The Dual-Receptor Recognition of Botulinum Neurotoxins

Abstract

The neurospecificity of the botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) is one important reason for their extraordinarily high toxicity. This neurospecific binding is mediated by the interaction with two receptor components. All BoNTs and TeNT bind first to complex polysialo-gangliosides abundantly present on the outer leaflet of neuronal membranes. The ganglioside binding occurs in BoNT/A, B, E, F, G and TeNT via a conserved ganglioside-binding pocket within the most carboxyl-terminal 25-kDa domain HCC, whereas BoNT/C and D display two different ganglioside-binding sites within this HCC domain. Subsequently, upon exocytosis, the intraluminal domains of synaptic vesicle proteins are exposed and can be accessed by the surface-accumulated neurotoxins. BoNT/B, DC and G bind with their HCC domain to a 15–17mer membrane-juxtaposed segment of the intraluminal domain of synaptotagmin-I and synaptotagmin-II, respectively. In contrast, the HC fragment of BoNT/A and E interacts via an extensive surface with the intraluminal domain 4 of the synaptic vesicle glycoprotein 2 (SV2). Whereas BoNT/A interacts with all three SV2 isoforms, BoNT/E only binds SV2A and SV2B. Also, BoNT/D, F and TeNT are supposed to employ SV2 for neurospecific uptake although a direct interaction has to be demonstrated. Thereafter, the synaptic vesicle is recycled and the bound neurotoxin is endocytosed. Acidification of the vesicle lumen triggers membrane insertion of the translocation domain while the protein receptor binding is maintained, pore formation and, finally, translocation of the enzymatically active light chain.