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Abstractions

First Author

Despite their current uses for treating neuromuscular disorders and erasing wrinkles, botulinum neurotoxins are among the most poisonous naturally occurring substances in the world. A single molecule can kill a neuron. Working with botulinum expert Raymond Stevens at the Scripps Research Institute in La Jolla, California, postdocs Qing Chai and Joseph Arndt were the first to establish the full crystal structure of one such neurotoxin and how it recognizes cell-surface receptors. As reported on page 1096, this revealed how botulinum toxins bind to cellular receptors and that their complex structure is crucial to their toxicity. Nature caught up with Chai and Arndt to find out more about their work.

Given the potential downsides, what's the best part of working with botulinum neurotoxins on a daily basis?

Well, we have very smooth skin... Actually, it's a fascinating molecule. Three different functional parts of this protein — one that binds to the receptor, one that moves the toxin into the cell and one that disrupts cell functioning — are all necessary for its level of toxicity. It's so well orchestrated.

Does the structure of the neurotoxin–receptor complex you describe help explain botulinum's toxicity?

We think so. It's the first molecular snapshot of its toxicity. The first step for toxicity is binding to the nerve cell. The way that it binds explains why it's so specific and deadly. The toxin has to catch a moment when both a protein receptor, which is not always exposed, and a sugar receptor are present on an active neuronal cell surface for the molecule to enter the cell. It's a clever and efficient molecule.

Were there any surprises about how the structure influences the toxin's behaviour?

Chemical assays suggested that the binding region of the receptor had no particular structure, much like a piece of spaghetti. But, surprisingly, when it binds to toxin it adopts a highly ordered helical structure, more like a phone cord. It seems that the toxin influences this structure, and that the proximity of the sugar to the protein receptor coordinates it. We'd like to investigate this further.

How is botulinum neurotoxin being explored as a discovery tool in neurobiology?

It's like a Trojan horse. The part of the toxin that disrupts neuronal function can be replaced with an experimental molecule. In this way, scientists can use the binding and translocation efficiency of the botulinum neurotoxin to get the neuron to unwittingly accept experimental proteins or signalling molecules. Such proteins are known as fusion proteins.

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Abstractions. Nature 444, xi (2006). https://doi.org/10.1038/7122xib

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