Structural highlights
Function
[BXD_CLOBO] Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves the '60-Lys-|-Leu-61' bond of synaptobrevins-1 and -2.
Publication Abstract from PubMed
Botulinum Neurotoxins (BoNTs) are organized into seven serotypes, A-G. While several BoNT serotypes enter neurons through synaptic vesicle cycling utilizing dual receptors (a ganglioside and a synaptic vesicle associated protein), the entry pathway of BoNT/D is less well understood. While BoNT/D entry is ganglioside dependent, alignment and structural studies show that BoNT/D lacks key residues within a conserved ganglioside binding pocket that are present in BoNT serotypes A, B, E, F, and G, which indicate that BoNT/D-ganglioside interactions may be unique. In this study, BoNT/D is shown to have a unique association with ganglioside relative to the other BoNT serotypes, utilizing a ganglioside binding loop (GBL, residues Tyr1235-Ala1245) within the receptor binding domain of BoNT/D (HCR/D) via b-series gangliosides, including GT1b, GD1b, and GD2. HCR/D bound gangliosides and entered neurons dependent upon the aromatic ring of Phe1240 within the GBL. This is the first BoNT-ganglioside interaction that is mediated by a phenylalanine. In contrast, Trp1238, located near the N terminus of the GBL, was mostly solvent inaccessible and appeared to contribute to maintaining the loop structure. BoNT/D entry and intoxication were enhanced by membrane depolarization via synaptic vesicle cycling, where HCR/D colocalized with synaptophysin, a synaptic vesicle marker, but immunoprecipitation experiments did not detect direct association with synaptic vesicle protein 2 (SV2). Thus, BoNT/D utilizes unique associations with gangliosides and synaptic vesicles to enter neurons, which may facilitate new neurotoxin therapies.
Novel ganglioside-mediated entry of botulinum neurotoxin serotype D into neurons.,Kroken AR, Karalewitz AP, Fu Z, Kim JJ, Barbieri JT J Biol Chem. 2011 Jun 1. PMID:21632541[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kroken AR, Karalewitz AP, Fu Z, Kim JJ, Barbieri JT. Novel ganglioside-mediated entry of botulinum neurotoxin serotype D into neurons. J Biol Chem. 2011 Jun 1. PMID:21632541 doi:10.1074/jbc.M111.254086
