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Toward a Kinder, Gentler Toxin
by Tracie Thompson
The poison produced by Clostridium botulinum has undergone a reputation makeover—from feared to favored. In the 1950s, food-borne botulism killed one in four of its victims; half a century later, more than 3 million Americans paid for commercial Botox injections to smooth their wrinkles and frown lines.
Botulinum could have far greater impacts at both ends of this spectrum. Its potential as a vehicle for innovative medical therapies, or as a devastating weapon of mass destruction, imparts a special urgency to the work of two HHMI scientists.
HHMI investigator Edwin R. Chapman, a physiology professor at the University of Wisconsin-Madison, and biophysicist Axel T. Brunger, an HHMI investigator at Stanford University, are broadly interested in neurotransmission—the passage of signals from one nerve cell to another. Both have been looking specifically at how botulinum neurotoxins (BoNTs) impair the release of chemical neurotransmitters at junctions between nerves and muscles, resulting in paralysis that ranges from therapeutic to lethal.
"These are among the most potent toxins on earth," says Chapman. "Once we've figured out how they do what they have evolved to do, we can begin working on getting them to do what we want them to do." Applications might include antitoxins that combat botulism poisoning, vaccines that prevent it, and a range of disease therapies derived from a better understanding of botulinum's efficiency in targeting and shutting down neurons.
The latest findings by Chapman and Brunger build on earlier research indicating that BoNTs attach to their target neurons in a high-affinity bind involving proteins and gangliosides (sugar-containing lipids). In 2003, Chapman's group singled out a protein called synaptotagmin II as a cell entry mediator for BoNT/B, one of the seven types of BoNT. Brunger, in 2004, showed how BoNT/A recognizes and ensnares its target protein on the nerve cell; in 2006, Chapman's group published its discovery of the protein receptor for BoNT/A.
This past December, Brunger and Chapman both presented crystal structures of BoNT/B binding in papers published simultaneously in Nature. The groups used different approaches to crystallize the complex between BoNT/B and synaptotagmin II. Brunger's group collaborated with researchers from Germany's Medizinische Hochschule, Hannover (Hannover Medical School); Chapman worked with Ray Stevens of The Scripps Research Institute.
With resulting crystal structures that were very similar, both teams found that synaptotagmin II forms a short helix that binds to a water-repellent groove within BoNT/B. And both found that just a slight change, or mutation, of the synaptotagmin receptor disrupts the binding.
Illustration: Julia Breckenreid