Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A |
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| Authors: | Jasmin Strotmeier Stefan Mahrhold Nadja Krez Constantin Janzen Jianlong Lou James D. Marks Thomas Binz Andreas Rummel |
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| Affiliation: | 1. Institut für Toxikologie, OE 5340, Medizinische Hochschule Hannover, 30623 Hannover, Germany;2. Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany;3. Department of Anesthesia, University of California, San Francisco, CA 94110, USA |
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| Abstract: | Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by hydrolysing SNARE proteins. The most important serotype BoNT/A employs the synaptic vesicle glycoprotein 2 (SV2) isoforms A-C as neuronal receptors. Here, we identified their binding site by blocking SV2 interaction using monoclonal antibodies with characterised epitopes within the cell binding domain (HC). The site is located on the backside of the conserved ganglioside binding pocket at the interface of the HCC and HCN subdomains. The dimension of the binding pocket was characterised in detail by site directed mutagenesis allowing the development of potent inhibitors as well as modifying receptor binding properties. |
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| Keywords: | BoNT, botulinum neurotoxin GBS, ganglioside binding site GST, glutathion-S-transferase HC, heavy chain HC, carboxyl-terminal half of HC HCA, HCE, HCF, HCG, HCX, HC fragment of BoNT serotype A, E, F, G or A-G respectively HN, amino-terminal half of HC H6F3HCXS, N-terminal 6× His tag, 3× Flag tag, HC fragment of serotype A-G, C-terminal Streptag LC, light chain mAb, monoclonal antibody MPN assay, mice phrenic nerve hemidiaphragm assay scFv, single-chain variable fragments rSV2A, B, C, rat synaptic vesicle glycoprotein 2 isoform A, B, or C Syt, synaptotagmin CD, circular dichroism |
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