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.
