By Karla Gale

WESTPORT, CT (Reuters Health) – Researchers have identified a membrane protein that binds to a component of the toxin secreted by Bacillus anthracis. As reported in a paper to be published in the November 8th issue of Nature, a soluble version of this protein protects cells from the toxin in vitro.

In the same issue of Nature, another research team reports the structure of a different component of the toxin that inhibits signaling pathways in human cells.

In the first report, Dr. John A. T. Young, of the University of Wisconsin in Madison, and associates note that anthrax toxin is made up of edema factor and lethal factor, delivery of which is mediated by a third component, protective antigen. They were able to isolate the cDNA clone of the putative receptor, which they termed anthrax toxin receptor (ATR), that the protective antigen binds to.

"The most notable feature of ATR is the presence of an extracellular von Willebrand factor type A domain," which binds directly to the anthrax protective antigen, the investigators write.

Co-author Kenneth A. Bradley told Reuters Health, "von Willebrand factor A is a structural domain that is a clotting factor in blood. Since its discovery, it has been found in many proteins, including integrins, and has been identified as important for protein-to-protein interactions."

"While we don't know the natural function of this domain in anthrax toxin receptor, we do know it is the important binding component or target to which anthrax toxin binds," Bradley added.

The research team found that a soluble version of the von Willebrand factor A domain blocks the binding of anthrax toxin to cells. They foresee the identification of similar small proteins that will be of therapeutic use in the treatment of anthrax infection.

Bradley said that he and his associates have been working to identify the anthrax toxin receptor for over 2 years. "We're hoping that a pharmaceutical company can develop a high-throughput assay for finding small-molecule inhibitors that would block the interaction between the toxin and the receptor," Bradley added.

In the second report, Dr. Robert C. Liddington of the Burnham Institute in La Jolla, California and colleagues note that the lethal factor component of anthrax toxin "is a potential target for therapeutic agents that would inhibit its catalytic activity or block its association with protective antigen." Its only cellular substrate is the mitogen-activated protein kinase kinase (MAPKK) family.

Dr. Liddington's group solved the crystal structure of lethal factor, which has four domains. Domain I binds protective antigen and is linked to domain II. "Domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK-2 before cleavage" with "high and unusual specificity."

nature.com