Toll-like receptor 3 (TLR3) extracellular domain (ECD)
Homo sapiens (human)
There are two types of immune systems, innate immunity and adaptive immunity, which defend the human body from pathogens. The latter immunity is a novel strategy which can be used only by vertebrates. At the first infection it memorizes the features of pathogen, and it attack faster at the next infection. While the adaptive immune system requires more than one week for its adaptation, propagation of pathogens takes only a few hours after infection. The innate immunity acts in such an early stage of infection.
The plants also have the innate immunity which is primitive and has been conserved for billions of years. It recognizes the rough feature of pathogen with pattern recognition receptor protein, and start the pathogen degrading system and gene expression program of this immunity. There are two types of pattern recognition proteins. The one is the Toll-like receptor which exists at the surface of a host cell, the other is dissolved in blood.
In human, about ten TLRs are known which bind different ligands such as lipopolysaccharide, peptide glycan, bacterial flagella, or viral DNA/RNA. It has been experimentally known that TLR3s recognize invading viral dsRNA, and start innate immunity. However, the binding site of dsRNA was not clear at the molecular scale.
The structure shown here is the extracellular domain (ECD) of human TLR3 which is one of the TLRs and works to sense foreign bodies. This X-ray crystallographic analysis of TLR3 revealed the horseshoe-shaped solenoid structure whose arc spans 270 degree, including 23 leucine-rich-repeats (LRRs). LRR is often observed in the TLR family, but TLR3 has the longest LRR among LRR-containing proteins with known structures. The concave (inner) surface is formed from 25 parallel beta strands, 23 from LRRs and one each from the N- and C-terminal cap regions, that assemble into a highly curved, continuous beta sheet. The glycosylation sites were also revealed, and it was found that one of two lateral face is not glycosilated, and two sugers are arranged to plug the hole. The inner surface is negatively charged, and the one sector of glycosylation-free face and outer surface close to the N terminus are positively charged.
It had been hypothesized that the dsRNA binded the inner side of TLR3. Thishypothesisis now denied because of steric hindrance and electrostatic repulsion. On the contrary, the authors suggest that the positively charged lateral face would be the binding site of dsRNA, and two TLR3 monomers could potentially sandwich dsRNA in a ternary complex of two TLR3s and one dsRNA.
Protein Data Bank (PDB)
author: Sachiyo Nomura , translated by Takahiro Kudou