Coupling of cholesterol and cone-shaped lipids in bilayers augments membrane permeabilization by the cholesterol-specific toxins streptolysin O and Vibrio cholerae cytolysin

Vibrio cholerae cytolysin (VCC) forms oligomeric pores in lipid bilayers co ntaining cholesterol, Membrane permeabilization is inefficient if the stero l is embedded within bilayers prepared from phosphatidylcholine only but is greatly enhanced if the target membrane also contains ceramide, Although t he enhancement of VCC action is stereospecific with respect to cholesterol, we show here that no such specificity applies to the two stereocenters in ceramide; all four stereoisomers of ceramide enhanced VCC activity in chole sterol-containing bilayers, A wide variety of ceramide analogs were as effe ctive as D-erythro-ceramide, as was diacylglycerol, suggesting that the eff ect of ceramide exemplifies a general trend of lipids with a small headgrou p to augment the activity of VCC, Incorporation of these cone-shaped lipids into cholesterol-containing bilayers also gave similar effects with strept olysin O, another cholesterol-specific but structurally unrelated cytolysin , In contrast, the activity of staphylococcal alpha -hemolysin, which does not share with the other toxins the requirement for cholesterol, was far le ss affected by the presence of lipids with a conical shape. The collective data indicate that sphingolipids and glycerolipids do not interact with the cytolysins specifically, Instead, lipids that have a conical molecular sha pe appear to effect a change in the energetic state of membrane cholesterol that in turn augments the interaction of the sterol with the cholesterol-s pecific cytolysins.