title: Two Feet on the Membrane: Uptake of Clostridial Neurotoxins.
abstract: The extraordinary potency of botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT) is mediated by their high neurospecificity, targeting peripheral cholinergic motoneurons leading to flaccid and spastic paralysis, respectively, and successive respiratory failure. Complex polysialo gangliosides accumulate BoNT and TeNT on the plasma membrane. The ganglioside binding in BoNT/A, B, E, F, G, and TeNT occurs via a conserved ganglioside-binding pocket within the most carboxyl-terminal 25 kDa domain HCC, whereas BoNT/C, DC, and D display here two different ganglioside binding sites. This enrichment step facilitates subsequent binding of BoNT/A, B, DC, D, E, F, and G to the intraluminal domains of the synaptic vesicle glycoprotein 2 (SV2) isoforms A-C and synaptotagmin-I/-II, respectively. Whereas an induced α-helical 20-mer Syt peptide binds via side chain interactions to the tip of the HCCdomain of BoNT/B, DC and G, the preexisting, quadrilateral β-sheet helix of SV2C-LD4 binds the clinically most relevant serotype BoNT/A mainly through backbone-backbone interactions at the interface of HCCand HCN. In addition, the conserved, complex N559-glycan branch of SV2C establishes extensive interactions with BoNT/A resulting in delayed dissociation providing BoNT/A more time for endocytosis into synaptic vesicles. An analogous interaction occurs between SV2A/B and BoNT/E. Altogether, the nature of BoNT-SV2 recognition clearly differs from BoNT-Syt. Subsequently, the synaptic vesicle is recycled and the bound neurotoxin is endocytosed. Acidification of the vesicle lumen triggers membrane insertion of the translocation domain, pore formation, and finally translocation of the enzymatically active light chain into the neuronal cytosol to halt release of neurotransmitters.
authors.affiliation: Institut Für Toxikologie, Medizinische Hochschule Hannover, 30623, Hannover, Germany. rummel.andreas@mh-hannover.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rummel
mesh_terms: D001905:Botulinum Toxins / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding; D013572:Synaptic Vesicles / Q000378:metabolism; D013744:Tetanus Toxin / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D013744:Tetanus Toxin; D001905:Botulinum Toxins