Scientists at The Scripps Research Institute have solved the structure of a crucial human immune system molecule called TLR3, an acronym for Toll-like receptor three. In an upcoming issue of the journal Science, the protein is described as a large horseshoe-shaped coil composed of 23 leucine-rich repeats (LRRs).
The structure reveals details of TLR3 that have never been seen before, an essential step toward fully understanding the critical role this protein--and other TLRs--play in the human innate immune system to rapidly detect invading pathogens.
"We don't know functionally how TLR proteins work," says Professor Ian Wilson, D.Phil., who is a professor in the Department of Molecular Biology at The Scripps Research Institute and a member of the The Skaggs Institute for Chemical Biology. "but But the structure has given us great insights into experiments we can design to explore their function. In advance, we wouldn't have known where to look."
In addition to helping scientists better understand how TLRs work, the structure may also help scientists take steps toward improving human health, since TLRs are implicated in a number of diseases and, hence, constitute potential therapeutic targets.
Humans, like all other organisms, are constantly challenged in a world filled with microbial pathogens. We are bathed in bacteria, confronted with fungi, pilloried with parasites, and invaded by viruses. And yet, most of the time, we survive.
We survive because we possess an ancient and crucial defense mechanism known as innate immune system, which is active in eukaryotic organisms as diverse as humans and fruit flies. Broadly speaking, the innate immune system works something like this. Certain cells have the ability to recognize foreign molecules such as components of membrane like LPS or other protein molecules unique to microorganisms . The presence of these pathogen-specific molecules activates the immune system, which responds with a multi-stage biochemical defense starting with the unleashing of an army of white blood cells, like macrophages, which engulf and destroy pathogens. The macrophages also fight the pathogens by producing large amounts of chemicals that induce inflammation and help the body clear the infection.
One of the components of the innate immune system that scientists have been studying for the last several years is a family of receptor proteins called the Toll-like receptors (TLR)--a name that comes from their resemblance to a fruit fly receptor called "Toll." In the fly, Toll is important for both embryonic development and for immune functions of the adult organism. In adult fruit flies, the protein is an essential receptor molecule that defends against fungal infections.
In humans, TLRs play a critical role in the immune system because they are the molecules responsible for detecting some of the antigens produced by pathogens. For this reason, Toll-like receptors have been called the eyes of the innate immune system. Normally, when human or mouse cells encounter bacteria or viruses, they recognize proteins, lipids, or other molecular components of these foreign invaders through a family of TLR proteins, and then trigger the immune system's multi-stage biochemical attack on the pathogens.
Humans have at least 10 different TLRs, each of which recognizes a specific subset of antigens. For instance, TLR4 recognizes lipopolysaccharide, a chemical component of the cell walls of certain bacteria like Neisseria meningitides--one of the leading causes of bacterial meningitis. TLR9 recognizes bacterial DNA that contains distinguishing CpG dinucleotides motifs .