Botulinum toxins showcase diversity

Botulinum neurotoxins (BoNTs) are a family of potent toxins that cleave host proteins required for the fusion of synaptic vesicles during neurotransmitter release. In addition to the seven main serotypes, multiple mosaic toxins exist, that are thought to have originated from the recombination of different BoNT genes. So far, it has remained unclear whether these mosaic toxins have acquired different receptor-binding properties. On page 3233, Min Dong and colleagues now demonstrate that, indeed, the mosaic BoNT/D-C binds to different receptors than its parental toxin BoNT/C. BoNT/D-C, but not BoNT/C, enters neurons through synaptic vesicle recycling by binding to synaptotagmin (SYT) 1 and 2. Depletion of SYT1 – the main synaptotagmin in hippocampal neurons – prevents entry of BoNT/D-C. Analysis of the binding interface between BoNT/D-C and SYT1 and SYT2 reveals that BoNT/D-C uses the same binding site as BoNT/B and BoNT/G, but that the mosaic toxin and the receptor form a distinct binding interface. Moreover, mutagenesis studies indicate that human SYT2 is not an effective receptor for BoNT/D-C, BoNT/B or BoNT/G because of a single amino acid change within the toxin binding site. Collectively, these observations highlight the diversity of BoNTs and the way their interactions with receptors are restricted in humans.