The zinc-dependent protease activity of the botulinum neurotoxins

Frank J Lebeda, Regina Z Cer, Uma Mudunuri, Robert Stephens, Bal Ram Singh, Michael Adler, Frank J Lebeda, Regina Z Cer, Uma Mudunuri, Robert Stephens, Bal Ram Singh, Michael Adler

Abstract

The botulinum neurotoxins (BoNT, serotypes A-G) are some of the most toxic proteins known and are the causative agents of botulism. Following exposure, the neurotoxin binds and enters peripheral cholinergic nerve endings and specifically and selectively cleaves one or more SNARE proteins to produce flaccid paralysis. This review centers on the kinetics of the Zn-dependent proteolytic activities of these neurotoxins, and briefly describes inhibitors, activators and factors underlying persistence of toxin action. Some of the structural, enzymatic and inhibitor data that are discussed here are available at the botulinum neurotoxin resource, BotDB (http://botdb.abcc.ncifcrf.gov).

Keywords: Km; catalysis; energy; kcat; superactivation.

Figures

Figure 1
Figure 1
Representation of the four structural domains of the BoNT/B holotoxin (PDB ID 1EPW) [16]. The “Structures” section of the BotDB presently contains 90 3D protein structures found in the Protein Data Bank (PDB) [5]. From left to right, the order of these domains is: HCC, (red) HCN, (yellow-orange) HN (green), LC (blue).
Figure 2
Figure 2
Values of Km and kcat obtained from cell-free assays depend on the forms of the toxic moiety and the substrate molecule used. The LC of BoNT/A (LC-A) and full length SNAP-25 (residues 1-206) are associated with values of Km (closed symbols) that are less than those associated with the LC-A and a 17-mer of SNAP-25 (residues 146-206; open symbols). Larger values for kcat tended to be associated with a 17-mer of SNAP-25 and the holotoxin (open triangles). Open circles: LC-A used with 17-mer SNAP-25 fragment; closed circles: LC-A used with full-length SNAP-25 (1-206) containing His-6 tag. Closed diamond: data associated with the largest kcat/Km ratio in this data set (see text). Dashed vertical line: arbitrarily positioned below Km = 100 mM to visually separate high and low values of Km. Data collected from [48,49,50] and references therein.
Figure 3
Figure 3
Example list of compounds in the BotDBI that have been evaluated as blockers of BoNT/A action.
Figure 4
Figure 4
Output of the IC50-to-Ki converter tool at the BotDB website that shows the different possible results based on whether the inhibitor mechanism is competitive, uncompetitive or noncompetitive.

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