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Abstract
Botulinum neurotoxins (BoNTs) typically bind the neuronal cell surface via dual interactions
with both protein receptors and gangliosides. We present here the 1.9-A X-ray structure
of the BoNT serotype G (BoNT/G) receptor binding domain (residues 868-1297) and a
detailed view of protein receptor and ganglioside binding regions. The ganglioside
binding motif (SxWY) has a conserved structure compared to the corresponding regions
in BoNT serotype A and BoNT serotype B (BoNT/B), but several features of interactions
with the hydrophilic face of the ganglioside are absent at the opposite side of the
motif in the BoNT/G ganglioside binding cleft. This may significantly reduce the affinity
between BoNT/G and gangliosides. BoNT/G and BoNT/B share the protein receptor synaptotagmin
(Syt) I/II. The Syt binding site has a conserved hydrophobic plateau located centrally
in the proposed protein receptor binding interface (Tyr1189, Phe1202, Ala1204, Pro1205,
and Phe1212). Interestingly, only 5 of 14 residues that are important for binding
between Syt-II and BoNT/B are conserved in BoNT/G, suggesting that the means by which
BoNT/G and BoNT/B bind Syt diverges more than previously appreciated. Indeed, substitution
of Syt-II Phe47 and Phe55 with alanine residues had little effect on the binding of
BoNT/G, but strongly reduced the binding of BoNT/B. Furthermore, an extended solvent-exposed
hydrophobic loop, located between the Syt binding site and the ganglioside binding
cleft, may serve as a third membrane association and binding element to contribute
to high-affinity binding to the neuronal membrane. While BoNT/G and BoNT/B are homologous
to each other and both utilize Syt-I/Syt-II as their protein receptor, the precise
means by which these two toxin serotypes bind to Syt appears surprisingly divergent.
Copyright (c) 2010. Published by Elsevier Ltd.