The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves.
Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by selectively cleaving core components of the vesicular fusion machinery. The synaptic vesicle proteins Synaptotagmin-I and -II act as receptors for BoNT/B and BoNT/G. Here we show that BoNT/A also interacts with a synaptic vesicle protein, the synaptic vesicle glycoprotein 2C (SV2C), but not with the homologous proteins SV2A and SV2B. Binding of BoNT/A occurs at the membrane juxtaposed region preceding transmembrane domain 8. A peptide comprising the intravesicular domain between transmembrane domains 7 and 8 specifically reduces the neurotoxicity of BoNT/A at phrenic nerve preparations demonstrating the physiological relevance of this interaction.
Mahrhold
Stefan
S
Institute of Biochemistry, OE 4310, Carl-Neuberg-Strasse 1, Medical School Hannover, 30623 Hannover, Germany.
Rummel
Andreas
A
Bigalke
Hans
H
Davletov
Bazbek
B
Binz
Thomas
T
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010791:Phrenic Nerve / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C485753:Sv2c protein, mouse; D019274:Botulinum Toxins, Type A