Navigation Links
Disarming the botulinum neurotoxin
Date:2/23/2012

LA JOLLA, Calif., February 23, 2012 Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) and the Medical School of Hannover in Germany recently discovered how the botulinum neurotoxin, a potential bioterrorism agent, survives the hostile environment in the stomach on its journey through the human body. Their study, published February 24 in Science, reveals the first 3D structure of a neurotoxin together with its bodyguard, a protein made simultaneously in the same bacterium. The bodyguard keeps the toxin safe through the gut, then lets go as the toxin enters the bloodstream. This new information also reveals the toxin's weak spota point in the process that can be targeted with new therapeutics.

"Now that we better understand the structure of the bacterial machinery that was designed for highly efficient toxin protection and delivery, we can see more clearly how to break it," said Rongsheng Jin, Ph.D., assistant professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study.

The Janus-faced toxin

The botulinum neurotoxin is two-faced. On one side, it's the most poisonous substance known to man, causing botulism. Accidental botulinum neurotoxin poisoning is usually food-borne, but it's also considered a potential bioterrorism agent. On the other side, botulinum neurotoxin is also used an effective therapy and popular cosmetic, such as in BOTOX.

The neurotoxin accomplishes both the good and the bad using the same trickparalyzing muscle cells by disrupting their connections with the nerves that tell them how and when to move. But before the neurotoxin can gain access to muscles and the neurons that control them, it must make a remarkable journey through the bodysurviving the digestive enzymes and extreme acidic environment in the stomach, penetrating the small intestine, and entering the bloodstream.

Sneaking a peek at the neurotoxin and its bodyguard

This latest study on the botulinum neurotoxin was the result of a close collaboration between the Jin group and a research group at the Institute of Toxicology at the Medical School of Hannover, led by Andreas Rummel, Ph.D., an expert on clostridial neurotoxins. They used a technique called X-ray crystallography, which uses powerful X-ray beams to produce 3D images of proteins at the atomic level, to study a genetically inactivated, nontoxic version of the botulinum neurotoxin.

These experiments helped the team visualize the atomic structure of all three parts of the toxin: 1) the region that recognizes neurons, 2) the enzyme that acts like a pair of scissors to cut human neural proteins and cause paralysis, and 3) the needle that punches holes to help deliver the enzyme to the nerve terminal. What's more, the researchers also captured the toxin's interaction with a second bacterial protein, called nontoxic nonhemagglutinin (NTNHA).

"We were surprised to see that NTNHA, which is not toxic, turned out to be remarkably similar to botulinum neurotoxin. It's composed of three parts, just like a copy of the toxin itself. These two proteins hug each other and interlock with what looks like a handshake," said Jin.

As the toxin moves through the body, NTNHA acts as its bodyguard, keeping it from being degraded when times are tough in the acidic stomach. However, as this study revealed, the toxin has a weak spot: when the toxin/NTNHA complex punches its way out of the small intestine, it's the change in pH that triggers a conformational change, breaks up the duo, and releases only the unprotected toxin into the bloodstream.

Towards prevention and therapy

According to Jin, this new knowledge about how the botulinum neurotoxin and NTNHA balance the need for strong binding and a timely release could be exploited to outsmart them.

"We now hope we might be able to fool the toxin and its bodyguard using a small molecule that sends the wrong signalmimicking pH change, prematurely breaking up their protective embrace, and leaving the stomach's digestive enzymes and acid to do their job," he said. "We envision this type of therapyeither alone or in combination with other therapies currently in developmentcould be given preventively at a time when botulinum neurotoxin contamination becomes a public health concern."

Moreover, this type of therapy could be designed for oral delivery, rather than injection, making it easier to treat large numbers of people during an outbreak. A similar strategy could be used to deliver other protein-based drugs that usually need to be injected. "Here, protein drugs could be linked to a botulinum neurotoxin fragment and protected with NTNHA. Then we could possibly take them by mouth," Jin said.


'/>"/>

Contact: Heather Buschman, Ph.D.
hbuschman@sanfordburnham.org
858-795-5343
Sanford-Burnham Medical Research Institute
Source:Eurekalert  

Related biology technology :

1. Quanterix Receives Funding From the Department of Homeland Security to Develop Test for Botulinum Toxin
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Disarming the botulinum neurotoxin
(Date:5/24/2016)... , May 24, 2016   MedyMatch Technology Ltd ., ... artificial intelligence, real-time decision support tools in the emergency room, ... the 2016 Israeli Advanced Technology Industries (IATI) BioMed Conference. ... Israel,s 15th National Life Sciences and Technology Week, ... David Intercontinental Hotel in Tel Aviv, Israel ...
(Date:5/23/2016)... ... 23, 2016 , ... The need for blood donations in South Texas and across the nation ... Blood & Tissue Center, blood donations are on the decline. In fact, donations across the ... 21 percent in South Texas in the last four years alone. , There is no ...
(Date:5/23/2016)... Oxitec CEO Hadyn Parry ... a.m. ET before the United States House Committee on Science, ... play in controlling the spread of the Aedes aegypti ...      (Logo: http://photos.prnewswire.com/prnh/20150630/227348 ) Oxitec ... gene. Trials in Brazil , ...
(Date:5/23/2016)... , ... May 23, 2016 , ... ... organization focused on molecular nanotechnology, announced the winners for the 2015 Foresight Institute ... Richard Feynman, are given in two categories, one for experiment and the other ...
Breaking Biology Technology:
(Date:4/15/2016)... , April 15, 2016  A new ... make more accurate underwriting decisions in a fraction ... timely, competitively priced and high-value life insurance policies ... screenings. With Force Diagnostics, rapid testing ... lifestyle data readings (blood pressure, weight, pulse, BMI, ...
(Date:3/31/2016)... 2016  Genomics firm Nabsys has completed a financial ... Bready , M.D., who returned to the company in ... leadership team, including Chief Technology Officer, John Oliver ... Nurnberg and Vice President of Software and Informatics, ... Dr. Bready served as CEO of Nabsys from ...
(Date:3/21/2016)... WAKEFIELD, Massachusetts , March 22, 2016 ... and facial recognition with passcodes for superior security ... MESG ), a leading provider of secure digital communications ... pilot their biometric technology and offer enterprise customers, particularly ... provide secure facial recognition and voice authentication within a ...
Breaking Biology News(10 mins):