LPS varies in composition between different bacteria but essentially consists of a polysaccharide core attached to an amphipathic lipid, lipid A, with a variable number of fatty-acid chains per molecule (see Fig. 2.7). To recognize LPS, the ectodomain of TLR-4 uses an accessory protein, MD-2. MD-2 initially binds to TLR-4 within the cell and is necessary both for the correct trafficking of TLR-4 to the cell surface and for the recognition of LPS. MD-2 associates with the central section of the curved ectodomain of TLR-4, binding off to one side as shown in Fig. 3.12. When the TLR4-MD-2 complex encounters LPS, five lipid chains of LPs bind to a deep hydrophobic pocket of MD-2, but not directly to TLR-4, while a sixth remains exposed on the surface of MD-2. This lipid chain and parts of the LPS polysaccharide backbone bind directly to a region on the convex surface of the ectodomain of a second TLR-4 molecule. Thus, the TLR-4 dimerization required to activate intracellular signaling depends on both indirect and direct interactions with LPS.