Human synaptotagmin-II is not a high affinity receptor for botulinum neurotoxin B and G: Increased therapeutic dosage and immunogenicity

Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by hydrolysing SNARE proteins essential for exocytosis. The synaptic vesicle protein synaptotagmin-II of rat and mouse acts as neuronal high affinity receptor for BoNT/B and BoNT/G. Here, we show that human synaptotagmin-II is not a high affinity receptor for BoNT/B and G due to a phenylalanine to leucine mutation in its luminal domain present only in humans and chimpanzees. It eliminates one of three major interactions between synaptotagmin-II and BoNT/B and hereby explains the disparity in potency of BoNT/B in humans and mice as well as the 40-fold higher dosage of rimabotulinumtoxinB versus onabotulinumtoxinA.Structured summary of protein interactionsrSyt-IIbinds to BoNT/G by pull down (View Interaction: 1, 2)rSyt-IIbinds to BoNT/B by pull down (View Interaction: 1, 2)

► Synaptotagmin-II of rat and mouse acts as neuronal high affinity receptor for BoNT/B and G. ► Mutation F54L converts rat synaptotagmin-II to a low affinity receptor of BoNT/B and G. ► F54 corresponds to L51 in human synaptoagmin-II. ► Human synaptotagmin-II is not a high affinity receptor for BoNT/B and G due to L51.