Lipopolysaccharide-binding protein-mediated interaction of lipid A from different origin with phospholipid membranes

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Abstract
Investigations are reported into the interaction of lipid A, the ‘endotoxic principle’ of bacterial lipopolysaccharide (LPS), with phospholipid membranes in the absence and presence of an acute-phase lipid transport protein, lipopolysaccharide-binding protein (LBP) applying Fourier-transform infrared (FTIR) and fluorescence resonance energy transfer (FRET) spectroscopy. In the absence of LBP, intermixing of phospholipids with lipid A takes place on the time-scale of hours, while in the presence of LBP this process takes place in the order of minutes. A comparison of chemically different lipid A shows that a prerequisite for the intercalation of lipid A into the phospholipid membrane is a sufficiently high negative charge density of lipid A. Variations in the lipid A acyl chain fluidity may modulate the intercalation, whereas the type of lipid A aggregate structure has no influence on the intercalation.The intercalation is a necessary, but not sufficient prerequisite for cell activation. Only lipid A with a conical molecular shape and a tilt angle of more than 40° of the backbone with respect to the direction of the acyl chains induces cytokine induction in human mononuclear cells, while lipid A with a cylindrical shape and a small tilt angle does not exhibit this biological activity but may act antagonistically. This antagonistic effect may be explained by blocking of the binding-sites of the putative signal-transducing protein, possibly an ion channel, by the antagonist.

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