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.
Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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