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Structural characterisation of the catalytic domain of botulinum neurotoxin X - high activity and unique substrate specificity.
Department of Urology, USA; Department of Microbiology and Immunobiology, USA; Department of Surgery, USA.
Department of Urology, USA; Department of Microbiology and Immunobiology, USA; Department of Surgery, USA.
Department of Urology, USA; Department of Microbiology and Immunobiology, USA; Department of Surgery, USA.
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed) Published
Abstract [en]

Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6. Here we report the 1.35 Å X-ray crystal structure of the light chain of BoNT/X (LC/X). LC/X shares the core fold common to all other BoNTs, demonstrating that LC/X is a bona fide member of BoNT-LCs. We found that access to the catalytic pocket of LC/X is more restricted, and the regions lining the catalytic pocket are not conserved compared to other BoNTs. Kinetic studies revealed that LC/X cleaves VAMP1 with a ten times higher efficiency than BoNT/B and the tetanus neurotoxin. The structural information provides a molecular basis to understand the convergence/divergence between BoNT/X and other BoNTs, to develop effective LC inhibitors, and to engineer new scientific tools and therapeutic toxins targeting distinct SNARE proteins in cells.

Place, publisher, year, edition, pages
2018.
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:su:diva-157950DOI: 10.1038/s41598-018-22842-4OAI: oai:DiVA.org:su-157950DiVA, id: diva2:1229012
Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-06-29

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