4.5 Article

Identification of the SV2 protein receptor-binding site of botulinum neurotoxin type E

期刊

BIOCHEMICAL JOURNAL
卷 453, 期 -, 页码 37-47

出版社

PORTLAND PRESS LTD
DOI: 10.1042/BJ20130391

关键词

botulinum neurotoxin E; C-terminal fragment of the heavy chain (H-C-fragment); synaptic vesicle glycoprotein 2 (SV2); synaptotagmin

资金

  1. Deutsche Forschungsgemeinschaft [IIB2-Bi 660/2-3]
  2. National Institute of Allergy and Infectious Diseases [U54 AI065359]
  3. Robert Koch-Institut [1362/I-979]

向作者/读者索取更多资源

The highly specific binding and uptake of BoNTs (botulinum neurotoxins; A-G) into peripheral cholinergic motoneurons turns them into the most poisonous substances known. Interaction with gangliosides accumulates the neurotoxins on the plasma membrane and binding to a synaptic vesicle membrane protein leads to neurotoxin endocytosis. SV2 (synaptic vesicle glycoprotein 2) mediates the uptake of BoNT/A and /E, whereas Syt (synaptotagmin) is responsible for the endocytosis of BoNT/B and /G. The Syt-binding site of the former was identified by co-crystallization and mutational analyses. In the present study we report the identification of the SV2-binding interface of BoNT/E. Mutations interfering with SV2 binding were located at a site that corresponds to the Syt-binding site of BoNT/B and at an extended surface area located on the back of the conserved ganglioside-binding site, comprising the N- and C-terminal half of the BoNT/E-binding domain. Mutations impairing the affinity also reduced the neurotoxicity of full-length BoNT/E at mouse phrenic nerve hemidiaphragm preparations demonstrating the crucial role of the identified binding interface. Furthermore, we show that a monoclonal antibody neutralizes BoNT/E activity because it directly interferes with the BoNT/E-SV2 interaction. The results of the present study suggest a novel mode of binding for BoNTs that exploit SV2 as a cell surface receptor.

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