Widespread Sequence Variations in VAMP1 across Vertebrates Suggest a Potential Selective Pressure from Botulinum Neurotoxins

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Botulinum neurotoxins (BoNTs) target peripheral motor neurons and act by cleaving SNARE proteins, which are essential for neurotransmitter release from nerve terminals. SNARE proteins occur in multiple homologues and it has been difficult to determine which one is the physiologically relevant toxin target in motor nerve terminals among closely related SNARE homologues such as VAMP1 and VAMP2. Here we report that, in contrast to the highly conserved VAMP2, sequence variations in VAMP1 that confer resistance to BoNTs are widespread across vertebrates. In particular, residue 48 of VAMP1 is polymorphic between BoNT/D-sensitive residue M and BoNT/D-resistant residue I in rats. Taking advantage of this finding, we carried out an intra-species comparison, which showed that diaphragm motor nerve terminals from rats with I48 in VAMP1 were insensitive to BoNT/D as compared to those with M48. Since VAMP2 is conserved in rats, these data demonstrate that VAMP1 is the physiologically relevant toxin target in motor neurons. Interestingly, human VAMP1 encodes the BoNT/D-resistant residue I48, which may explain why humans are insensitive to BoNT/D. Finally, we found that residue 48 of VAMP1 switches frequently between M and I among 17 primate species, suggesting a potential selective pressure from BoNT/D for resistance in primates.

Vyšlo v časopise: Widespread Sequence Variations in VAMP1 across Vertebrates Suggest a Potential Selective Pressure from Botulinum Neurotoxins. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004177
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004177

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