Structural biology of the LPS recognition.
Bacterial endotoxin (lipopolysaccharide - LPS) as one of the most potent inducers of the immune system is recognized by a complex cascade of extracellular "pattern recognition receptors", which chaperone the LPS from the bacterial membrane to the transmembrane receptor TLR4. Recent structural, biochemical and physiological investigations have advanced our understanding of the molecular pattern recognized by the receptors. The proposed mechanism of LPS recognition by the innate immune system involves as the first step binding of the LPS-binding protein (LBP) to LPS, which leads to a disruption of LPS aggregates Cationic amino acid residues at the tip of LBP play the most important role. The carboxyl-terminal domain of LBP, which interacts with CD14 or with the cell membrane, is required to streamline LPS signalling. The monomeric CD14:LPS complex is soluble, as the acyl chains of the lipid A are to a large extent protected from the solvent by interaction with the hydrophobic pocket of CD14. CD14 does not have a strong cationic cluster, characteristic of LBP and MD-2. Besides lipid A, CD14 recognizes also the carbohydrate chains of LPS and along with LBP governs the activation of the MyD88-independent signalling pathway of TLR4. The final cellular acceptor for LPS is MD-2, which comprises both a strong cationic and a hydrophobic binding site. MD-2 binds the LPS monomer and is sensitive to the acylation pattern of the lipid A moiety. Association of the MD-2:LPS complex to the ectodomain of Toll-like receptor 4 (TLR4) finally transduces the signal through the association of intracellular TIR domain, recruiting the adapter proteins triggering the signalling cascade.
Jerala
Roman
R
Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia. roman.jerala@ki.si
D000818:Animals; D004731:Endotoxins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*
D004731:Endotoxins; D011971:Receptors, Immunologic