title: The molecular mechanism of species-specific recognition of lipopolysaccharides by the MD-2/TLR4 receptor complex.
abstract: Lipid A, a component of bacterial lipopolysaccharide, is a conserved microbe-associated molecular pattern that activates the MD-2/TLR4 receptor complex. Nevertheless, bacteria produce lipid A molecules of considerable structural diversity. The human MD-2/TLR4 receptor most efficiently recognizes hexaacylated bisphosphorylated lipid A produced by enterobacteria, but in some animal species the immune response can be elicited also by alternative lipid A varieties, such as tetraacylated lipid IVa or pentaacylated lipid A of Rhodobacter spheroides. Several crystal structures revealed that hexaacylated lipid A and tetraacylated lipid IVa activate the murine MD-2/TLR4 in a similar manner, but failed to explain the antagonistic vs. agonistic activity of lipid IVa in the human vs. equine receptor, respectively. Targeted mutagenesis studies of the receptor complex revealed intricate combination of electrostatic and hydrophobic interactions primarily within the MD-2 co-receptor, but with a contribution of TLR4 as well, that contribute to species-specific recognition of lipid A. We will review current knowledge regarding lipid A diversity and species-specific activation of the MD-2/TLR4 receptor complex in different species (e.g. human, mouse or equine) by lipid A varieties.
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Alja
authors.initials: A
authors.lastname: Oblak
authors.affiliation: Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; Centre of Excellence EN-FIST, Dunajska 156, SI-1000 Ljubljana, Slovenia. Electronic address: roman.jerala@ki.si.
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000276:immunology*; D013045:Species Specificity; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4
keywords: Innate immunity; Lipid A; Lipopolysaccharide; MD-2; Selectivity; TLR4