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Botulism Toxin Ensnares Its Target
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 search for the location of the
exosites, Breidenbach created crystals of a particular botulinum neurotoxin bound to its target SNARE. The researchers
determined the structure of the bound proteins using x-ray diffraction, a widely used analytical technique whereby beams of
x-rays are directed through crystallized proteins. The resulting pattern of diffraction is analyzed to deduce the protein's
atomic structure.
Their structural analysis revealed that the neurotoxin wraps itself in a segment of the SNARE protein by attaching at
numerous exosites. This interaction enables the toxin to recognize the SNARE protein with high specificity, said Brunger.
"Our structure has shown for the first time that it's a very extensive interaction on the protein surface, far from the
active site, that actually determines specificity," said Brunger. "This extensive interaction is very unusual for a protease.
Up to this point, it's the largest known interface area for such a complex, with numerous points of contact."
Another notable finding, said Brunger, was that binding of the toxin to its target causes significant conformational change
of the enzyme, which quite likely activates its ability to cleave the protein.
When the researchers compared the amino acid sequences of the type of botulinum toxin they studied with other known toxin
sequences, they found that the region they had found to contact the SNARE was variable. They theorize that such differences
among toxins give them their specificity for their target SNAREs; among toxins that recognize the same SNARE, amino acid
variations in the contact region might allow each to cleave its target at different sites.
According to Brunger, the discovery of the mechanism by which the toxins recognize their target proteins could provide new
information that will aid in developing drugs that can block the toxins more quickly. "Finding these remote exosites suggests
the possibility of developing drugs that could compete with the toxin for an exosite and disrupt the protease's ability to
attack its target," he said. "Such a drug would act instantaneously once it crossed into the cell. And it would not interfere
with other essential similar proteases in the cell, because it wouldn't be attacking the active site of the enzyme itself."
While this kind of drug could prove useful in treating late-stage botulism or tetanus, noted Brunger, effective antibiotics
and vaccines already exist to treat the diseases in most cases, if they are caught early.
In further studies, the researchers will extend their analysis to tetanus toxins, and to the other types of botulinum toxins.
Such studies, he said, could reveal differences in how the toxins recognize their targets.
"These bacteria have developed very clever enzymatic machines for recognizing proteins, and it may be possible, given our
structural knowledge, to modify these proteases for clinical use," Brunger said. "An intriguing possibility would be to use
their specificity as the basis for enzymes engineered to attack proteins involved in disease".
Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
Botulismul toxice Ensnares þintã - Botulism Toxin Ensnares Its Target - articole medicale engleza - startsanatate