Membrane-perturbing activity of Viperidae myotoxins: an electrostatic surface potential approach to a puzzling problem.
Phospholipase-like myotoxins are a class of proteins present in Viperidae venom. Despite the high level of amino acid and structural homology with soluble phospholipases A(2), myotoxins are devoid of enzymatic activity and share cytolytic activity by means of a totally unknown mechanism involving the lipid bilayer perturbation. The distribution of electrostatic surface potentials of four myotoxins and seven phospholipases A(2) has been compared. The charge distribution is similar in all active non-cytolytic phospholipases with a strongly positive side corresponding to the domain interacting with the micellar substrate and with the opposite side negatively charged. In contrast, all myotoxins examined are positively charged on both sides. Myotoxin III, the only known example of a myotoxin sharing enzymatic activity, displays the same electrostatic surface potential as other related toxins. Using liposomes made with non-hydrolysable phospholipids, we demonstrate that myotoxin III perturbs the lipid bilayer like other myotoxins. Based on these results, a molecular model for myotoxin-membrane perturbing activity is proposed. In this model, potential double-face binding of myotoxic phospholipases A(2) to lipid surfaces could trigger a lipid bilayer destabilization and could generate a stable fusion pore, probably because of the presence of hydrophobic moieties that flank the cationic sites.
Falconi
M
M
INFM and Department of Biology, University of Rome 'Tor Vergata', via della Ricerca Scientifica, 00133 Rome, Italy.
Desideri
A
A
Rufini
S
S
D002463:Cell Membrane Permeability / Q000187:drug effects; D003435:Crotalid Venoms; D054501:Group II Phospholipases A2; D008051:Lipid Bilayers; D008081:Liposomes / Q000187:drug effects; D008956:Models, Chemical; D009498:Neurotoxins / Q000737:chemistry* / Q000494:pharmacology; D010741:Phospholipases A / Q000737:chemistry* / Q000494:pharmacology; D010743:Phospholipids; D030162:Reptilian Proteins; D055672:Static Electricity
D003435:Crotalid Venoms; D008051:Lipid Bilayers; D008081:Liposomes; D009498:Neurotoxins; D010743:Phospholipids; D030162:Reptilian Proteins; D010741:Phospholipases A; D054501:Group II Phospholipases A2; C080300:myotoxin III, Bothrops asper