Exploration of endogenous substrate cleavage by various forms of botulinum neurotoxins.
Botulinum neurotoxins are the most potent protein neurotoxin known to human. The dual roles of BoNTs as both the causative agent of human botulism and a widely used protein-based therapeutic agent for treatment of numerous neuromuscular disorders/cosmetic uses make it an extremely hot topic of research. Biochemical characterization of these toxins was mainly confined to the recombinant light chains and substrate and little is known about their efficiency on the cleavage of endogenous substrates. In the present study, we showed that BoNTs exhibited variable activities on their endogenous substrates and that their efficiency to cleave recombinant and endogenous substrate was not consistent, presumably due to the differential recognition of their respective substrates in the natural SNARE complex format. Through testing the combinatorial effects of different BoNTs on cleavage of endogenous substrates, we showed that the combinations of LC/A and LC/B, as well as LC/A and LC/F, could enhance the activity of each individual BoNT. This finding may shed light on the future development of new BoNT serotypes for clinical application, and formulation of combinatorial uses of different BoNTs to minimize the development of immuno-resistance by using a lower amount of individual type.
Shenzhen Key Lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, PR China; State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
Jiubiao
J
Guo
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, PR China.
Jinglin
J
Wang
Shenzhen Key Lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, PR China; State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
Edward Waichi
EW
Chan
Shenzhen Key Lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, PR China; State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. Electronic address: sheng.chen@polyu.edu.hk.
Sheng
S
Chen
D000818:Animals; D001905:Botulinum Toxins / Q000378:metabolism*; D002460:Cell Line; D003013:Clostridium / Q000378:metabolism*; D051379:Mice; D050600:SNARE Proteins / Q000378:metabolism; D013379:Substrate Specificity
D050600:SNARE Proteins; D001905:Botulinum Toxins
Botulinum neurotoxins; Combinational uses; Endogenous substrate cleavage; Therapeutic application