Structures of the Toll-like Receptor Family and Its Ligand Complexes

Abstract

Toll-like receptors (TLRs) play central roles in the innate immune response by recognizing conserved structural patterns in diverse microbial molecules. Here, we discuss ligand binding and activation mechanisms of the TLR family. Hydrophobic ligands of TLR1, TLR2, and TLR4 interact with internal protein pockets. In contrast, dsRNA, a hydrophilic ligand, interacts with the solvent-exposed surface of TLR3. Binding of agonistic ligands, lipopeptides or dsRNA, induces dimerization of the ectodomains of the various TLRs, forming dimers that are strikingly similar in shape. In these "m"-shaped complexes, the C termini of the extracellular domains of the TLRs converge in the middle. This observation suggests the hypothesis that dimerization of the extracellular domains forces the intracellular TIR domains to dimerize, and this initiates signaling by recruiting intracellular adaptor proteins.

NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses

“…Viral pathogen-associated molecular patterns interact with TLR2 and TLR4 on the plasma membrane (14). Pathogen-associated molecular pattern binding induces TLR2 and TLR4 homo-or heterodimerization (15), followed by recruitment of Toll/IL-1 receptor (TIR) domain-containing adaptor proteins such as myeloid differentiation factor 88 (MyD88) and TIR domain-containing adapter protein (TIRAP)/MyD88 adaptor-like (MAL) or TIR domain-containing adapter-inducing IFNβ (TRIF) and TRIF-related adaptor molecule (TRAM) (14). In the MyD88-dependent and the TRIF-dependent pathways, activation of TNF receptor-associated factor 6 results in IκBα phosphorylation and degradation, allowing release of the NFκB complex, composed of p65/p50 or p65/p52 heterodimers, into the cell nucleus.…”

Cleavage and activation of a Toll-like receptor by microbial proteases

“…Numerous functional and crystallization studies have clarified the basic principles of TLR activation (5). Although structurally diverse, all TLR ligands appear to bridge two TLR ligand-sensing domains.…”

Structure and dynamic behavior of Toll‐like receptor 2 subfamily triggered by malarial glycosylphosphatidylinositols of Plasmodium falciparum

“…The selected docked complexes of Man 4 ‐GPI and sn‐2 lyso GPI also confirmed this unique characteristic of TLR2 (Figs 2A and 4A). Moreover, the convex region ligand‐binding pocket of TLR2 that heterodimerizes with TLR1 and TLR6 to recognize the lipopeptides is present at the edge of the central and C ‐terminal domains 16. The Man 4 ‐GPI and sn‐2 lyso GPI binding sites were the same as observed for Pam 3 CSK 4 and Pam 2 CSK 4 , respectively.…”

“…In addition, these reported structures indicate that TLRs 1, 2, 4 and 6 are members of the ‘atypical’ subfamily of the LRR superfamily, whereas TLR3 and 5 are ‘typical’ subfamily members of the LRR superfamily 16. Structural differences between these two subfamilies in their LRR domains arise from the irregular arrangements of β‐sheets; the ‘atypical’ LRR subfamily can be divided into N ‐terminal, central and C ‐terminal subdomains 16. The central domain is predicted to play a key role in ligand recognition 16.…”