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Details on Person UniProt:Q00496 botE
| Class:Id | ReferenceGeneProduct:181453 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Fri February 6 2015;chain:2-422 added on Fri February 6 2015;chain:423-1251 added on Fri February 6 2015;initiator methionine:1 for 181453 removed on Fri Nov 03 2023;initiator methionine: for 181453 added on Fri Nov 03 2023;initiator methionine: for 181453 removed on Fri Aug 15 2025;initiator methionine:1 for 181453 added on Fri Aug 15 2025 |
| _displayName | UniProt:Q00496 botE |
| _timestamp | 2025-08-15 21:21:12 |
| chain | initiator methionine:1 chain:2-1251 chain:2-422 chain:423-1251 |
| checksum | B05AA65FF1B30362 |
| comment | FUNCTION 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).FUNCTION 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).FUNCTION 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:19476346, PubMed:19650874). 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).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:1429690, PubMed:15157097, PubMed:15938619, PubMed:19118561).ACTIVITY REGULATION Proteolysis of SNAP25 by whole toxin inhibited by dipicolinic acid, 1,10-phenanthroline and EDTA (PubMed:8294407).BIOPHYSICOCHEMICAL PROPERTIES kcat is 257 min(-1) with botulinum neurotoxin E light chain.SUBUNIT Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC); cleavage occurs after bacterial export by host proteases (PubMed:19118561, PubMed:4030755, PubMed:6353669). 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).SUBCELLULAR LOCATION At pH 4.4 in the presence of ganglioside GT1b, becomes a membrane-associated hydrophobic protein (PubMed:22720883).SUBCELLULAR LOCATION Has protease activity (PubMed:8243676, PubMed:8294407, PubMed:9886085).DOMAIN 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:19476346, PubMed:19650874).BIOTECHNOLOGY Double mutants Gln-213/Gln-336 or Gln-213/Ala-351 might be suitable as vaccine candiates (PubMed:15938619).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 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).MISCELLANEOUS 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:19118561, PubMed:4030755, PubMed:6353669, PubMed:8294407).SIMILARITY Belongs to the peptidase M27 family. |
| created | [InstanceEdit:181561] Gopinathrao, G, 2006-06-14 16:40:11 |
| description | recommendedName: Botulinum neurotoxin type E shortName evidence="21"BoNT/E alternativeName: Bontoxilysin-E component recommendedName: Botulinum neurotoxin E light chain shortName: LC ecNumber evidence="17"3.4.24.69 /component component recommendedName: Botulinum neurotoxin E heavy chain shortName: HC /component |
| geneName | botE |
| identifier | Q00496 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Direct protein sequencing Disulfide bond Host cell membrane Host cytoplasm Host cytoplasmic vesicle Host membrane Host synapse Hydrolase Lipid-binding Membrane Metal-binding Metalloprotease Neurotoxin Protease Secreted Toxin Transmembrane Virulence Zinc |
| modified | [InstanceEdit:392885] Kanapin, AA, 2009-03-09 12:07:18 [InstanceEdit:400710] Schmidt, EE, 2009-03-25 05:33:35 [InstanceEdit:423310] Kanapin, AA [InstanceEdit:435478] Kanapin, AA [InstanceEdit:435871] Kanapin, AA [InstanceEdit:447347] Kanapin, AA [InstanceEdit:525883] Kanapin, AA [InstanceEdit:613449] Kanapin, AA [InstanceEdit:797602] Kanapin, AA [InstanceEdit:937368] Yung, CK [InstanceEdit:1042053] Yung, CK [InstanceEdit:1220657] Yung, CK [InstanceEdit:1300696] Yung, CK [InstanceEdit:1301627] Yung, CK [InstanceEdit:1551960] Weiser, JD [InstanceEdit:1995863] Weiser, JD [InstanceEdit:2132304] Weiser, JD [InstanceEdit:2265580] Weiser, JD [InstanceEdit:5634237] Weiser, JD [InstanceEdit:5673015] Weiser, JD [InstanceEdit:5691543] Weiser, JD [InstanceEdit:6791590] Weiser, JD [InstanceEdit:6807888] Weiser, JD [InstanceEdit:8856987] Weiser, JD [InstanceEdit:8869714] Weiser, JD [InstanceEdit:8934940] Weiser, JD [InstanceEdit:8944791] Weiser, JD [InstanceEdit:8964659] Weiser, JD [InstanceEdit:9037114] Weiser, JD [InstanceEdit:9616384] Weiser, JD [InstanceEdit:9627708] Weiser, JD [InstanceEdit:9637257] Weiser, JD [InstanceEdit:9676415] Weiser, JD [InstanceEdit:9730071] Weiser, JD [InstanceEdit:9796772] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | botE |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| secondaryIdentifier | BXE_CLOBO Q45862 |
| sequenceLength | 1251 |
| species | [Species:168825] Clostridium botulinum |
| (referenceEntity) | [EntityWithAccessionedSequence:181464] BoNT Type E precursor protein [extracellular region] [Clostridium botulinum] [EntityWithAccessionedSequence:181476] botE LC disulfide bonded [plasma membrane] [Clostridium botulinum] [EntityWithAccessionedSequence:181503] botE LC disulfide bonded [synaptic vesicle membrane] [Clostridium botulinum] [EntityWithAccessionedSequence:181528] botE LC disulfide bonded [extracellular region] [Clostridium botulinum] [EntityWithAccessionedSequence:181554] BoNT Heavy Chain (Type E) with inserted N-terminal [extracellular region] [Clostridium botulinum] [EntityWithAccessionedSequence:181571] botE HC disulfide bonded [plasma membrane] [Clostridium botulinum] [EntityWithAccessionedSequence:181574] botE HC disulfide bonded [extracellular region] [Clostridium botulinum] [EntityWithAccessionedSequence:181575] botE HC disulfide bonded [synaptic vesicle membrane] [Clostridium botulinum] [EntityWithAccessionedSequence:181579] botE LC [cytosol] [Clostridium botulinum] [EntityWithAccessionedSequence:5228952] botE HC [synaptic vesicle membrane] [Clostridium botulinum] |
| (referenceSequence) | [InterChainCrosslinkedResidue:5228672] Inter-chain Crosslink via L-cystine (cross-link) at 426 and 412 [InterChainCrosslinkedResidue:5228675] Inter-chain Crosslink via L-cystine (cross-link) at 412 and 426 |
| (secondReferenceSequence) | [InterChainCrosslinkedResidue:5228672] Inter-chain Crosslink via L-cystine (cross-link) at 426 and 412 [InterChainCrosslinkedResidue:5228675] Inter-chain Crosslink via L-cystine (cross-link) at 412 and 426 |
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No pathways have been reviewed or authored by UniProt:Q00496 botE (181453)
