Title : The structural basis of
lipopolysaccharide recognition by the
TLR4-
MD-2 complex
Abstract :
- The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response
- Toll-like receptor ( TLR) 4 and myeloid differentiation factor 2 2 (MD-2 ) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules
- To understand the ligand specificity and receptor activation mechanism of the TLR4- MD-2-LPS complex we determined its crystal structure
- LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4- MD-2-LPS complex arranged symmetrically
- LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer
- Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2 , forming a hydrophobic interaction with the conserved phenylalanines of TLR4
- The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4
- Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approximately 5 A towards the solvent area
- This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2
- The TLR4- MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family, which is essential for defence against diverse microbial infection