The Botulinum neurotoxins -structure and mechanism of the most potent toxins of all

Botulinum neurotoxins (BoNTs) are the most potent toxins known, causing paralysis by severing the communication between nerves and muscles.

At minute concentrations, these neurotoxins are injected into tens of millions of patients worldwide for over 90 indications, both medicinal and aesthetic.

The mechanism of action of BoNTs has been studied for decades, and while there is a working model on how their paralytic effects are mediated, many key questions remain unanswered. We have recently discovered the first novel BoNTs in 50-years, opening a new and exciting research field.

By combining structural, biophysical and biochemical studies of both previously known and newly discovered types of BoNTs, we aim to provide a comprehensive model of how BoNTs work.What questions will we study?

The species, cell and receptor specificity of both canonical and novel botulinum toxins.Structure and pH dependence of several novel 300 kDa BoNT-NTNH complexes.The complex substrate recognition of the toxins.How the toxin forms a membrane pore that can translocate the 50 kDa light chain.Engineering of neurotoxins to improve existing and develop new applications.The novel toxins we recently discovered, together with the detailed knowledge of the toxin’s specificity, which we will gain during the proposed project, will dramatically expand our possibilities to engineer toxins, both for use as scientific tools and for therapeutic applications.