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Title: Novel Ganglioside-mediated Entry of Botulinum Neurotoxin Serotype D into Neurons

Abstract

Botulinum Neurotoxins (BoNTs) are organized into seven serotypes, A-G. Although 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. Although 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 Tyr-1235-Ala-1245) 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 Phe-1240 within the GBL. This is the first BoNT-ganglioside interaction that is mediated by a phenylalanine. In contrast, Trp-1238, located near the N terminus of the ganglioside binding loop, 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 experimentsmore » did not detect direct association with synaptic vesicle protein 2. Thus, BoNT/D utilizes unique associations with gangliosides and synaptic vesicles to enter neurons, which may facilitate new neurotoxin therapies.« less

Authors:
; ; ; ;  [1]
  1. MCW
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHNIAID
OSTI Identifier:
1032655
Resource Type:
Journal Article
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 286; Journal Issue: 30; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ALIGNMENT; AROMATICS; DEPOLARIZATION; GANGLIOSIDES; GLYCOLIPIDS; MEMBRANES; NERVE CELLS; PHENYLALANINE; PROTEINS; RESIDUES; TOXINS

Citation Formats

Kroken, Abby R, Karalewitz, Andrew P.-A., Fu, Zhuji, Kim, Jung-Ja P, and Barbieri, Joseph T. Novel Ganglioside-mediated Entry of Botulinum Neurotoxin Serotype D into Neurons. United States: N. p., 2012. Web. doi:10.1074/jbc.M111.254086.
Kroken, Abby R, Karalewitz, Andrew P.-A., Fu, Zhuji, Kim, Jung-Ja P, & Barbieri, Joseph T. Novel Ganglioside-mediated Entry of Botulinum Neurotoxin Serotype D into Neurons. United States. https://doi.org/10.1074/jbc.M111.254086
Kroken, Abby R, Karalewitz, Andrew P.-A., Fu, Zhuji, Kim, Jung-Ja P, and Barbieri, Joseph T. 2012. "Novel Ganglioside-mediated Entry of Botulinum Neurotoxin Serotype D into Neurons". United States. https://doi.org/10.1074/jbc.M111.254086.
@article{osti_1032655,
title = {Novel Ganglioside-mediated Entry of Botulinum Neurotoxin Serotype D into Neurons},
author = {Kroken, Abby R and Karalewitz, Andrew P.-A. and Fu, Zhuji and Kim, Jung-Ja P and Barbieri, Joseph T},
abstractNote = {Botulinum Neurotoxins (BoNTs) are organized into seven serotypes, A-G. Although 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. Although 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 Tyr-1235-Ala-1245) 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 Phe-1240 within the GBL. This is the first BoNT-ganglioside interaction that is mediated by a phenylalanine. In contrast, Trp-1238, located near the N terminus of the ganglioside binding loop, 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. Thus, BoNT/D utilizes unique associations with gangliosides and synaptic vesicles to enter neurons, which may facilitate new neurotoxin therapies.},
doi = {10.1074/jbc.M111.254086},
url = {https://www.osti.gov/biblio/1032655}, journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 30,
volume = 286,
place = {United States},
year = {Tue Feb 07 00:00:00 EST 2012},
month = {Tue Feb 07 00:00:00 EST 2012}
}