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

FEBS Lett. 2012 Feb 17;586(4):310-3. doi: 10.1016/j.febslet.2011.12.037. Epub 2012 Jan 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Binding Sites / genetics
  • Botulinum Toxins / administration & dosage
  • Botulinum Toxins / immunology
  • Botulinum Toxins / metabolism*
  • Botulinum Toxins, Type A
  • Conserved Sequence
  • Evolution, Molecular
  • Humans
  • Kinetics
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Pan troglodytes / genetics
  • Protein Structure, Tertiary
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Synaptotagmin II / chemistry
  • Synaptotagmin II / genetics
  • Synaptotagmin II / metabolism*

Substances

  • Recombinant Fusion Proteins
  • SYT2 protein, human
  • Synaptotagmin II
  • rimabotulinumtoxinB
  • botulinum toxin type G
  • Botulinum Toxins
  • Botulinum Toxins, Type A