ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract : Tetanus toxin and the seven serologically distinctbotulinal neurotoxins (BoNT/A to BoNT/G) abrogate synaptic transmission atnerve endings through the action of their light chains (L chains), whichproteolytically cleave VAMP (vesicle-associated membraneprotein)/synaptobrevin, SNAP-25 (synaptosome-associated protein of 25 kDa), orsyntaxin. BoNT/C was reported to proteolyze both syntaxin and SNAP-25. Here,we demonstrate that cleavage of SNAP-25 occurs between Arg198 andAla199, depends on the presence of regions Asn93 toGlu145 and Ile156 to Met202, and requiresabout 1,000-fold higher L chain concentrations in comparison with BoNT/A andBoNT/E. Analyses of the BoNT/A and BoNT/E cleavage sites revealed that changesin the carboxyl-terminal residues, in contrast with changes in theamino-terminal residues, drastically impair proteolysis. A proteolyticallyinactive BoNT/A L chain mutant failed to bind to VAMP/synaptobrevin andsyntaxin, but formed a stable complex (KD = 1.9 ×10-7M) with SNAP-25. The minimal essential domain ofSNAP-25 required for cleavage by BoNT/A involves the segmentMet146-Gln197, and binding was optimal only withfull-length SNAP-25. Proteolysis by BoNT/E required the presence of the domainIle156-Asp186. Murine SNAP-23 was cleaved by BoNT/E and,to a reduced extent, by BoNT/A, whereas human SNAP-23 was resistant to allclostridial L chains. Lys185Asp or Pro182Arg mutations of human SNAP-23 induced susceptibility toward BoNT/E or toward both BoNT/A and BoNT/E, respectively.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.1999.0720327.x
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