MD-2: the Toll 'gatekeeper' in endotoxin signalling.
Lipopolysaccharide (LPS) from the outer cell wall of Gram-negative bacteria is a potent stimulator of the mammalian innate immune system. The Toll-like receptor 4 (TLR4) pathway triggers the inflammatory responses induced by LPS in a process that requires the interaction of LPS-bound myeloid differentiation-2 (MD-2) with TLR4. Here we propose two possible mechanisms for LPS recognition and signalling that take into account both the structural information available for TLR4 and MD-2, and the determinants of endotoxicity, namely, the acylation and phosphorylation patterns of LPS. In our first model, LPS induces the association of two TLR4-MD-2 heterodimers by binding to two different molecules of MD-2 through the acyl chains of lipid A. In our second model, the binding of LPS to a single TLR4-MD-2 complex facilitates the recruitment of a second TLR4-MD-2 heterodimer. These models contrast with the activation of Drosophila Toll, where the receptor is crosslinked by a dimeric protein ligand.
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. mg308@cam.ac.uk
Monique
M
Gangloff
Nicholas J
NJ
Gay
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D002240:Carbohydrate Sequence; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000954:Antigens, Surface; D029721:Drosophila Proteins; D004731:Endotoxins; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors