Sensing of microbial molecular patterns by Toll-like receptors.

Toll-like receptors (TLRs) sense structural patterns in microbial molecules and initiate immune defense mechanisms. The structures of many extracellular and intracellular domains of TLRs have been studied in the last 10 years. These structures reveal the extraordinary diversity of TLR-ligand interactions. Some TLRs use internal hydrophobic pockets to bind bacterial ligands and others use solvent-exposed surfaces to bind hydrophilic ligands. The structures suggest a common activation mechanism for TLRs: ligand binding to extracellular domains induces dimerization of the intracellular domains and so activates intracellular signaling pathways. Recently, the structure of the death domain complex of one of the signaling adapters, myeloid differentiation factor 88 (MyD88), has been determined. This structure shows how aggregation of signaling adapters recruits downstream kinases. However, we are still far from a complete understanding of TLR activation. We need to study the structures of TLR7-10 in complex with their ligands. We also need to determine the structures of TLR-adapter aggregates to understand activation mechanisms and the specificity of the signaling pathways. Ultimately, we will have to study the structures of the complete TLR signaling complexes containing full-length receptors, ligands, signaling, and bridging adapters, and some of the downstream kinases to understand how TLRs sense microbial infections and activate immune responses against them.