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Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2004 Jul 16; Vol. 279 (29), pp. 30865-70. Date of Electronic Publication: 2004 Apr 30. - Publication Year :
- 2004
-
Abstract
- Botulinum neurotoxins (BoNTs) induce muscle paralysis by selectively entering cholinergic motoneurons and subsequent specific cleavage of core components of the vesicular fusion machinery. Complex gangliosides are requisite for efficient binding to neuronal cells, but protein receptors are critical for internalization. Recent work evidenced that synaptotagmins I and II can function as protein receptors for BoNT/B (Dong, M., Richards, D. A., Goodnough, M. C., Tepp, W. H., Johnson, E. A., and Chapman, E. R. (2003) J. Cell Biol. 162, 1293-1303). Here, we report the protein receptor for a second BoNT serotype. Like BoNT/B, BoNT/G employs synaptotagmins I and II to enter phrenic nerve cells. Using pull-down assays we show that only BoNT/G, but neither the five remaining BoNTs nor tetanus neurotoxin, interacts with synaptotagmins I and II. In contrast to BoNT/B, interactions with both isoforms are independent of the presence of gangliosides. Peptides derived from the luminal domain of synaptotagmin I and II are capable of blocking the neurotoxicity of BoNT/G in phrenic nerve preparations. Pull-down and neutralization assays further established the membrane-juxtaposed 10 luminal amino acids of synaptotagmins I and II as the critical segment for neurotoxin binding. In addition, we show that the carboxyl-terminal domain of the cell binding fragment of BoNT/B and BoNT/G mediates the interaction with their protein receptor.
- Subjects :
- Animals
Botulinum Toxins, Type A
Cell Membrane metabolism
Electrophoresis, Polyacrylamide Gel
Gangliosides chemistry
Glutathione Transferase metabolism
Membrane Glycoproteins metabolism
Mice
Nerve Tissue Proteins metabolism
Peptides chemistry
Phrenic Nerve metabolism
Plasmids metabolism
Protein Binding
Protein Isoforms
Protein Structure, Tertiary
Recombinant Fusion Proteins metabolism
Recombinant Proteins chemistry
Synaptotagmin I
Synaptotagmin II
Synaptotagmins
Botulinum Toxins chemistry
Botulinum Toxins metabolism
Calcium-Binding Proteins
Membrane Glycoproteins physiology
Nerve Tissue Proteins physiology
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 279
- Issue :
- 29
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15123599
- Full Text :
- https://doi.org/10.1074/jbc.M403945200