The TLR4 signalling pathway.

(A) Overview of the TLR4 signalling pathway. Both the NF-κB and the interferon pathways are induced by stimulation with lipopolysaccharide. Adapted from [2], [3]. (B) Mechanism of signal transduction by TLR4. The curved ectodomains (ECD) are illustrated in light blue and the co-receptor protein MD-2 in grey. The TIR domains are shown in yellow and red respectively. M = membrane, L = LPS. (i) Prior to activation, receptor molecules are able to diffuse in the membrane and may form transient dimers. The ectodomains are rigidly connected to the cytoplasmic TIRs by the transmembrane helix. (ii) Receptor dimerization following activation by LPS binding to MD2. By analogy with Drosophila Toll (see [45]), which is activated by a dimeric protein ligand, the receptor complexes are likely to be symmetrical. Conformational rearrangements constrain the TIR domains to interact through equivalent surfaces forming a symmetrical dimer. (iii) The dimerized TIRs provide a new molecular surface that can bind to the ‘bridging adaptor’ molecules TRAM and Mal with high affinity. Interaction with the downstream adaptors TRIF and MyD88 leads to NFκB and IRF3 mediated signalling respectively.