How A Toxin Avoids Digestion

The structure of a botulinum neurotoxin bound to a protein shield provides clues as to how the toxin survives the digestive tract, according to a new report (Science, DOI: 10.1126/science.1214270). The results may point to ways to prevent botulism specifically. More generally, they could suggest ways to orally deliver protein-based drugs, which now must be injected to avoid digestion.

Botulism is muscle paralysis caused when a neurotoxin produced by the bacterium Clostridium botulinum inhibits release of a neurotransmitter. One way to get the disease is by eating toxin-contaminated food, but how the large protein survives the digestive tract to get to the bloodstream and neurons has been an open question.

Researchers knew that the neurotoxin is protected by another protein, called nontoxic nonhemagglutinin (NTNHA), but not how the shielding works.

A group led by Rongsheng Jin, a neuroscience professor at Sanford-Burnham Medical Research Institute in La Jolla, Calif., has now solved the crystal structure of an inactivated botulinum neurotoxin complexed to its protector NTNHA. The structure shows that NTNHA largely surrounds the part of the toxin involved in binding neuron receptors and moving through membranes. The two proteins associate through electrostatic interactions between a positively charged toxin surface and a negatively charged NTNHA surface, the researchers found.

At low pH, such as in the gut, key toxin glutamate and aspartate residues would be protonated, promoting association with NTNHA. At pH 7.5, such as in the bloodstream, the residues would be deprotonated, allowing release of the toxin from NTNHA.

The new structural information helps explain the toxin’s oral toxicity, says Luisa Cheng, a U.S. Department of Agriculture biologist who was not involved in the work.

The work won’t lead directly to a treatment for botulism, because symptoms appear only once the toxin reaches neurons. But a way to disrupt toxin-NTNHA association could stop the disease in the face of a potential outbreak, Jin says. It could also inspire new oral delivery methods for protein pharmaceuticals, such as by combining a therapeutic, a toxin fragment, and NTNHA.