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Study helps explain why botulinum toxin is so deadly

grips the cell immediately before entering it.

UW-Madison has long been a center of botulism research. In 2003, Min Dong, a post-doctoral fellow in Chapman's lab, showed that a known protein receptor for one botulinum toxin was a key point of entry into the nerve cell. Dong shares first authorship on the current study along with Qing Chai and Joseph Arndt of Scripps.

The Nature paper is an elaboration on that 2003 discovery, which was published in The Journal of Cell Biology. Stevens's lab bombarded a crystal of the toxin bound to a small sub-region of the primary receptor with X-rays, then measured the reflections to portray the toxin and the receptor bound in deadly embrace.

The research could have several practical applications. Botulinum toxin is a potential biological weapon, so the U.S. military is interested in finding anti-toxins to protect soldiers -- molecules that attach to the binding site on the toxin or on the cell. The search for such a blocking molecule becomes easier now that the exact structure of the link between the toxin and the nerve cell are known.

Better knowledge of botulinum toxin's structure could also enhance the growing number of treatments that use the toxin to block nerve signals. The medical treatments "are not just for wrinkles," Chapman says. "People with paralysis get spasms in the muscles that are shut off, and this could solve that. In a wide variety of dystonias, where spasms can cause really severe pain, this can relax the muscles."

A third potential benefit is further down the line. After the researchers found the binding site on the protein receptor, they varied it until the toxin could no longer bind to it. If a mutated toxin was made to attach to the mutated receptor, the combination might target botulinum toxin against over-active cells in the body, Chapman suggests.

Using genetic engineering, "you might be able to sensitize whatever cell you want to the toxin," he says. Theoretically,
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Contact: Edwin Chapman
chapman@physiology.wisc.edu
608-263-1762
University of Wisconsin-Madison
13-Dec-2006


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