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Literature summary for 3.4.24.69 extracted from

  • Montal, M.
    Botulinum neurotoxin: a marvel of protein design (2010), Annu. Rev. Biochem., 79, 591-617.
    View publication on PubMed
Search for more literature for 3.4.24.69

Crystallization (Commentary)

Crystallization (Comment) Organism
sructures of BoNT/A, BoNT/B, and BoNT/E holotoxins Clostridium botulinum

Metals/Ions

Metals/Ions Comment Organism Structure
Zn2+ the zinc ion in the active site is purely catalytic, the light chain module is a Zn2+-metalloprotease with a thermolysin-like fold Clostridium botulinum

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
cytosolic SNARE + H2O Clostridium botulinum host cytosolic SNARE, i.e. soluble NSF attachment protein receptor, a central helical protein-conducting channel, which chaperones the protease across host endosomes, modelling, overview. Sequence-specific claveage by the endoprotease activity of the BoNT light chains ?
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 ?
membrane-anchored SNARE + H2O Clostridium botulinum host membrane-anchored SNARE, proteolytically cleaved by BoNT/C ?
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 ?
additional information Clostridium botulinum BoNTs exert their neurotoxic effect by a multistep mechanism: binding, internalization, membrane translocation, intracellular traffic, and proteolytic degradation of target. The protein receptors are SV2 for BoNT/A, BoNT/E, and BoNT/F, and synaptotagmin I and II for BoNT/B and BoNT/G. BoNTs enter sensitive host cells via receptor-mediated endocytosis, detailed overview. The protease is chaperoned across host endosomes, DELTApH of early endosomes is finely tuned to elicit drastic conformational changes, leading to the insertion of BoNT into the membrane, while it is auspiciously set to interrupt further processing in the harsh acidic conditions existent inside lysosomes. HC dictates the target cell specificity and, during cell binding and intracellular traffic, serves to chaperone the light chain and HN, which ensures that partial unfolding of the light chain is concomitant with HN channel formation, thereby promoting productive light chain translocation ?
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 ?
SNAP-25 + H2O Clostridium botulinum i.e. synaptosome-associated protein of 25 kDa, a plasma membrane-associated protein, proteolytically cleaved by BoNT types A, C, and E ?
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 ?
synaptobrevin + H2O Clostridium botulinum a vesicle-associated membrane protein, also known as VAMP, the most abundant SV entity, proteolytically cleaved by BoNT types B, D, F, and G ?
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 ?
Syntaxin + H2O Clostridium botulinum proteolytically cleaved by BoNT/C ?
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 ?

Organism

Organism UniProt Comment Textmining
Clostridium botulinum
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 seven serologically distinct BoNT isoforms A-G
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Posttranslational Modification

Posttranslational Modification Comment Organism
proteolytic modification the inactive precursor protein is cleaved either by clostridial or tissue proteases into a 50-kDa light chain and a 100 kDa heavy chain linked by an essential interchain disulfide bridge and by the belt, a loop from the heavy chain that wraps around the light chain. Intracellular processing of the toxin, importance of unfolding for efficient translocation, detailed overview Clostridium botulinum

Source Tissue

Source Tissue Comment Organism Textmining
additional information BoNTs enter sensitive host cells via receptor-mediated endocytosis. Exposure of the BoNT-receptor complex to the acidic milieu of endosomes induces a conformational change, leading to the insertion of the HC into the endosomal membrane, thereby forming a transmembrane protein-conducting channel that translocates the light chain to the cytosol where it acts. Disulfide reduction prior to translocation dissociates the light chain from the heavy chain, thereby generating a channel devoid of translocation activity, the channel-forming entity is confined to HN, overview Clostridium botulinum
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Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
cytosolic SNARE + H2O host cytosolic SNARE, i.e. soluble NSF attachment protein receptor, a central helical protein-conducting channel, which chaperones the protease across host endosomes, modelling, overview. Sequence-specific claveage by the endoprotease activity of the BoNT light chains Clostridium botulinum ?
-
 ?
cytosolic SNARE + H2O host cytosolic SNARE, i.e. soluble NSF attachment protein receptor, a central helical protein-conducting channel, which chaperones the protease across host endosomes, modelling, overview. Sequence-specific claveage by the endosprotease activity of the BoNT light chains. Enzyme-substrate complex, overview Clostridium botulinum ?
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 ?
membrane-anchored SNARE + H2O host membrane-anchored SNARE, proteolytically cleaved by BoNT/C Clostridium botulinum ?
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 ?
additional information BoNTs exert their neurotoxic effect by a multistep mechanism: binding, internalization, membrane translocation, intracellular traffic, and proteolytic degradation of target. The protein receptors are SV2 for BoNT/A, BoNT/E, and BoNT/F, and synaptotagmin I and II for BoNT/B and BoNT/G. BoNTs enter sensitive host cells via receptor-mediated endocytosis, detailed overview. The protease is chaperoned across host endosomes, DELTApH of early endosomes is finely tuned to elicit drastic conformational changes, leading to the insertion of BoNT into the membrane, while it is auspiciously set to interrupt further processing in the harsh acidic conditions existent inside lysosomes. HC dictates the target cell specificity and, during cell binding and intracellular traffic, serves to chaperone the light chain and HN, which ensures that partial unfolding of the light chain is concomitant with HN channel formation, thereby promoting productive light chain translocation Clostridium botulinum ?
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 ?
additional information enzyme-substrate complex, detailed overview. BoNT/C is unique among the BoNTs, in that it cleaves both SNAP-25 and syntaxin, another plasma membrane-anchored SNARE Clostridium botulinum ?
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 ?
SNAP-25 + H2O i.e. synaptosome-associated protein of 25 kDa, a plasma membrane-associated protein, proteolytically cleaved by BoNT types A, C, and E Clostridium botulinum ?
-
 ?
synaptobrevin + H2O a vesicle-associated membrane protein, also known as VAMP, the most abundant SV entity, proteolytically cleaved by BoNT types B, D, F, and G Clostridium botulinum ?
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 ?
Syntaxin + H2O proteolytically cleaved by BoNT/C Clostridium botulinum ?
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 ?

Subunits

Subunits Comment Organism
More BoNT is a modular enzyme of trimodular protein architecture with an N-terminal Zn2+-metalloprotease, which cleaves the SNARE substrate and chaperones the protease across endosomes, and a C-terminal receptor binding module, consisting of two subdomains that determine target specificity by binding to a ganglioside and a protein receptor on the cell surface and triggering endocytosis, overview. The activated mature toxin consists of the three modules: the N-terminal LC Zn2+-metalloprotease, the heavy chain that encompasses the N-terminal translocation domain HN, and the C-terminal receptor-binding domain HC. The latter comprises two subdomains, a beta-sheet jelly roll fold, denoted HCN, and a beta-tree foil fold carboxy subdomain, known as HCC, structure, overview Clostridium botulinum

Synonyms

Synonyms Comment Organism
Botulinum neurotoxin
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 Clostridium botulinum

pH Stability

pH Stability pH Stability Maximum Comment Organism
5.5
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 the BoNT complex and its components precipitate below pH 5.5, overview Clostridium botulinum

General Information

General Information Comment Organism
malfunction BoNT proteases are blockers of synaptic transmission in host peripheral cholinergic nervous system synapses, they disable host synaptic vesicle exocytosis by cleaving their cytosolic SNARE, i.e. soluble NSF attachment protein receptor, substrates through cleavage by its N-terminal Zn2+-metalloprotease activity, and are the causative agent of botulism and the most poisonous protein known. Presence of BoNT heavy chain in endosomes or the light chain in the cytosol during intoxication may disrupt the host regulatory networks involved in neuronal protein homeostasis and may trigger a stress response comparable to the endoplasmic reticulum unfolded protein response Clostridium botulinum