Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/21901
Title: Molecular mechanisms of substrate recognition and specificity of botulinum neurotoxin serotype F
Authors: Chen, S 
Wan, HY
Keywords: Botulinum neurotoxin serotype F (BoNT/F)
Mechanism of action
Specificity
Structure function
Substrate
Vesicle-associated membrane protein 2 (VAMP-2)
Issue Date: 2011
Publisher: Portland Press Ltd
Source: Biochemical journal, 2011, v. 433, no. 2, p. 277-284 How to cite?
Journal: Biochemical Journal 
Abstract: BoNTs (botulinum neurotoxins) are both deadly neurotoxins and natural toxins that are widely used in protein therapies to treat numerous neurological disorders of dystonia and spinal spasticity. Understanding the mechanism of action and substrate specificity of BoNTs is a prerequisite to develop antitoxin and novel BoNT-derived protein therapy. To date, there is a lack of detailed information with regard to how BoNTs recognize and hydrolyse the substrate VAMP-2 (vesicle-associated membrane protein 2), even though it is known to be cleaved by four of the seven BoNT serotypes, B, D, F, G and TeNT (tetanus neurotoxin). In the present study we dissected the molecular mechanisms of VAMP-2 recognition by BoNT serotype F for the first time. The initial substrate recognition was mediated through sequential binding of VAMP-2 to the B1, B2 and B3 pockets in LC/F (light chain of BoNT serotype F), which directed VAMP-2 to the active site of LC/F and stabilized the active site substrate recognition, where the P2, P1′ and P2′ sites of VAMP-2 were specifically recognized by the S2, S1′ and S2′ pockets of LC/F to promote substrate hydrolysis. The understanding of the molecular mechanisms of LC/F substrate recognition provides insights into the development of antitoxins and engineering novel BoNTs to optimize current therapy and extend therapeutic interventions.
URI: http://hdl.handle.net/10397/21901
DOI: 10.1042/BJ20101310
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