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dc.contributor.authorPeng, Lishengen_US
dc.contributor.authorAdler, Michaelen_US
dc.contributor.authorDemogines, Annen_US
dc.contributor.authorBorrell, Andrewen_US
dc.contributor.authorLiu, Huishengen_US
dc.contributor.authorTao, Liangen_US
dc.contributor.authorTepp, William H.en_US
dc.contributor.authorZhang, Su-Chunen_US
dc.contributor.authorJohnson, Eric A.en_US
dc.contributor.authorSawyer, Sara L.en_US
dc.contributor.authorDong, Minen_US
dc.date.accessioned2014-08-13T13:59:39Z
dc.date.issued2014en_US
dc.identifier.citationPeng, L., M. Adler, A. Demogines, A. Borrell, H. Liu, L. Tao, W. H. Tepp, et al. 2014. “Widespread Sequence Variations in VAMP1 across Vertebrates Suggest a Potential Selective Pressure from Botulinum Neurotoxins.” PLoS Pathogens 10 (7): e1004177. doi:10.1371/journal.ppat.1004177. http://dx.doi.org/10.1371/journal.ppat.1004177.en
dc.identifier.issn1553-7366en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12717507
dc.description.abstractBotulinum neurotoxins (BoNT/A-G), the most potent toxins known, act by cleaving three SNARE proteins required for synaptic vesicle exocytosis. Previous studies on BoNTs have generally utilized the major SNARE homologues expressed in brain (VAMP2, syntaxin 1, and SNAP-25). However, BoNTs target peripheral motor neurons and cause death by paralyzing respiratory muscles such as the diaphragm. Here we report that VAMP1, but not VAMP2, is the SNARE homologue predominantly expressed in adult rodent diaphragm motor nerve terminals and in differentiated human motor neurons. In contrast to the highly conserved VAMP2, BoNT-resistant variations in VAMP1 are widespread across vertebrates. In particular, we identified a polymorphism at position 48 of VAMP1 in rats, which renders VAMP1 either resistant (I48) or sensitive (M48) to BoNT/D. Taking advantage of this finding, we showed that rat diaphragms with I48 in VAMP1 are insensitive to BoNT/D compared to rat diaphragms with M48 in VAMP1. This unique intra-species comparison establishes VAMP1 as a physiological toxin target in diaphragm motor nerve terminals, and demonstrates that the resistance of VAMP1 to BoNTs can underlie the insensitivity of a species to members of BoNTs. Consistently, human VAMP1 contains I48, which may explain why humans are insensitive to BoNT/D. Finally, we report that residue 48 of VAMP1 varies frequently between M and I across seventeen closely related primate species, suggesting a potential selective pressure from members of BoNTs for resistance in vertebrates.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.ppat.1004177en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092145/pdf/en
dash.licenseLAAen_US
dc.subjectBiology and Life Sciencesen
dc.subjectEvolutionary Biologyen
dc.subjectMicrobiologyen
dc.titleWidespread Sequence Variations in VAMP1 across Vertebrates Suggest a Potential Selective Pressure from Botulinum Neurotoxinsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS Pathogensen
dash.depositing.authorTao, Liangen_US
dc.date.available2014-08-13T13:59:39Z
dc.identifier.doi10.1371/journal.ppat.1004177*
dash.authorsorderedfalse
dash.contributor.affiliatedTao, Liang
dash.contributor.affiliatedDong, Min


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