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Toll-like receptors (TLRs) play key roles in activating immune responses during infection. The human TLR3 ectodomain structure at 2.1 angstroms reveals a large horseshoe-shaped solenoid assembled from 23 leucine-rich repeats (LRRs). Asparagines conserved in the 24-residue LRR motif contribute extensive hydrogen-bonding networks for solenoid stabilization. TLR3 is largely masked by carbohydrate, but one face is glycosylation-free, which suggests its potential role in ligand binding and oligomerization. Highly conserved surface residues and a TLR3-specific LRR insertion form a homodimer interface in the crystal, whereas two patches of positively charged residues and a second insertion would provide an appropriate binding site for double-stranded RNA.
Innate immunity is based on an ancient and ubiquitous system of cells and molecules that defend the host against infection. This system can recognize virtually all microbes, using a limited repertoire of germ-line-encoded receptors that recognize broadly conserved components of bacterial and fungal cell walls or genetic material, such as double-stranded viral RNA (1, 2).
The Toll-like receptors (TLRs) are among the most important sensors of the innate immune system (3). The ten known human Toll-like receptors recognize pathogen-associated molecules, such as lipoteichoic acid (recognized by TLR2), lipopolysaccharide (TLR4), flagellin (TLR5), and unmethylated CpG DNA motifs (TLR9). Binding of these ligands to TLRs initiates a series of signaling processes that stimulate and orchestrate the innate and adaptive immune responses (4, 5). Human TLRs are implicated in a number of diseases and, hence, constitute potential therapeutic targets (6, 7).
TLRs are integral membrane proteins located either on the cell surface or in intracellular compartments. Their extracellular or ectodomains (ECDs) are responsible for ligand binding and contain 19 to 25 leucine-rich repeat (LRR) motifs that are also found in a number of other proteins with diverse cellular functions (8). The intracellular domain, known as the Toll/ interleukin-1 receptor homology (TIR) domain, recruits adaptor molecules, such as MyD88, TRIP, and TIRAP, to initiate the signaling process (4, 9).
Human TLR3 is activated by double-stranded RNA (dsRNA) associated with viral infection (10), endogeneous cellular mRNA (11), and sequence-independent small interfering RNAs (12). TLR3 is distinct from other TLRs in that it is not dependent on MyD88 but rather on TRJF for signaling (13). Other key features of TLR3 signaling include a requirement for phosphorylation of tyrosine...