Scientists reveal structure of new botulism nerve toxin subtype
December 22, 2008
Computer-generated “ribbon” representations of the molecular structure of botulinum neruotoxin subtypes E (left) and B (right). The accompanying schematics show that in subtype E, both the binding domain (yellow) and the catalytic domain (red — which cleaves cellular proteins to block the release of neurotransmitters) lie on one side of the translocation domain (green). On subtype B, the binding and catalytic domains flank the central translocation domain. This structural difference may explain why subtype E is a faster-acting toxin. Image: BNL
(PhysOrg.com) -- Scientists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory have determined the atomic-level structure of a third subtype of botulinum neurotoxin — a deadly toxin produced by certain bacteria that causes the disease botulism, and is also used in cosmetic and therapeutic applications such as reducing wrinkles and calming a hyperactive bladder. The detailed structure, published online December 22, 2008, by the Journal of Molecular Biology, reveals a unique arrangement of the active components that may help explain why botulinum neruotoxin subtype E (one of seven distinct subtypes) is faster-acting than other subtypes previously studied at Brookhaven Lab — and may have implications for improving vaccines and/or therapeutic agents.
"Understanding the differences among the seven botulinum neurotoxin subtypes is particularly imperative at a time of heightened concern about the potential use of these toxins as bioterror weapons," said Brookhaven biologist and lead author Subramanyam Swaminathan, who has conducted extensive research on botulinum neurotoxins supported by DOE, the U.S. Army, and the National Institutes of Health. Although experimental vaccines administered prior to exposure can inhibit the neurotoxin's destructive action, no effective pharmacological treatment exists.
All seven neurotoxin subtypes cause their deadly effects using a common mechanism, with each step being activated by a different portion, or domain, of the toxin protein. First the neurotoxin binds to a nerve cell; then it moves into the cell; and then it cleaves specific proteins that block the release of neurotransmitters, the chemicals nerve cells use to communicate with one another and with muscles. Without that communication, muscles, including those used to breathe, become paralyzed.
"Blocking any of these steps could thwart the toxins' deadly action," Swaminathan said. "But to do that, we need to understand the details of the proteins' structures."
Swaminathan and his team had previously analyzed the molecular-level structures of various fragments of botulinum neurotoxin subtypes A to F, and that of the whole neurotoxin B, using x-ray crystallography at the National Synchrotron Light Source (NSLS) at Brookhaven Lab. In this technique, scientists beam high-intensity x-rays at a crystalline sample of the protein and measure how the x-rays scatter off the sample to locate the positions of individual atoms.
These studies revealed that in subtypes A and B, the three domains were arranged in the same way: with the binding and protein-cleaving domains "flanking" a longer central region known as the translocation domain, essential for moving the toxin into the cell.
"Because the genes that code for these proteins have a large degree of similarity and all the subtypes incapacitate nerve cells in a very similar way, many biologists had assumed that all seven botulinum neurotoxins would have a similar structural arrangement," Swaminathan said.
The current study of botulinum subtype E, also conducted at the NSLS, disproved that assumption, taking the scientists by surprise. Instead of the flanking arrangement, the binding and protein-cleaving domains of subtype E are both on the same side of the translocation domain. In addition, while all other subtypes are made of two protein chains, subtype E is a single-chain molecule.
"This arrangement may have an effect on translocation, with the molecule strategically positioned for quick entry into the cell," Swaminathan said. Though he emphasizes that further confirming research is essential, this could be a plausible explanation for why botulism caused by subtype E sets in faster than that caused by other subtypes.
This finding may help scientists develop faster-acting vaccines and therapeutic agents.
For example, in the treatment of hyperactive bladder disorders, botulinum neurotoxin subtype A is currently used to inhibit neurotransmitter release and control bladder muscles. But it can take days or a week for the drug to be effective. A faster-acting neurotoxin might improve the response.
Additionally, patients sometimes develop resistance to botulinum treatments, developing antibodies that break down the toxin. So having an additional subtype for therapeutic use could be of benefit in situations where treatments must be repeated.
Finally, considering the threat of botulinum neurotoxin being used as a bioterror weapon, Swaminathan said, "The finding of a significant variation in the structural arrangement of subtype E also makes it clear that we must study the structures of the four remaining subtypes to gain a better understanding of their individual characteristics so that appropriate countermeasures can be developed for all seven forms."
Provided by Brookhaven National Laboratory
-
Neurons from stem cells could replace mice in botulinum test
Feb 06, 2012 |
5 / 5 (2) |
0
-
UCSF botulism research translates into bioterrorism treatment
May 06, 2011 |
not rated yet |
0
-
Understanding methods of assessing botulinum neurotoxin exposure
Apr 05, 2011 |
not rated yet |
0
-
Genome sequencing used to assess a novel form of Clostridium botulinum
Mar 07, 2011 |
not rated yet |
0
-
Study questions botox use for migraines
Feb 08, 2011 |
5 / 5 (1) |
0
-
Engineers build first sub-10-nm carbon nanotube transistor
Feb 01, 2012 |
4.9 / 5 (31) |
30
-
Something old, something new: Evolution and the structural divergence of duplicate genes
Jan 31, 2012 |
4.6 / 5 (7) |
1
-
The hidden nanoworld of ice crystals: Revealing the dynamic behavior of quasi-liquid layers
Jan 30, 2012 |
5 / 5 (3) |
1
-
Stock market network reveals investor clustering
Jan 27, 2012 |
3.9 / 5 (23) |
8
-
Of microchemistry and molecules: Electronic microfluidic device synthesizes biocompatible probes
Jan 26, 2012 |
5 / 5 (1) |
0
More news stories
The power of estrogen -- male snakes attract other males
A new study has shown that boosting the estrogen levels of male garter snakes causes them to secrete the same pheromones that females use to attract suitors, and turned the males into just about the sexiest ...
10 hours ago |
4.8 / 5 (5) |
0
|
Grass to gas: Researchers' genome map speeds biofuel development
Researchers at the University of Georgia have taken a major step in the ongoing effort to find sources of cleaner, renewable energy by mapping the genomes of two originator cells of Miscanthus x giganteus, a large perenn ...
7 hours ago |
3.7 / 5 (3) |
0
|
Experts reveal how plants don't get sunburn
(PhysOrg.com) -- Experts at the University of Glasgow have discovered how plants survive the harmful rays of the sun.
10 hours ago |
5 / 5 (2) |
0
|
Protein libraries in a snap
(PhysOrg.com) -- A Rice University undergraduate will depart with not only a degree but also a possible patent for his invention of an efficient way to create protein libraries, an important component of biomolecular ...
14 hours ago |
5 / 5 (3) |
0
|
Miami battling invasion of giant African snails
No one knows how they got there. But an invasion of African giant snails has southern Florida in a panic over potential crop damage, disease and general yuckiness surrounding the slimy gastropods.
14 hours ago |
4 / 5 (1) |
4
Google users warned of threat to smartphone wallets
Users of Google smartphone wallets were being warned on Friday that there is a way to crack pass codes intended to thwart thieves from going on illicit shopping sprees.
Anonymous knocks CIA website offline (Update)
The website of the Central Intelligence Agency was inaccessible on Friday after the hacker group Anonymous claimed to have knocked it offline.
Complex wiring of the nervous system may rely on a just a handful of genes and proteins
Researchers at the Salk Institute have discovered a startling feature of early brain development that helps to explain how complex neuron wiring patterns are programmed using just a handful of critical genes. ...
New error-correcting codes guarantee the fastest possible rate of data transmission
Error-correcting codes are one of the triumphs of the digital age. Theyre a way of encoding information so that it can be transmitted across a communication channel such as an optical fiber o ...
Putting the squeeze on planets outside our solar system
(PhysOrg.com) -- Using high-powered lasers, scientists at Lawrence Livermore National Laboratory and collaborators discovered that molten magnesium silicate undergoes a phase change in the liquid state, abruptly ...
NASA sees wide-eyed cyclone Jasmine
Cyclone Jasmine's eye has opened wider on NASA satellite imagery, as it moves through the Southern Pacific Ocean.