Linked Life Data

19650874

Source:http://linkedlifedata.com/resource/pubmed/id/19650874

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2009-9-11
pubmed:abstractText
The high toxicity of clostridial neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven botulinum neurotoxin serotypes A-G (BoNT/A-G) inhibit acetylcholine release, leading to flaccid paralysis, while tetanus neurotoxin blocks neurotransmitter release in inhibitory neurons, resulting in spastic paralysis. Uptake of BoNT/A, B, E and G requires a dual interaction with gangliosides and the synaptic vesicle (SV) proteins synaptotagmin or SV2, whereas little is known about the entry mechanisms of the remaining serotypes. Here, we demonstrate that BoNT/F as wells depends on the presence of gangliosides, by employing phrenic nerve hemidiaphragm preparations derived from mice expressing GM3, GM2, GM1 and GD1a or only GM3. Subsequent site-directed mutagenesis based on homology models identified the ganglioside binding site at a conserved location in BoNT/E and F. Using the mice phrenic nerve hemidiaphragm assay as a physiological model system, cross-competition of full-length neurotoxin binding by recombinant binding fragments, plus accelerated neurotoxin uptake upon increased electrical stimulation, indicate that BoNT/F employs SV2 as protein receptor, whereas BoNT/C and D utilise different SV receptor structures. The co-precipitation of SV2A, B and C from Triton-solubilised SVs by BoNT/F underlines this conclusion.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1471-4159
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
110
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1942-54
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:19650874-Animals, pubmed-meshheading:19650874-Binding, Competitive, pubmed-meshheading:19650874-Binding Sites, pubmed-meshheading:19650874-Botulinum Toxins, pubmed-meshheading:19650874-Diaphragm, pubmed-meshheading:19650874-Dose-Response Relationship, Drug, pubmed-meshheading:19650874-Electric Stimulation, pubmed-meshheading:19650874-Gangliosides, pubmed-meshheading:19650874-Isometric Contraction, pubmed-meshheading:19650874-Membrane Glycoproteins, pubmed-meshheading:19650874-Mice, pubmed-meshheading:19650874-Mice, Inbred C57BL, pubmed-meshheading:19650874-Mice, Knockout, pubmed-meshheading:19650874-Models, Molecular, pubmed-meshheading:19650874-Mutagenesis, Site-Directed, pubmed-meshheading:19650874-Nerve Tissue Proteins, pubmed-meshheading:19650874-Phrenic Nerve, pubmed-meshheading:19650874-Protein Binding, pubmed-meshheading:19650874-Protein Isoforms, pubmed-meshheading:19650874-Rats, pubmed-meshheading:19650874-Synaptic Vesicles
pubmed:year
2009
pubmed:articleTitle
Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor.
pubmed:affiliation
Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany. rummel.andreas@mh-hannover.de
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't