Physical contact between lipopolysaccharide and toll-like receptor 4 revealed by genetic complementation.
Some mammalian species show an ability to discriminate between different lipopolysaccharide (LPS) partial structures (for example, lipid A and its congener LA-14-PP, which lacks secondary acyl chains), whereas others do not. Using a novel genetic complementation system involving the transduction of immortalized macrophages from genetically unresponsive C3H/HeJ mice, we now have shown that the species-dependent discrimination between intact LPS and tetra-acyl LPS partial structures is fully attributable to the species origin of Toll-like receptor 4 (Tlr4), an essential membrane-spanning component of the mammalian LPS sensor. Because Tlr4 interprets the chemical structure of an LPS molecule, we conclude that LPS must achieve close physical proximity with Tlr4 in the course of signal transduction.
Poltorak
A
A
The Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9050, USA.
Ricciardi-Castagnoli
P
P
Citterio
S
S
Beutler
B
B
D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D029721:Drosophila Proteins; D005816:Genetic Complementation Test; D006801:Humans; D008050:Lipid A / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D015415:Biomarkers; D029721:Drosophila Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors