TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, but on one face that includes the interface between these two horseshoes, there is a large surface that is sugar-free, suggesting that this is where the TLR3 might bind to its target molecule. This surface also contains two distinct patches that are rich in positively-charged residues, suggesting it as a possible binding site for negatively-charged double-stranded RNA.
"It's a sensational piece of work," says Scripps Research Professor Bruce Beutler, M.D., who studies TLR signaling together with his group in the TSRI Department of Immunology. "All of us in the TLR field have been dying to see the structure of a TLR ectodomain since the innate immune function of TLRs was discovered seven years ago. This will open the way to a great many other studies that will allow us to understand exactly how signaling occurs."
Significantly, says Wilson, the structure is also another milestone of sorts. These membrane-spanning proteins are rich in repeats that contain a high percentage of the amino acid leucine. This fact was important to Wilson and his colleagues because the leucine-rich proteins are often decorated with sugars (glycans), and fall into the class of biological molecules known as "glycoproteins."
"Amazingly there is still this prevalent idea [many scientists have] that glycoproteins don't crystallize," says Wilson. Crystallization of a protein is a crucial initial step in solving its structure via x-ray crystallography, the technique that Wilson and his colleagues employ. Because glycoproteins are covered with sugars, they are heterogenous due to the multiple gly
Source:Scripps Research Institute