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Synaptotagmin Binding to Botulinum Neurotoxins
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2020 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 59, no 4, p. 491-498Article in journal (Refereed) Published
Abstract [en]

Botulinum neurotoxins (BoNTs) are exceptionally toxic proteins that cause paralysis but are also extensively used as treatment for various medical conditions. Most BoNTs bind two receptors on neuronal cells, namely, a ganglioside and a protein receptor. Differences in the sequence between the protein receptors from different species can impact the binding affinity and toxicity of the BoNTs. Here we have investigated how BoNT/B, /DC, and /G, all three toxins that utilize synaptotagmin I and II (Syt-I and Syt- II, respectively) as their protein receptors, bind to Syt-I and -II of mouse/rat, bovine, and human origin by isothermal titration calorimetry analysis. BoNT/G had the highest affinity for human Syt-I, and BoNT/DC had the highest affinity for bovine Syt-II. As expected, BoNT/B, /DC, and /G showed very low levels of binding to human Syt-II. Furthermore, we carried out saturation transfer difference (STD) and STD-TOCSY NMR experiments that revealed the region of the Syt peptide in direct contact with BoNT/G, which demonstrate that BoNT/G recognizes the Syt peptide in a model similar to that in the established BoNT/B-Syt-II complex. Our analyses also revealed that regions outside the Syt peptide's toxin-binding region are important for the helicity of the peptide and, therefore, the binding affinity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020. Vol. 59, no 4, p. 491-498
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-168345DOI: 10.1021/acs.biochem.9b00554ISI: 000511509600017PubMedID: 31809018Scopus ID: 2-s2.0-85076990418OAI: oai:DiVA.org:umu-168345DiVA, id: diva2:1395051
Available from: 2020-02-20 Created: 2020-02-20 Last updated: 2023-03-24Bibliographically approved

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Berntsson, Ronnie Per-Arne

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Berntsson, Ronnie Per-ArneWidmalm, GöranStenmark, Pål
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Department of Medical Biochemistry and BiophysicsWallenberg Centre for Molecular Medicine at Umeå University (WCMM)
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