Figure 4.

Hypothetical phenomena of synergistically enhanced cell lysis mediated by cytotoxin-PLA₂ or melittin-PLA₂ hetero-oligomers on phospholipid bilayer membranes. (A) Cytotoxins (monomers or oligomers) likely bind to anionic extracellular proteins or carbohydrates (Harvey, 2018), which may lead to further oligomerization and formation of membrane pores, leading to cell lysis (Forouhar et al., 2003; Konshina et al., 2011). (B) When combined with PLA₂s, cytotoxins are more likely to easily bind to the neutral outer membrane on the lipid binding surface of the molecule (Singer et al., 2002; Burke and Dennis, 2009), resulting in synergistically enhanced lysis. (C) Different to cytotoxins, which are proteins of predominantly beta sheet structure, the helical structure of melittin provides better opportunities for melittin interaction with neutral membranes (Dempsey, 1990; Kleinschmidt et al., 1997), which is possibly mediated via electrostatic attraction between basic amino acid residues of melittin and the phosphate group of phosphatidylcholine (Dempsey, 1990; Kleinschmidt et al., 1997). The melittin-phospholipid binding enables melittin oligomerization, formation of membrane pores, and lysis (Yang et al., 2001; Pucca et al., 2019). (D) As for cytotoxins, PLA₂s can also facilitate melittin binding in the cell membrane, resulting in synergistically enhanced lysis. (E) PLA₂-induced hydrolysis also affects membrane integrity through the detergent action of the hydrolytic products of phospholipids, which may also contribute to the lytic effects (Lomonte and Gutiérrez, 2011). The last hypothetical phenomenon is unlikely to account for the synergistic effects observed for MII, since this toxin lacks enzymatic activity.