Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2
Copyright policy )Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2
Lipopolysaccharide (LPS), also known as endotoxin, activates the innate immune response through toll-like receptor 4 (TLR4) and its coreceptor, MD-2. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. Tetraacylated lipid IVa, a synthetic lipid A precursor, acts as a weak agonist to mouse TLR4/MD-2, but as an antagonist to human TLR4/MD-2. However, it remains unclear as to how LPS and lipid IVa show agonistic or antagonistic activities in a species-specific manner. The present study reports the crystal structures of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa complexes at 2.5 and 2.7 Å resolutions, respectively. Mouse TLR4/MD-2/LPS exhibited an agonistic “m”-shaped 2:2:2 complex similar to the human TLR4/MD-2/LPS complex. Mouse TLR4/MD-2/lipid IVa complex also showed an agonistic structural feature, exhibiting architecture similar to the 2:2:2 complex. Remarkably, lipid IVa in the mouse TLR4/MD-2 complex occupied nearly the same space as LPS, although lipid IVa lacked the two acyl chains. Human MD-2 binds lipid IVa in an antagonistic manner completely differently from the way mouse MD-2 does. Together, the results provide structural evidence of the agonistic property of lipid IVa on mouse TLR4/MD-2 and deepen understanding of the ligand binding and dimerization mechanism by the structurally diverse LPS variants.
- Osaka University Japan
- University of Tokyo Japan
Lipopolysaccharides, Binding Sites, Static Electricity, Lymphocyte Antigen 96, Crystallography, X-Ray, Protein Structure, Tertiary, Toll-Like Receptor 4, Mice, Lipid A, Species Specificity, X-Ray Diffraction, Scattering, Small Angle, Animals, Humans, Glycolipids, Protein Multimerization, Protein Structure, Quaternary, Hydrophobic and Hydrophilic Interactions, Protein Binding
Lipopolysaccharides, Binding Sites, Static Electricity, Lymphocyte Antigen 96, Crystallography, X-Ray, Protein Structure, Tertiary, Toll-Like Receptor 4, Mice, Lipid A, Species Specificity, X-Ray Diffraction, Scattering, Small Angle, Animals, Humans, Glycolipids, Protein Multimerization, Protein Structure, Quaternary, Hydrophobic and Hydrophilic Interactions, Protein Binding
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