Similar structures but different roles-an updated perspective on TLR structures

Toll-like receptors (TLRs) are pattern recognition receptors that recognize conserved structures in pathogens, trigger innate immune responses, and prime antigen-specific adaptive immunity. Elucidation of crystal structures of TLRs interacting with their ligands such as TLR1-2 with triacylated lipopeptide, TLR2-6 with diacylated lipopeptide, TLR4-MD-2 with LPS, andTLR3 with double-stranded RNA (dsRNA) have enabled an understanding of the initiation ofTLR signaling. Agonistic ligands such as LPS, dsRNA, and lipopeptides induce " m" shaped TLR dimers in which C-termini converge at the center. Such central convergence is necessary to bring the two intracellular receptorTIR domains closer together and promote their dimerization, which serves as an essential step in downstream signaling. In this review, we summarize TLR ECD structures that have been reported to date with special emphasis on ligand recognition and activation mechanism.