lipid core of the membrane and their hydrophilic surfaces point inward producing an aqueous pore (Fig. 7.3). Amphipatic a-helical lytic peptides which act on a specific or several types of cells including bacteria, fungi and mammalian cells, were among the first to be discovered, and therefore used as models for mode-of-action studies. It has been suggested that following binding, linear amphipatic a-helical peptides would form transmembrane pores, presumably via a barrel-stave mechanism (Ehrenstein and Lecar 1977) (Fig. 7.3). The experimental evidence for this model was predominantly the ability of many of these peptides to induce single channels in planar lipid membranes (Christensen et al. 1988; Westerhoff et al. 1989; Duclohier et al. 1989; Matsuzaki et al. 1991). Peptides that act via the barrel-stave mechanism need to insert into the hydrophobic lipidic core of the membrane, and therefore their interaction with the target membrane is governed predominantly by hydrophobic interactions. The following steps are involved in the barrel-stave mechanism: (1) the peptides bind onto the surface of the membrane and self-associate; (2) the bundle inserts into the membrane to

Fig. 7.3. A cartoon illustrating the formation of channels/pores via the barrel-stave model. Peptides reach the membrane either as monomers or oligomers and assemble on the surface of the membrane (step A). In the next step they insert into the lipid core of the membrane following recruitment ofadditional monomers (step B)

Fig. 7.3. A cartoon illustrating the formation of channels/pores via the barrel-stave model. Peptides reach the membrane either as monomers or oligomers and assemble on the surface of the membrane (step A). In the next step they insert into the lipid core of the membrane following recruitment ofadditional monomers (step B)

form a transmembrane pore; (3) the pore increases due to the recurrent of more monomers; (4) a minimal length of -22 aa is required for a peptide to transverse the lipid bilayers if it adopts an a-helical structure, or ~8 aa if the peptide adopts a P-sheeted structure. Studies have shown that only a few lytic amphipatic peptides act via the barrel-stave mechanism. All of these peptides bind to membranes via hydrophobic interactions and are usually very toxic to all types of cells including bacteria, mammalian cells and fungi. Examples include alamethicin (Sansom 1993; Rizzo et al. 1987), melittin (DeGrado et al. 1982; Vogel et al. 1983; Dempsey and Butler 1992; Ladokhin and White 2001), pardaxin (Shai et al. 1990; Rapaport and Shai 1991,1992), and the helix a5 of 6-endotoxin (Gazit and Shai 1993; Gazit et al. 1994).

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