What's the beef? Bovine antibodies X-rayed

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  • Published: Jun 15, 2013
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: What's the beef? Bovine antibodies X-rayed

Complementary cattle

Reshaping Antibody Diversity Bullock in a field by David Bradley

US researchers have used X-ray diffraction to study several novel bovine antibodies that might one day lead to new types of agent against infectious pathogens.

Cattle have been with us for millennia providing us with nutrition, clothing, shoes and most recently a new clue to creating novel therapeutic agents that harness the cud chewers' unique immune system. Vaughn Smider of The Scripps Research Institute and colleagues have focused on the puzzling mechanism by which the immune system of cattle can adapt to create the necessary diversity to fight infection.

Antibodies are large proteins present in the mammalian immune system, they have a Y shape, in which the "arms" are tuned to identify and bind to antigens present on alien particles that enter the body, including viruses and the like. Antigen binding essentially flags the particle to which the antigen is attached as alien and white blood cells then engulf and digest it. At the active end of each antibody arm is a small set of protein loops called complementarity-determining regions, or CDRs, which are the sites through which antigen binding occurs. Rearrangements and mutations allow our immune systems to generate a diverse population of antibodies at least one of which can then bind to almost any antigen presented to it. In the wake of an infection, the successful arrangements are duplicated to fight the pathogen.

Antibodies, with knobs on

The largest CDR, H3, governs this behaviour in humans and many other mammals, most of an antibody’s specificity for a target is governed by the largest CDR region. It seems that an unusually long CDR H3 bodes well for an individual being able to fight particularly lethal infections, such as HIV and influenza. These antibodies have CDR H3 regions twice the normal length. The longer a CDR, the deeper it can probe the crevices of a pathogenic particle and thus latch on to otherwise out of reach antigens and so flag the particle for attack by white blood cells responding to the molecular call to arms. Long CDRs are rare in humans, but cattle often have antibodies of this type; indeed, about 10% of the animal's antibodies are of this long type containing up to just over 60 amino acids.

Smider and his colleagues' work focuses on generating therapeutic antibodies and the recent discoveries concerning long CDRs set them thinking about how they might learn from cattle with their rather long CDR antibodies. Smider and colleagues in the groups of Ian Wilson and Peter Schultz therefore performed a detailed X-ray crystallographic structural and gene sequence analysis of two of the unusually long CDR H3 cow antibodies to find out how they are produced naturally with a view to finding a way to engineer such entities in the laboratory.

Although structures of the long CDR H3 protein in human anti-HIV and anti-influenza antibodies had seemed unusual, the corresponding structure in the cow antibodies is unique in the known world of animal antibodies. The long "stalk" element has an antigen-binding "knob," the team says. Sequencing revealed this to contain an abundance of the sulfur-containing amino acid cysteine, which is wont to form bonds with neighbouring cysteines on the same protein chain forming loops. Moreover, DNA analysis showed that in cows, its antibody-making B-cells are susceptible to regular point mutations that change the number of cysteines present in the antibody knob; this has the effect of changing the overall weave of the antigen-grabbing loops in the knob. This represents, therefore, a very intriguing way to create new protein folds and is apparently the principal means by which the cow immune system generates the necessary diversity in its long CDR H3 antibodies for fighting infection; the different antibody knobs being able to bind antigens on a range of viruses, for instance.

Cashing in on cattle CDRs

The researchers suggest that this unique antibody system in cattle evolved as a way to cope with the animal's unique grass-fermenting digestive system, allowing it to protect itself from microorganisms that escape from the stomachs into the bloodstream or other tissues. The "stalk-and-knob" structure also resembles insect poisons and other proteins that target ion channels and pores in the walls of cells. The researchers are investigating whether these long CDR antibodies might target human pathogens with a view to generating novel therapeutic agents.

Smider's spin-out company Fabrus Inc is also hoping to generate extensive "libraries" of long CDR H3 antibodies in the laboratory and select for those antibodies that have a desired effect. "These antibodies’ structure and their mechanism for creating diversity haven’t been seen before in other animals’ antibodies," Smider says. "It's somewhat rare in science that you find something so unexpected and then have the opportunity to study it in depth - and then get to develop real biomedical applications from it," he adds.

Related Links

Cell 2013, 153, 1379-1393: "Reshaping Antibody Diversity"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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