Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A

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• 作者：Jasmin Strotmeier^a ; Stefan Mahrhold^a ; ^b ; Nadja Krez^a ; Constantin Janzen^a ; Jianlong Lou^c ; James D. Marks^c ; Thomas Binz^b ; Andreas Rummel^a ; ^{Rummel.Andreas@mh-hannover.de" class="auth_mail}
• 关键词：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 ; r
• 刊名：FEBS Letters
• 出版年：2 April, 2014
• 年：2014
• 卷：588
• 期：7
• 页码：1087-1093
• 全文大小：1112 K

文摘

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 (H_C). The site is located on the backside of the conserved ganglioside binding pocket at the interface of the H_CC and H_CN 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.