Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A

• Published in: Nature (London) 2014-01, Vol.505 (7481), p.108-111
• Main Authors: Benoit, Roger M., Frey, Daniel, Hilbert, Manuel, Kevenaar, Josta T., Wieser, Mara M., Stirnimann, Christian U., McMillan, David, Ceska, Tom, Lebon, Florence, Jaussi, Rolf, Steinmetz, Michel O., Schertler, Gebhard F. X., Hoogenraad, Casper C., Capitani, Guido, Kammerer, Richard A.
• Format: Article
• Language: English
• Subjects: 101/1; 13/109; 14/35; 14/63; 631/535/1266; 82/51; 82/80; 82/83; 96/34; Anisotropy; Antitoxins; Binding Sites; Botulinum toxin; Botulinum Toxins, Type A - chemistry; Botulinum Toxins, Type A - metabolism; Crystal structure; Crystallography, X-Ray; Endocytosis - drug effects; Glycerol; HEK293 Cells; Humanities and Social Sciences; Humans; Hydrogen bonds; letter; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Models, Molecular; multidisciplinary; Muscles; Neostriatum - cytology; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurotoxins; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Properties; Protein research; Proteins; Science; Structure-Activity Relationship; Synaptic vesicles; Toxins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12732

Botulinum neurotoxin A (BoNT/A) is considered the most toxic substance known but is also used as a therapeutic drug for a growing number of diseases and conditions; researchers have now obtained a high-resolution crystal structure of the receptor-binding domain of the BoNT/A in complex with the luminal domain of synaptic vesicle protein 2C (SV2C), one of its receptors, allowing the identification of a peptide that can inhibit complex formation. How Botox hits its target Botulinum neurotoxin A (BoNT/A) is at the same time one of the most dangerous of bioweapons and, as botox, is familiar to all as an antiwrinkle agent. The toxin acts by inhibiting neurotransmitter release through cleavage of SNAP-25, and this study presents the high-resolution crystal structure of the BoNT/A receptor-binding domain in complex with the luminal domain of synaptic vesicle protein 2C (SV2C), one of the receptors for BoNT/A. The structure indicates that SV2C forms a right-handed quadrilateral β-helix that associates with the toxin mainly via backbone–backbone interactions, reminiscent of the interstrand interactions seen in amyloid structures. The authors also identify a peptide that can act as an inhibitor of complex formation, suggesting a possible route to novel antitoxin agents. Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons 1 . Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders 2 . BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport) 3 . BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals 4 . Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other 5 : gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin 5 . Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor 6 . In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain 7 , but the molecular details of the