Navigation Links
Scientists reveal structure of new botulism nerve toxin subtype
Date:12/22/2008

UPTON, NY 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."


'/>"/>

Contact: Karen McNulty Walsh
kmcnulty@bnl.gov
631-344-8350
DOE/Brookhaven National Laboratory
Source:Eurekalert

Related medicine news :

1. New prion protein discovered by Canadian scientists may offer insight into mad cow disease
2. Scientists Probe Sepsis Deadly Secrets
3. Scientists puzzled by severe allergic reaction to cancer drug in the middle Southern US
4. Scientists Develop Natural Protection for Stored Foods
5. Scientists detect presence of marburg virus in african fruit bats
6. Scientists Spot Brains Free Will Center
7. Scientists ID Likely Culprit in Popcorn Lung
8. Scientists explain how insulin secreting cells maintain their glucose sensitivity
9. Scripps Research scientists shed new light on how antibodies fight HIV
10. Scientists, physicians present latest findings in personalized cancer treatment and prevention
11. Scientists demonstate link between genetic variant and effectiveness of smoking cessation meds
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/12/2017)... ... 12, 2017 , ... IsoComforter, Inc. ( https://isocomforter.com ), one of ... innovative new design of the shoulder pad. The shoulder pad provides optimal support ... your pain while using cold therapy. By utilizing ice and water that is circulated ...
(Date:10/12/2017)... (PRWEB) , ... October 12, 2017 , ... ... AccentCare, a leader in post-acute health care, have expanded their existing home health ... Home Health. , AccentCare has been operating a joint venture home health company ...
(Date:10/12/2017)... , ... October 12, 2017 , ... ... Hair Restoration, has recently contributed a medical article to the newly revamped ... Dr. Mohebi’s article spotlights the hair transplant procedure known as Follicular Unit ...
(Date:10/12/2017)... , ... October 12, 2017 , ... Leading pediatric oncology ... in Washington, D.C., for the 49th Congress of the International Society of Paediatric ... President of the Center for Cancer and Blood Disorders at Children’s National, ...
(Date:10/12/2017)... Mich. (PRWEB) , ... October 12, 2017 , ... ... has been named one of Michigan’s 2017 Best and Brightest in Wellness® by ... Brightest in Wellness® awards program on Friday, Oct. 20 from 7:30 a.m. to ...
Breaking Medicine News(10 mins):
(Date:9/27/2017)... Sept. 27, 2017  DarioHealth Corp. (NASDAQ: DRIO), a leading global digital ... its MyDario product is expected to appear on The Dr. Oz Show ... Oz Show airs in your area: http://www.doctoroz.com/page/where-watch-dr-oz-show ... The nine-time Emmy award-winning, The Dr. Oz Show kicked off ... The segment features ...
(Date:9/25/2017)...  EpiVax, Inc., a leader in the fields ... announced the launch of EpiVax Oncology Inc., a ... cancer vaccines. EpiVax has provided $500,000 in seed ... technologies to the new precision immunotherapy venture. Gad ... as Chief Executive Officer. Gad brings over 25 ...
(Date:9/22/2017)... ROCKVILLE, Md. , Sept. 22, 2017  As ... by Republican Senators Bill Cassidy (R-LA) and ... Kalorama Information notes that the medical device industry is ... the medical device tax, the 2.3% excise tax on ... Act.  But they also want covered patients, increased visits ...
Breaking Medicine Technology: