An extraordinary family of antibodies found in the humble cow may lead to new medicines to fight diseases in humans, scientists believe.
"These antibodies' structure and their mechanism for creating diversity haven't been seen before in other animals' antibodies," said Vaughn V Smider, assistant professor of cell and molecular biology at The Scripps Research Institute (TSRI) and principal investigator for the study.
Antibodies, part of our immune system, are large proteins that resemble lobsters - with a tail and two identical arms for grabbing specific targets (called antigens, often parts of bacteria or viruses).
At the business end of each arm is a small set of protein loops called complementarity-determining regions or CDRs, which actually do the grabbing.
By rearranging and mutating the genes that code for CDRs, an animal's immune system can generate a vast and diverse population of antibodies which collectively can bind to just about any of the body's foreign invaders.
In humans and in many other mammals, most of an antibody's specificity for a target is governed by the largest CDR region, CDR H3.
Researchers have been finding hints that an unusually long version of this domain can sometimes be the key to a successful defense against a dangerous infection.
For example, in a study reported in Nature last year, Ian A Wilson, who is Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI, and collaborators isolated an anti-HIV antibody with a long CDR H3 region which allows it to grab a crucial structure on the virus and thereby neutralise the infectivity of most HIV strains.
Scientists performed a detailed structural and sequence analysis of these unusually long CDR H3 cow antibodies, to gain insight into how they are made naturally and how such structures might be engineered in the laboratory.
Although the structure of the long CDR H3 protein in Wilson's human anti-HIV antibody had seemed unusual, the corresponding structure in the cow antibodies turned out to be unique in the known world of animal antibodies: a long 'stalk' element topped by an antigen-binding 'knob'.
Sequencing of the DNA that codes for the knob region revealed an unusual abundance of cysteine, a sulfur-containing amino acid that is apt to bond to a nearby cysteine on the same protein chain, thus forming a loop.
Smider has founded a company, Fabrus, which is constructing libraries of long CDR H3 antibodies in the laboratory, as a source of potential therapeutic candidates.
The study was published in the journal Cell.
