The first detailed structure of a botulism toxin attached to its target protein reveals that the toxin snakes the protein around itself -- a sort of "reverse anaconda" -- to recognize the receptor. The new studies show how the toxins that cause botulism and tetanus can recognize and attack particular nerve cell proteins at the neuromuscular junction, which leads to paralysis. The researchers said their findings could lead to new knowledge that could speed the development of drugs to block botulism or tetanus toxins more rapidly in cases that have progressed beyond the stage at which antibiotics are effective. Howard Hughes Medical Institute investigator Axel T. Brunger and graduate student Mark Breidenbach at Stanford University reported their findings December 12, 2004, in an advance online publication in the journal Nature.

The neurotoxins from bacteria that cause the paralysis associated with both botulism and tetanus contain enzymes called proteases that cleave specific nerve cell proteins. The nerve cell proteins are called SNAREs, which are key components of the machinery that nerve cells use to fire bursts of neurotransmitter chemicals to trigger neighboring nerves or activate muscle cells. Without SNAREs, nerve function is blocked.

Neurotoxin proteases that act by cleaving SNARE proteins are highly specific for their targets meaning that each toxin specifically recognizes and attacks one of three different neuronal SNARE proteins. Since most of these toxin proteases have virtually the same structures at the regions that perform the cleavage, or active sites, a key question has been how they recognize their particular targets, Brunger said. What was known previously is that other regions of the neurotoxin protein, which they called "exosites," might be involved in target recognition. However, the location and shape of these exosites were unknown. To sear
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
12-Dec-2004

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