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FUNCTION Botulinum toxin causes flaccid paralysis by inhibiting neurotransmitter (acetylcholine) release from the presynaptic membranes of nerve terminals of the eukaryotic host skeletal and autonomic nervous system, with frequent heart or respiratory failure (PubMed:15123599). Precursor of botulinum neurotoxin G which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins found in synaptic vesicles (PubMed:15123599). Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them. Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway. When the pH of the toxin-containing endosome drops a structural rearrangement occurs so that the N-terminus of the HC forms pores that allows the light chain (LC) to translocate into the cytosol. Once in the cytosol the disulfide bond linking the 2 subunits is reduced and LC cleaves its target protein on synaptic vesicles, preventing their fusion with the cytoplasmic membrane and thus neurotransmitter release (By similarity). Binds to host peripheral neuronal presynaptic membranes via synaptotagmins 1 and 2 (SYT1 and SYT2) (PubMed:15123599). Toxin binds to the membrane proximal extra-cytoplasmic region of SYT1 and SYT2 that is transiently exposed outside of cells during exocytosis; exogenous gangliosides do not enhance binding and subsequent uptake of toxin into host cells (PubMed:15123599). Toxin activity can be blocked by the appropriate synaptotagmin protein fragments in cell culture (PubMed:15123599).FUNCTION Has proteolytic activity. After translocation into the eukaryotic host cytosol acts as a zinc endopeptidase that cleaves synaptobrevins-1, -2 and -3 (also called VAMP1, VAMP2 and VAMP3) (PubMed:7910017). Hydrolyzes the '81-Ala-|-Ala-82' bond of VAMP2, and probably also the equivalent 'Ala-|-Ala' sites in VAMP1 and VAMP3 (PubMed:7910017). Has low activity on A.californica synaptobrevin and none on D.melanogaster synaptobrevin or cellubrevin, have a slightly different sequence (PubMed:7910017).FUNCTION Responsible for host cell targeting and translocation of light chain (LC) into host cytosol. Composed of 3 subdomains; the translocation domain (TD), and N-terminus and C-terminus of the receptor-binding domain (N-RBD, C-RBD). The RBD is responsible for the adherence of the toxin to the cell surface. It simultaneously recognizes 2 coreceptors; polysialated gangliosides and the receptor proteins SYT1 and SYT2 in close proximity on host synaptic vesicles (PubMed:17185412). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site; it may also prevent premature LC dissociation from the translocation channel and protect toxin prior to translocation (By similarity). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (By similarity). Has 2 coreceptors; complex gangliosides found primarily on neural tissue and host synaptotagmin-1 and -2 (SYT1 and SYT2) which bind to separate sites at the tip of the HC (PubMed:17185412). HC alone binds to host receptors SYT1 and SYT2; C-RBD interacts with host SYT2 (PubMed:15123599). Has equal affinity for SYT1 and SYT2; gangliosides are not required for (or only very slightly improve) binding to a membrane-anchored receptor fragment (PubMed:17185412, PubMed:20219474). Has also been shown to only bind SYT1; the assay methods were different (PubMed:20507178). Binds ganglioside GT1b (PubMed:20507178). Significantly decreases uptake and toxicity of whole BoNT/B and BoNT/G (PubMed:19650874).CATALYTIC ACTIVITY Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on small molecule substrates.COFACTOR Binds 1 zinc ion per subunit (PubMed:16008342).SUBUNIT Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC). The LC has the proteolytic/pharmacological activity, while the N- and C-termini of the HC mediate channel formation and toxin binding, respectively. Interacts with host receptors synaptotagmin-1 and -2 (SYT1 and SYT2) (PubMed:15123599, PubMed:17185412, PubMed:20219474).SUBCELLULAR LOCATION Has protease activity (PubMed:7910017).DOMAIN Has 3 functional domains. The translocation domain (TD) which probably forms membrane channels to allow light chain (LC) into the host cytosol (Probable). The C-terminal receptor-binding domain (RBD) has 2 further subdomains, N-RBD (Hcn) and C-RBD (Hcc) (PubMed:20219474, PubMed:20507178). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site and may be a pseudosubstrate inhibitor which serves as an intramolecular chaperone for the LC prior to its translocation into the host cytosol (By similarity). The RBD binds transiently exposed coreceptors on the host presynaptic cell membrane (Probable).MISCELLANEOUS There are seven antigenically distinct forms of botulinum neurotoxin: Types A, B, C, D, E, F, and G; new subtypes are quite frequent.MISCELLANEOUS Botulism poisoning is usually food-borne, either by ingesting toxin or bacterial-contaminated food, or less frequently by inhalation poisoning. In both cases the neurotoxin binds to the apical surface of epithelial cells in the gut or airway. Toxin undergoes receptor-mediated endocytosis (using a different receptor than on target nerve cells), transcytosis across the epithelial cells and release into the general circulation. Once in the general circulation it binds to its target cells.MISCELLANEOUS Type G toxin has been isolated from soil samples and human autopsy specimens but has not been clearly implicated as the cause of human paralytic illness or death (Ref.4). Strain 89 was isolated from soil in Mendoza province, Argentiana (PubMed:4922309). Administration of strain 89 toxin to mouse, chicken, guinea pig and rhesus monkeys causes botulism symptoms and in most cases death, while dog and sheep show no signs of botulism (PubMed:74236). In the original report 5-fold higher levels of toxin caused botulism and death in sheep (PubMed:4922309).MISCELLANEOUS Trypsinization of purified toxin increases its toxicity, suggesting it is released as a single chain (PubMed:4922309, PubMed:74236).SIMILARITY Belongs to the peptidase M27 family.
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