Botulinum neurotoxin D-C uses synaptotagmin I and II as receptors, and human synaptotagmin II is not an effective receptor for type B, D-C and G toxins
2012 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 125, no 13, 3233-3242 p.Article in journal (Refereed) Published
Botulinum neurotoxins (BoNTs) are classified into seven types (A-G), but multiple subtype and mosaic toxins exist. These subtype and mosaic toxins share a high sequence identity, and presumably the same receptors and substrates with their parental toxins. Here, we report that a mosaic toxin, type D-C (BoNT/D-C), uses different receptors from its parental toxin BoNT/C. BoNT/D-C, but not BoNT/C, binds directly to the luminal domains of synaptic vesicle proteins synaptotagmin (Syt) I and II, and requires expression of SytI/II to enter neurons. The SytII luminal fragment containing the toxin-binding site can block the entry of BoNT/D-C into neurons and reduce its toxicity in vivo in mice. We also found that gangliosides increase binding of BoNT/D-C to SytI/II and enhance the ability of the SytII luminal fragment to block BoNT/D-C entry into neurons. These data establish SytI/II, in conjunction with gangliosides, as the receptors for BoNT/D-C, and indicate that BoNT/D-C is functionally distinct from BoNT/C. We further found that BoNT/D-C recognizes the same binding site on SytI/II where BoNT/B and G also bind, but utilizes a receptor-binding interface that is distinct from BoNT/B and G. Finally, we also report that human and chimpanzee SytII has diminished binding and function as the receptor for BoNT/B, D-C and G owing to a single residue change from rodent SytII within the toxin binding site, potentially reducing the potency of these BoNTs in humans and chimpanzees.
Place, publisher, year, edition, pages
2012. Vol. 125, no 13, 3233-3242 p.
Botulinum neurotoxin, Botulinum neurotoxin B, Botulinum toxin, Botulism, Synaptotagmin
Cell Biology Biochemistry and Molecular Biology
Research subject Biochemistry; Cell Biology
IdentifiersURN: urn:nbn:se:su:diva-81806DOI: 10.1242/jcs.103564ISI: 000308417300022OAI: oai:DiVA.org:su-81806DiVA: diva2:567479
FunderSwedish Foundation for Strategic Research , ICA08-0001Swedish Research Council, 2010–5200The Wenner-Gren Foundation