Transfer of LPS onto TLR4

Stable Identifier
R-HSA-166041
Type
Reaction [binding]
Species
Homo sapiens
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The Toll-like receptor 4 (TLR4) is a membrane-spanning protein distantly related to the IL1 receptor. Both CD14 and members of the Toll family contain multiple leucine-rich repeats. In addition, the latter possess a Toll-homology domain in the cytoplasmic tail, which is important in the generation of a transmembrane signal linked to LPS-induced cell activation. Of all Toll family members, TLR4 is probably the exclusive receptor for LPS from most Gram negative organisms.

Toll-like receptor 4 and lymphocyte antigen 96 (LY96, also known as myeloid differentiation factor 2 (MD2)) form a heterodimer that specifically recognizes structurally diverse LPS molecules. A structural study of TLR4:LY96 complex revealed that LY96 (MD2) interaction with TLR4 relies on hydrogen and electrostatic bonds (Kim HM et al, 2007). LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. Both hydrophobic and hydrophilic interactions contribute to the main dimerization interaction between LY96, LPS and TLR4 multimer components. The phosphate groups of LPS also contribute to the receptor multimerization by forming ionic interactions with positively charged residues of TLR4 and LY96. (Park BS et al, 2009).

The activated TLR4 receptor is composed of two copies of the TLR4:LY96:LPS complex and initiates signal transduction by recruiting intracellular adaptor molecules.

Literature References
PubMed ID Title Journal Year
11274165 Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2

da Silva Correia, J, Soldau, K, Christen, U, Tobias, PS, Ulevitch, RJ

J. Biol. Chem. 2001
16303959 TLR4 mediates human retinal pigment epithelial endotoxin binding and cytokine expression

Elner, SG, Petty, HR, Elner, VM, Yoshida, A, Bian, ZM, Yang, D, Kindzelskii, AL

Invest. Ophthalmol. Vis. Sci. 2005
9665271 LPS-binding proteins and receptors

Fenton, MJ, Golenbock, DT

J Leukoc Biol 1998
15276183 MD-2: the Toll 'gatekeeper' in endotoxin signalling

Gangloff, M, Gay, NJ

Trends Biochem Sci 2004
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