The Structural Biology of Toll-like Receptors

The membrane-bound Toll-like receptors (TLRs) trigger innate immune responses after recognition of a wide variety of pathogen-derived compounds. Despite the wide range of ligands recognized by TLRs, the receptors share a common structural framework in their extracellular, ligand-binding domains. These domains all adopt horseshoe-shaped structures built from leucine-rich repeat motifs. Typically, on ligand binding, two extracellular domains form an “m”-shaped dimer sandwiching the ligand molecule bringing the transmembrane and cytoplasmic domains in close proximity and triggering a downstream signaling cascade. Although the ligand-induced dimerization of these receptors has many common features, the nature of the interactions of the TLR extracellular domains with their ligands varies markedly between TLR paralogs.

► TLRs recognize pathogen-derived ligands by their ectodomains ► TLR ECDs are horseshoe-shaped structures built from leucine-rich repeats ► TLR-ligands dimerize ectodomains via their lateral faces, forming “m”-shaped structures ► Dimerization leads to downstream signaling whose structural basis is still unknown