Study reveals molecular basis of botulism toxin's deadly activity

December 14, 2006

In the study, the scientists reveal the mysterious structural basis of the remarkably strong interaction that botulinum toxins form with nerve cells, a union so robust that a single toxin molecule can completely incapacitate a nerve cell. Because of this action, even in minute quantities these toxins are potentially deadly, leading to muscle weakness, paralysis, and sometimes respiratory failure.

"The structure finally helps to answer part of the mystery of how a very large protein can search through the body and locate the neuromuscular junction with such high affinity and specificity," says Scripps Research Professor Raymond Stevens, an author of the paper who has studied botulinum toxins for many years.

The toxins responsible for botulism are produced by the bacterium Clostridium botulinum. Humans can get the toxins from tainted food, certain wounds, and gastrointestinal tract colonization by the bacteria, the latter being particularly dangerous for infants. There is also growing concern that botulinum toxins might be used as weapons, with the Centers for Disease Control ranking them as one of the six highest-risk threats for bioterrorism.

Scientists had suspected for many years that botulinum toxins bind with nerve cells through a two-step process, but the details were unknown. Using x-ray crystallography on type B (there are seven structurally and functionally related botulinum neurotoxins, serotypes A through G) in action with receptors, the Scripps Research investigators took a molecular snapshot of regions critical to the process. Analyzing the data along with colleagues at the University of Wisconsin, Madison, and the Howard Hughes Medical Institute led to the discovery of just how the binding proceeds.

Botulinum toxins first attach to a portion of a protein found on the surface of nerve cells that mates with two parallel, narrow grooves on the toxin. Because this protein receptor is only exposed on active cells, the toxins target those nerves that are most important to a victim, such as muscles needed for breathing that are constantly in use.

The team was also able to model the structure of the second step in the process, where a separate region of a botulinum toxin binds with a sugar known as a ganglioside that acts as a second receptor. The gangliosides are found on the nerve cell surface close to the protein receptor. This double binding to the nerve cell orients the toxin in such a way that it can penetrate the nerve cell and break apart proteins that are essential to proper transmission of nerve signals.

Solving the structures opens the possibility of developing new botulism treatments, including improved small molecule drugs, vaccines, and antibody therapies.

Currently, botulism treatment rests on a cocktail of antibodies derived from horses. Because the antibodies are not human, rejection is a pervasive problem with severe potential side effects, including anaphylactic shock. The development of new types of antibodies could be a boon for treatment, and this possibility is explored by Stevens and colleagues in a paper to be published in Nature Biotechnology later this week.

In addition, the structure will help the development of other types of therapeutics to treat botulism infection. "You could essentially design smaller compounds that mimic those interactions," says Joseph Arndt, a Scripps Research postdoctoral fellow in the Stevens lab, who conducted the x-ray crystallography work for the study along with Qing Chai, another Scripps Research postdoctoral fellow. "If you block that step of recognition of the receptor, the toxin can't be internalized into the nerve cell, so it's basically shut down."

Another application for the new understanding of botulinum toxins is equally intriguing. Although botulinum toxins can have devastating effects, in very small concentrations injected directly into a specific muscle they can actually be a beneficial treatment for diseases such as cerebral palsy and multiple sclerosis that are caused by overactive nerve signaling, which the toxins can reduce. However, for reasons not completely clear, some patients do not respond to current treatments. This could be due to variations in their nerve cells that prevent the toxins from binding. If that is the case, researchers may be able to engineer toxins that bind to these variant receptors.

Source: Scripps Research Institute

Explore further: New botulinum neurotoxin discovered—potential to treat a number of medical conditions

Related Stories

New botulinum neurotoxin discovered—potential to treat a number of medical conditions

August 3, 2017
Botulinum toxins are currently applicable in more than 80 medical conditions including muscle spasms, overactive bladder, chronic migraine, cervical dystonia, sweating and cerebral palsy (CP). A new toxin, Botulinum neurotoxin ...

A new wrinkle for botox: Research reveals how botulinum toxins affect neuron survival

March 27, 2013
(Medical Xpress)—Botulinum toxins are feared as a food poison and bioterror threat, and for good reason. It takes only minute amounts of these bacterial toxins to block signals from nerve cells that control muscles. People ...

Study compares two types of botulinum toxin for cosmetic use

June 20, 2011
Not all varieties of botulinum toxin seem to be equally effective in reducing crow's feet wrinkles, according to a report published Online First today by Archives of Facial Plastic Surgery.

Study uses Botox to find new wrinkle in brain communication

May 2, 2013
National Institutes of Health researchers used the popular anti-wrinkle agent Botox to discover a new and important role for a group of molecules that nerve cells use to quickly send messages. This novel role for the molecules, ...

Disarming the botulinum neurotoxin

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 ...

Don't let botox go to your head…or should you?

January 8, 2013
Injecting botox into the arm muscles of stroke survivors, with severe spasticity, changes electrical activity in the brain and may assist with longer-term recovery, according to new research.

Recommended for you

Inflammation trains the skin to heal faster

October 18, 2017
Scars may fade, but the skin remembers. New research from The Rockefeller University reveals that wounds or other harmful, inflammation-provoking experiences impart long-lasting memories to stem cells residing in the skin, ...

Large variety of microbial communities found to live along female reproductive tract

October 18, 2017
(Medical Xpress)—A large team of researchers from China (and one each from Norway and Denmark) has found that the female reproductive tract is host to a far richer microbial community than has been thought. In their paper ...

Study of what makes cells resistant to radiation could improve cancer treatments

October 18, 2017
A Johns Hopkins University biologist is part of a research team that has demonstrated a way to size up a cell's resistance to radiation, a step that could eventually help improve cancer treatments.

New approach helps rodents with spinal cord injury breathe on their own

October 17, 2017
One of the most severe consequences of spinal cord injury in the neck is losing the ability to control the diaphragm and breathe on one's own. Now, investigators show for the first time in laboratory models that two different ...

Pair of discoveries illuminate new paths to flu and anthrax treatments

October 17, 2017
Two recent studies led by biologists at the University of California San Diego have set the research groundwork for new avenues to treat influenza and anthrax poisoning.

New method to measure how drugs interact

October 17, 2017
Cancer, HIV and tuberculosis are among the many serious diseases that are frequently treated with combinations of three or more drugs, over months or even years. Developing the most effective therapies for such diseases requires ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.