RNA takes a toll

Toll-like receptors ( TLRs) recognize and bind pathogen-associated molecules to initiate innate and adaptive immune responses. They can be found on the surface of cells and subcellular compartments and have a ligand-binding extracellular domain, or ectodomain ( ECD), comprised of leucine-rich repeats ( LRRs) and an intracellular domain that recruits downstream signaling partners. Human TLR3 can be activated by dsRNA associated with viral infection. Wilson and colleagues have determined the structure of human TLR3 ECD. It has 23 LRRs that form a horseshoe-shaped, right-handed solenoid. Although the ECD has 15 potential glycosylation sites, electron density is observed for only 1 or 2 sugar moieties at 8 of the sites. When oligomannans are modeled into all 15 sites, this reveals that most of the ECD surface, with the exception of one major face, iscovered with carbohydrates. Surprisingly, the inner concave surface is glycosylated and has many negatively charged residues, making it an unlikely site for RNA binding. The authors suggest instead that RNA binding occurs at a dense basic patch on the unglycosylated face. The authors propose that dsRNA binds to one face of a TLR3 ECD to form a ternary complex with two TLR3s. Crystal packing interactions indicate that a portion of the glycosylation-free surface may be part of a dimer interface, as it contains a cluster of conserved residues. Similar to growth factor and cytokine receptors, RNA binding may promote signal transduction either by causing a conformational change to a pre-existing receptor dimer or by inducing receptor dimerization.