title: Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity.
abstract: The high potency of the botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT) is mainly due to their neurospecific binding which is mediated by the interaction with two receptor components. TeNT and all BoNT 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 and G via a conserved ganglioside binding pocket within the most carboxyl-terminal 25 kDa domain H(CC) whereas TeNT, BoNT/C and D display two different ganglioside binding sites within their H(CC)-domain. Subsequently, upon exocytosis the intraluminal domains of synaptic vesicle proteins are exposed and can be accessed by the surface accumulated neurotoxins. BoNT/B and G bind with their H(CC)-domain to a 20-mer membrane juxtaposed segment of the intraluminal domain of synaptotagmin-I and -II, respectively. BoNT/A and E employ the intraluminal domain 4 of the synaptic vesicle glycoprotein 2 (SV2) as protein receptor. Whereas the 50 kDa cell binding domain H(C) of BoNT/A interacts with all three SV2 isoforms, BoNT/E H(C) only binds SV2A and SV2B. Also, BoNT/D, F, and TeNT employ SV2 for binding and uptake. Thereafter, the synaptic vesicle is recycled and the anchored neurotoxin is endocytosed. Acidification of the vesicle lumen triggers membrane insertion of the translocation domain followed by pore formation and finally translocation of the enzymatically active light chain to its site of action leading to block of neurotransmitter release.
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: D000818:Animals; D001665:Binding Sites; D001905:Botulinum Toxins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003014:Clostridium botulinum / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009928:Organ Specificity; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D005732:Gangliosides; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C489615:Sv2b protein, mouse; C034993:ganglioside receptor; D001905:Botulinum Toxins