Recognition of lipopolysaccharide pattern by TLR4 complexes

Abstract

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. Minute amounts of LPS released from infecting pathogens can initiate potent innate immune responses that prime the immune system against further infection. However, when the LPS response is not properly controlled it can lead to fatal septic shock syndrome. The common structural pattern of LPS in diverse bacterial species is recognized by a cascade of LPS receptors and accessory proteins, LPS binding protein (LBP), CD14 and the Toll-like receptor4 (TLR4)–MD-2 complex. The structures of these proteins account for how our immune system differentiates LPS molecules from structurally similar host molecules. They also provide insights useful for discovery of anti-sepsis drugs. In this review, we summarize these structures and describe the structural basis of LPS recognition by LPS receptors and accessory proteins.

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

“…CD14 first binds LPS and transfers LPS to MD-2, which lacks a transmembrane domain and does not transduce a signal itself, but is responsible for dimerization of TLR4 molecules once bound with LPS (31,38). The crystal structure of the TLR4/MD-2/LPS complex reveals that LPS binds to a hydrophobic pocket within MD-2 and alters the heterodimerized TLR4 complex (31,35,36). Ligand-induced dimerization results in the recruitment of MyD88 and autophosphorylation of members of the IL-1R-associated kinase (IRAK) family (IRAK-1 and IRAK-4), which trigger NF-kB activation via TRAF6 (39)(40)(41).…”

“…The major role for TLR4 is recognition of pathogenassociated molecular patterns, specifically LPS, from Gramnegative bacteria, which serves as a strong inducer of innate immunity (31)(32)(33)(34). LPS signaling through TLR4 requires the coreceptors CD14 and MD-2 because TLR4 does not bind LPS directly (35)(36)(37). CD14 first binds LPS and transfers LPS to MD-2, which lacks a transmembrane domain and does not transduce a signal itself, but is responsible for dimerization of TLR4 molecules once bound with LPS (31,38).…”

The role of protein–protein interactions in Toll-like receptor function

“…This is due to the nature of its main PAMP, lipopolysaccharide (LPS), a glycolipid from Gramnegative bacterial outer membranes [12,[47][48][49][50][51][52][53][54]. Only small amounts of LPS are required to stimulate the TLR4 pathway and hence alert the immune system to invading pathogens, and overstimulation of this pathway can lead to sepsis.…”

“…(LBP) and CD14, but the binding of agonistic LPS to MD-2 is the key factor in determining TLR4 signaling, since MD-2 binds to the amino-terminal region of TLR4 and mediates active complex formation [48][49][50][51][52][53][59][60][61].…”

“…LPS molecules can be sub-divided into an oligosaccharide core and variable O antigen region, plus a hydrophobic anchor containing multiple acyl tails and a phosphorylated glucosamine headgroup termed lipid A [55]. Lipid A is the main bioactive component of LPS [12,49], but subtle variations in its structure can have a major impact on stimulation of the TLR4 pathway. For example, hexa-acylated, bi-phosphorylated lipid A from E. coli is a potent agonist of TLR4 in all known species, whereas its biosynthetic intermediate, tetraacylated lipid IVa, is an antagonist in humans (but an agonist in mice and horses) [56].…”