SV2 is the protein receptor for botulinum neurotoxin A.
How the widely used botulinum neurotoxin A (BoNT/A) recognizes and enters neurons is poorly understood. We found that BoNT/A enters neurons by binding to the synaptic vesicle protein SV2 (isoforms A, B, and C). Fragments of SV2 that harbor the toxin interaction domain inhibited BoNT/A from binding to neurons. BoNT/A binding to SV2A and SV2B knockout hippocampal neurons was abolished and was restored by expressing SV2A, SV2B, or SV2C. Reduction of SV2 expression in PC12 and Neuro-2a cells also inhibited entry of BoNT/A, which could be restored by expressing SV2 isoforms. Finally, mice that lacked an SV2 isoform (SV2B) displayed reduced sensitivity to BoNT/A. Thus, SV2 acts as the protein receptor for BoNT/A.
Dong
Min
M
Howard Hughes Medical Institute and Department of Physiology, University of Wisconsin, Madison, WI 53706, USA.
Yeh
Felix
F
Tepp
William H
WH
Dean
Camin
C
Johnson
Eric A
EA
Janz
Roger
R
Chapman
Edwin R
ER
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000378:metabolism* / Q000633:toxicity; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis; D006624:Hippocampus / Q000166:cytology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D013572:Synaptic Vesicles / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D050683:R-SNARE Proteins; C489614:Sv2a protein, mouse; C489618:Sv2a protein, rat; D050857:Synaptotagmins; D019274:Botulinum Toxins, Type A