Botulinum toxin causes flaccid paralysis by inhibiting neurotransmitter (acetylcholine) release from the presynaptic membranes of nerve terminals of eukaryotic host skeletal and autonomic nervous system, with frequent heart or respiratory failure. Precursor of botulinum neurotoxin E which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins found in synaptic vesicles. Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them (PubMed:19476346, PubMed:19650874). 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 (PubMed:22720883). 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). Electrical stimulation increases uptake of toxin, probably by transiently exposing a receptor found in eukaryotic target synaptic vesicles (PubMed:19476346, PubMed:19650874). Uses the large lumenal domain of synaptic vesicle glycoproteins 2A and 2B (SV2A and SV2B) but not SV2C as receptor; an N-linked glycan of SV2 is essential for receptor function (PubMed:18815274, PubMed:19476346). Host cell gangliosides are also required for neurotoxin uptake and full toxicity (PubMed:18815274, PubMed:19650874). BoNT/E is a 'coincidence detector'; it requires simultaneous binding to coreceptor GT1b and low pH to transform into a membrane-bound, oligomeric channel (PubMed:22720883). Requires trypsinization and reduction before it can be used in assays in vitro (PubMed:8294407). Has proteolytic activity (PubMed:8243676, PubMed:8294407, PubMed:9886085). After translocation into the eukaryotic host cytosol, inhibits neurotransmitter release by acting as a zinc endopeptidase that catalyzes the hydrolysis of the '180-Arg-|-Ile-181' bond in SNAP25 (PubMed:8243676, PubMed:8294407, PubMed:9886085). Hydrolyzes the '185-Arg-|-Ile-186' bond of mouse SNAP23, but not in human which has a different sequence (PubMed:9886085). Recognizes the '146-Met--Asp-186' region of SNAP25 (PubMed:9886085). The reaction mechanism probably has a nucleophilic water held in place by Glu-213 (PubMed:15157097, PubMed:15938619). Reduction of the interchain disulfide bond occurs in the host cytosol and probably prevents retrotranslocation into the synaptic vesicle (PubMed:17666397). Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into host cytosol (PubMed:17666397). Composed of 3 subdomains; the translocation domain (TD), and N-terminus and C-terminus of the receptor-binding domain (RBD). The RBD is responsible for the adherence of the toxin to the cell surface (PubMed:10413679). It probably simultaneously recognizes 2 coreceptors; polysialated gangliosides and either of the receptor proteins SV2A and SV2B in close proximity on host synaptic vesicles (PubMed:18815274, PubMed:19650874, PubMed:19476346). The N-terminus of the TD wraps an extended belt around the perimeter of the light chain (LC), protecting Zn(2+) in the active site (PubMed:19118561). The belt may also prevent premature LC dissociation from the translocation channel and protect toxin prior to translocation (PubMed:17907800). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (By similarity). Responsible for adherence of the toxin to the cell surface; HC alone prevents uptake of whole toxin by neural cells, and delays paralysis onset by 154% (PubMed:10413679). Significantly decreases uptake and toxicity of whole BoNT/E, but also interferes with uptake of BoNT/C; binds GT1b in vitro (PubMed:19650874). Binds to synaptic vesicle glycoproteins SV2A and SV2B which serve as coreceptors with gangliosides (PubMed:18815274, PubMed:19650874). Interaction with SV2 proteins requires SV2 glycosylation (PubMed:19476346). HC alone significantly decreases uptake and toxicity of whole BoNT/E (PubMed:19650874). HC is responsible for translocation of LC into the host cytosol; an intact disulfide bond between the 2 subunits is required for translocation, which is reduced upon contact with the host cytosol (PubMed:17666397). Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on small molecule substrates. Binds 1 zinc ion per subunit (PubMed:1429690, PubMed:15157097, PubMed:15938619, PubMed:19118561). Proteolysis of SNAP25 by whole toxin inhibited by dipicolinic acid, 1,10-phenanthroline and EDTA (PubMed:8294407). kcat is 257 min (-1) with botulinum neurotoxin E light chain. Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC); cleavage occurs after bacterial export by host proteases (PubMed:6353669, PubMed:4030755, PubMed:19118561). The LC has the proteolytic/pharmacological activity, while the N- and C-terminal of the HC mediate channel formation and toxin binding, respectively. Oligomerizes in the presence of coreceptor ganglioside GT1b between pH 4.4 and 8.0; it might oligomerize on host cell surface (PubMed:22720883). Interacts with host synaptic vesicle glycoproteins SV2A and SV2B (PubMed:18815274, PubMed:19650874). HC interacts with a complex including at least host SV2 and synaptotagmin-1 (SYT1); copurification depends on glycosylation of SV2 (PubMed:19476346). At pH 4.4 in the presence of ganglioside GT1b, becomes a membrane-associated hydrophobic protein (PubMed:22720883). Has protease activity (PubMed:8243676, PubMed:8294407, PubMed:9886085). Has 3 functional domains; the translocation domain (TD) and the receptor-binding domain (RBD) which is further subdivided into N- and C-terminal domains (N-RBD and C-RBD) (PubMed:19118561). In BoNT/E the domains are arranged differently than BoNT/A and BoNT/B; in BoNT/E the LC and RBD are on the same side of the TD and are in contact, whereas in BoNT/A and BoNT/B the LC is separated from the RBD by the TD (PubMed:19118561). The putative transmembrane region is closer to the receptor-binding regions in this toxin, which may explain why it acts faster than BoNT/A and BoNT/B (PubMed:19118561). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, partially protecting Zn(2+) in the active site (PubMed:19118561). The belt may be a pseudosubstrate inhibitor which serves as an intramolecular chaperone for the LC prior to its translocation into the host cytosol (PubMed:17907800). The RBD binds transiently exposed coreceptors on the host presynaptic cell membrane (PubMed:18815274, PubMed:19650874, PubMed:19476346). Double mutants Gln-213/Gln-336 or Gln-213/Ala-351 might be suitable as vaccine candiates (PubMed:15938619). There are seven antigenically distinct forms of botulinum neurotoxin: Types A, B, C, D, E, F, and G; new subtypes are quite frequent. 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. Types A, B and E are the most frequent cause of adult human foodborne botulism; type A is the most severe, while type E has the shortest incubation period (PubMed:1431246). Unlike botulinum neurotoxin type A, type E is released from bacteria as a single chain and cleaved by host proteases into the active dichain (PubMed:6353669, PubMed:4030755, PubMed:19118561, PubMed:8294407). Belongs to the peptidase M27 family.