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Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity.

ABSTRACT: Botulinum neurotoxin serotype A (BoNT/A) is one of the most lethal toxins known. Its extreme toxicity is due to its light chain (LC), a zinc protease that cleaves SNAP-25, a synaptosome-associated protein, leading to the inhibition of neuronal activity. Studies on BoNT/A LC have revealed that two regions, termed exosites, can play an important role in BoNT catalytic activity. A clear understanding of how these exosites influence neurotoxin catalytic activity would provide a critical framework for deciphering the mechanism of SNAP-25 cleavage and the design of inhibitors. Herein, based on the crystallographic structure of BoNT/A LC complexed with its substrate, we designed an ?-exosite binding probe. Experiments with this unique probe demonstrated that ?-exosite binding enhanced both catalytic activity and stability of the LC. These data help delineate why ?-exosite binding is needed for SNAP-25 cleavage and also provide new insights into the extended lifetime observed for BoNT/A LC in vivo.

SUBMITTER: Xue S

PROVIDER: S-EPMC4222541 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity.

Xue Song S Javor Sacha S Hixon Mark S MS Janda Kim D KD

Biochemistry 20141021 43

Botulinum neurotoxin serotype A (BoNT/A) is one of the most lethal toxins known. Its extreme toxicity is due to its light chain (LC), a zinc protease that cleaves SNAP-25, a synaptosome-associated protein, leading to the inhibition of neuronal activity. Studies on BoNT/A LC have revealed that two regions, termed exosites, can play an important role in BoNT catalytic activity. A clear understanding of how these exosites influence neurotoxin catalytic activity would provide a critical framework fo ...[more]

PMID: 25295706

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Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity.

Publications

Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity.

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