title: Human synaptotagmin-II is not a high affinity receptor for botulinum neurotoxin B and G: increased therapeutic dosage and immunogenicity.
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.
authors.affiliation: Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Strotmeier
authors.forename: Gesche
authors.initials: G
authors.lastname: Willjes
authors.forename: Thomas
authors.initials: T
authors.lastname: Binz
authors.forename: Andreas
authors.initials: A
authors.lastname: Rummel
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001905:Botulinum Toxins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D019274:Botulinum Toxins, Type A; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D002679:Pan troglodytes / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D050861:Synaptotagmin II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; C494262:SYT2 protein, human; D050861:Synaptotagmin II; C096323:rimabotulinumtoxinB; C488535:botulinum toxin type G; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A