In recent years, considerable progress has been made towards understanding the mechanism by which endotoxin is detected by the cells of the immune system. Lipopolysaccharides are extracted in a soluble form by the serum LPS binding protein and then transferred sequentially to the extrinsic membrane protein CD14 and the co-receptor complex TLR4/MD-2. Our modelling studies suggest that acyl chains of lipid A are buried within the hydrophobic core of MD-2 and this induces crosslinking of the two TLR4/MD-2 complexes, an event that is required to trigger signal transduction. We also propose that, by analogy with the Drosophila Toll receptor, the mechanism of signal transduction is likely to be complex and to involve concerted protein conformational changes. In particular, we propose that receptor—receptor interactions mediated by juxtamembrane sequences play a critical role.
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