Neurotoxicity of clostridium toxins (Homo sapiens)

From WikiPathways

Revision as of 08:07, 17 July 2014 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
7, 106, 10, 198, 9, 11, 153, 4, 14, 168, 9, 11, 15173, 4, 14, 1655, 12, 203, 4, 14, 16148, 9, 11, 151, 2, 13, 18BoNT Light chainType C1 [cytosol]BoNT Light chainType D [cytosol]BoNT Light chainType A [cytosol]endocytic vesicleBoNT Light chainType E [cytosol]cytosolBoNT Light chainType F [cytosol]BoNT Light chainType B [cytosol]BoNT Light chainType ABoNT Light chainType BZn2+ [cytosol]BoNT F cleavedVAMP/SynaptobrevinZn2+ [cytosol]SNAP25VAMP2Zn2+ [cytosol]VAMP2(1-76)BoNT Light chainType C1BoNT withconformationalchange in Heavychain N-terminalBoNT Light chainType DBoNT Light chainType E polypeptide[cytosol]BoNT Light chainType Finternalized BoNTBoNT Light chainType C1 polypeptide[cytosol]BoNT Light chainType F polypeptide[cytosol]BoNT Light chainType EBoNT Light chainTypes A,C and EVAMP/SynaptobrevinZn2+ [cytosol]BoNT with Heavychain N-terminalinserted intoendosomal membraneSNAP25(1-197)Syntaxin fragmentSNAP25Activated BoNTBoNT Light chainType B polypeptide[cytosol]BoNT D cleavedVAMP/SynaptobrevinBoNT Light chainTypes B,D,F,GSyntaxinsBoNT Light chainType C1 polypeptideGangliosides:SynaptotagminZn2+ [cytosol]SNAP25(1-180)Zn2+ [cytosol]Gangliosides:SynaptogaminBoNT bound tomembrane receptorBoNT Light chainType D polypeptide[cytosol]BoNT Light chainType A polypeptide[cytosol]


Botulism, caused by botulinum neurotoxin (BoNT), is characterized by descending flaccid paralysis as a result of inhibition of neurotransmitter release at the neuromuscular junction - NMJ (Turton et al., 2002). According to their antigenic properties, BoNTs are classified into seven different toxin types (A, B, C1, D, E, F and G) although more than 50 sequences encoding 18 subtypes are known (Smith et al., 2005). The toxin is released as a 900 kDa complex containing some accessory proteins of unknown functions (Chen et al., 1998). The toxin types A, B and E are mainly involved in human botulism whereas C and D predominantly cause animal botulism (Poulain et al, 2006). The toxin is absorbed from the gut or other epithelium and reaches neuromuscular junctions by transcytosis (Park and Simpson, 2003). The binding sites for the toxins are distributed across the apical surface of the epithelium (Ahsan et al., 2005). It has been observed that the neurotoxin alone is capable of transcytosis across epithelial cells (Maksymowych and Simpson, 2004). Once internalized, the neurotoxin is dissociated from the non-toxic components of the progenitor toxin in endosome (Uotsu et al., 2006).
The neurological inhibition is caused by the specific cleavage of a group of proteins integral to NMJ exocytosis, SNARE proteins (soluble NSF-attachment protein receptors). One or more SNARE proteins are cleaved by BoNT, blocking the release of synaptic vesicular contents like acetylcholine as in the case of motor neurons.
BoNTs are synthesized as polypeptides of 150 kDa that are cleaved into heavy and light chains linked by a single disulfide bond. Cleavage takes place within a surface-exposed loop at the N-terminal of the Heavy chain subunit. Both bacterial and host endopeptidases can catalyze BoNT cleavage into heavy and light chains, but bacterial enzymes are thought to carry out this function in vivo.The Heavy Chain (HC) has two 50 kDa functional domains: the N-terminal translocation domain is capable of forming channels in lipid bilayers; the C-terminal ganglioside-binding domain is important for membrane binding and subsequent internalization of toxins by host neurons. The 50 kDa Light chain (LC) is a zinc-dependent endopeptidase specific for core components of neurotransmitter release complexes.
BoNT action proceeds in the following steps: binding of cleaved toxin to the target cell membrane; transcytosis from epithelial membrane to target neuromuscular junction cells; release of BoNT Light chain into the target cell cytosol; and proteolytic cleavage of target cell proteins catalyzed by the BoNT Light chain.
Original Pathway at Reactome:

Quality Tags

Ontology Terms



View all...
  1. Montal M.; ''Botulinum neurotoxin: a marvel of protein design.''; PubMed Europe PMC Scholia
  2. Dasgupta BR, Datta A.; ''Botulinum neurotoxin type B (strain 657): partial sequence and similarity with tetanus toxin.''; PubMed Europe PMC Scholia
  3. Giménez JA, DasGupta BR.; ''Botulinum neurotoxin type E fragmented with endoproteinase Lys-C reveals the site trypsin nicks and homology with tetanus neurotoxin.''; PubMed Europe PMC Scholia
  4. Foran P, Shone CC, Dolly JO.; ''Differences in the protease activities of tetanus and botulinum B toxins revealed by the cleavage of vesicle-associated membrane protein and various sized fragments.''; PubMed Europe PMC Scholia
  5. Schiavo G, Santucci A, Dasgupta BR, Mehta PP, Jontes J, Benfenati F, Wilson MC, Montecucco C.; ''Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds.''; PubMed Europe PMC Scholia
  6. Binz T, Blasi J, Yamasaki S, Baumeister A, Link E, Südhof TC, Jahn R, Niemann H.; ''Proteolysis of SNAP-25 by types E and A botulinal neurotoxins.''; PubMed Europe PMC Scholia
  7. Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz R, Chapman ER.; ''SV2 is the protein receptor for botulinum neurotoxin A.''; PubMed Europe PMC Scholia
  8. Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, Montecucco C.; ''Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin.''; PubMed Europe PMC Scholia
  9. Krieglstein K, Henschen A, Weller U, Habermann E.; ''Arrangement of disulfide bridges and positions of sulfhydryl groups in tetanus toxin.''; PubMed Europe PMC Scholia
  10. Rummel A, Häfner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, Binz T.; ''Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor.''; PubMed Europe PMC Scholia
  11. Hatheway CL.; ''Botulism: the present status of the disease.''; PubMed Europe PMC Scholia
  12. Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC.; ''Crystal structure of botulinum neurotoxin type A and implications for toxicity.''; PubMed Europe PMC Scholia
  13. Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, Montecucco C.; ''Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E.''; PubMed Europe PMC Scholia
  14. Yamasaki S, Binz T, Hayashi T, Szabo E, Yamasaki N, Eklund M, Jahn R, Niemann H.; ''Botulinum neurotoxin type G proteolyses the Ala81-Ala82 bond of rat synaptobrevin 2.''; PubMed Europe PMC Scholia
  15. Montecucco C, Schiavo G.; ''Mechanism of action of tetanus and botulinum neurotoxins.''; PubMed Europe PMC Scholia
  16. Lalli G, Bohnert S, Deinhardt K, Verastegui C, Schiavo G.; ''The journey of tetanus and botulinum neurotoxins in neurons.''; PubMed Europe PMC Scholia
  17. Link E, Edelmann L, Chou JH, Binz T, Yamasaki S, Eisel U, Baumert M, Südhof TC, Niemann H, Jahn R.; ''Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis.''; PubMed Europe PMC Scholia
  18. Karalewitz AP, Fu Z, Baldwin MR, Kim JJ, Barbieri JT.; ''Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry.''; PubMed Europe PMC Scholia
  19. Simpson LL.; ''Identification of the major steps in botulinum toxin action.''; PubMed Europe PMC Scholia
  20. Sun S, Suresh S, Liu H, Tepp WH, Johnson EA, Edwardson JM, Chapman ER.; ''Receptor binding enables botulinum neurotoxin B to sense low pH for translocation channel assembly.''; PubMed Europe PMC Scholia
  21. Barash JR, Arnon SS.; ''A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins.''; PubMed Europe PMC Scholia
  22. Chen C, Fu Z, Kim JJ, Barbieri JT, Baldwin MR.; ''Gangliosides as high affinity receptors for tetanus neurotoxin.''; PubMed Europe PMC Scholia
  23. Kumaran D, Eswaramoorthy S, Furey W, Navaza J, Sax M, Swaminathan S.; ''Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation.''; PubMed Europe PMC Scholia
  24. Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, Montecucco C.; ''Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc.''; PubMed Europe PMC Scholia
  25. Peng L, Tepp WH, Johnson EA, Dong M.; ''Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors.''; PubMed Europe PMC Scholia
  26. Dong M, Richards DA, Goodnough MC, Tepp WH, Johnson EA, Chapman ER.; ''Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells.''; PubMed Europe PMC Scholia
  27. Sun S, Tepp WH, Johnson EA, Chapman ER.; ''Botulinum neurotoxins B and E translocate at different rates and exhibit divergent responses to GT1b and low pH.''; PubMed Europe PMC Scholia
  28. Kroken AR, Karalewitz AP, Fu Z, Kim JJ, Barbieri JT.; ''Novel ganglioside-mediated entry of botulinum neurotoxin serotype D into neurons.''; PubMed Europe PMC Scholia
  29. Lee K, Gu S, Jin L, Le TT, Cheng LW, Strotmeier J, Kruel AM, Yao G, Perry K, Rummel A, Jin R.; ''Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity.''; PubMed Europe PMC Scholia
  30. Amatsu S, Sugawara Y, Matsumura T, Kitadokoro K, Fujinaga Y.; ''Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex.''; PubMed Europe PMC Scholia
  31. Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR.; ''Glycosylated SV2 and gangliosides as dual receptors for botulinum neurotoxin serotype F.''; PubMed Europe PMC Scholia
  32. Südhof TC, De Camilli P, Niemann H, Jahn R.; ''Membrane fusion machinery: insights from synaptic proteins.''; PubMed Europe PMC Scholia
  33. Mochida S, Poulain B, Weller U, Habermann E, Tauc L.; ''Light chain of tetanus toxin intracellularly inhibits acetylcholine release at neuro-neuronal synapses, and its internalization is mediated by heavy chain.''; PubMed Europe PMC Scholia
  34. Sakaguchi G.; ''Clostridium botulinum toxins.''; PubMed Europe PMC Scholia
  35. Swaminathan S, Eswaramoorthy S.; ''Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B.''; PubMed Europe PMC Scholia
  36. Arndt JW, Chai Q, Christian T, Stevens RC.; ''Structure of botulinum neurotoxin type D light chain at 1.65 A resolution: repercussions for VAMP-2 substrate specificity.''; PubMed Europe PMC Scholia
  37. Willjes G, Mahrhold S, Strotmeier J, Eichner T, Rummel A, Binz T.; ''Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: tyrosine 1186 and lysine 1191 cause its lower affinity.''; PubMed Europe PMC Scholia
  38. Blasi J, Chapman ER, Yamasaki S, Binz T, Niemann H, Jahn R.; ''Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin.''; PubMed Europe PMC Scholia
  39. Kozaki S, Kamata Y, Watarai S, Nishiki T, Mochida S.; ''Ganglioside GT1b as a complementary receptor component for Clostridium botulinum neurotoxins.''; PubMed Europe PMC Scholia
  40. Peng L, Berntsson RP, Tepp WH, Pitkin RM, Johnson EA, Stenmark P, Dong M.; ''Botulinum neurotoxin D-C uses synaptotagmin I and II as receptors, and human synaptotagmin II is not an effective receptor for type B, D-C and G toxins.''; PubMed Europe PMC Scholia
  41. Deinhardt K, Berninghausen O, Willison HJ, Hopkins CR, Schiavo G.; ''Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1.''; PubMed Europe PMC Scholia
  42. Schiavo G, Malizio C, Trimble WS, Polverino de Laureto P, Milan G, Sugiyama H, Johnson EA, Montecucco C.; ''Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond.''; PubMed Europe PMC Scholia
  43. Dong M, Liu H, Tepp WH, Johnson EA, Janz R, Chapman ER.; ''Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons.''; PubMed Europe PMC Scholia
  44. Agarwal R, Eswaramoorthy S, Kumaran D, Binz T, Swaminathan S.; ''Structural analysis of botulinum neurotoxin type E catalytic domain and its mutant Glu212-->Gln reveals the pivotal role of the Glu212 carboxylate in the catalytic pathway.''; PubMed Europe PMC Scholia
  45. Schmidt JJ, Sathyamoorthy V, DasGupta BR.; ''Partial amino acid sequence of the heavy and light chains of botulinum neurotoxin type A.''; PubMed Europe PMC Scholia
  46. Turton K, Chaddock JA, Acharya KR.; ''Botulinum and tetanus neurotoxins: structure, function and therapeutic utility.''; PubMed Europe PMC Scholia
  47. Koriazova LK, Montal M.; ''Translocation of botulinum neurotoxin light chain protease through the heavy chain channel.''; PubMed Europe PMC Scholia
  48. Vaidyanathan VV, Yoshino K, Jahnz M, Dörries C, Bade S, Nauenburg S, Niemann H, Binz T.; ''Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C, and E: domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage.''; PubMed Europe PMC Scholia
  49. Benefield DA, Dessain SK, Shine N, Ohi MD, Lacy DB.; ''Molecular assembly of botulinum neurotoxin progenitor complexes.''; PubMed Europe PMC Scholia
  50. Fujinaga Y, Sugawara Y, Matsumura T.; ''Uptake of botulinum neurotoxin in the intestine.''; PubMed Europe PMC Scholia
  51. Yamasaki S, Baumeister A, Binz T, Blasi J, Link E, Cornille F, Roques B, Fykse EM, Südhof TC, Jahn R.; ''Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin.''; PubMed Europe PMC Scholia
  52. Sathyamoorthy V, Dasgupta BR, Foley J, Niece RL.; ''Botulinum neurotoxin type A: cleavage of the heavy chain into two halves and their partial sequences.''; PubMed Europe PMC Scholia
  53. Henderson I, Whelan SM, Davis TO, Minton NP.; ''Genetic characterisation of the botulinum toxin complex of Clostridium botulinum strain NCTC 2916.''; PubMed Europe PMC Scholia
  54. Foran P, Lawrence GW, Shone CC, Foster KA, Dolly JO.; ''Botulinum neurotoxin C1 cleaves both syntaxin and SNAP-25 in intact and permeabilized chromaffin cells: correlation with its blockade of catecholamine release.''; PubMed Europe PMC Scholia
  55. Sudhof TC.; ''The synaptic vesicle cycle.''; PubMed Europe PMC Scholia


View all...
113137view11:20, 2 November 2020ReactomeTeamReactome version 74
112368view15:30, 9 October 2020ReactomeTeamReactome version 73
101270view11:16, 1 November 2018ReactomeTeamreactome version 66
100808view20:44, 31 October 2018ReactomeTeamreactome version 65
100349view19:21, 31 October 2018ReactomeTeamreactome version 64
99894view16:04, 31 October 2018ReactomeTeamreactome version 63
99451view14:38, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99115view12:40, 31 October 2018ReactomeTeamreactome version 62
93784view13:36, 16 August 2017ReactomeTeamreactome version 61
93317view11:20, 9 August 2017ReactomeTeamreactome version 61
87757view09:56, 25 July 2016RyanmillerOntology Term : 'disease pathway' added !
87755view09:56, 25 July 2016RyanmillerOntology Term : 'infectious disease pathway' added !
87752view09:53, 25 July 2016RyanmillerOntology Term : 'bacterial infectious disease' added !
86402view09:17, 11 July 2016ReactomeTeamreactome version 56
83321view10:46, 18 November 2015ReactomeTeamVersion54
81748view09:47, 26 August 2015ReactomeTeamVersion53
76848view08:07, 17 July 2014ReactomeTeamFixed remaining interactions
76552view11:53, 16 July 2014ReactomeTeamFixed remaining interactions
75885view09:54, 11 June 2014ReactomeTeamRe-fixing comment source
75585view10:42, 10 June 2014ReactomeTeamReactome 48 Update
74940view13:46, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74584view08:37, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
Activated BoNTComplexREACT_11835 (Reactome)
BoNT D cleaved VAMP/SynaptobrevinProteinREACT_11414 (Reactome)
BoNT F cleaved VAMP/SynaptobrevinProteinREACT_11808 (Reactome)
BoNT Light chain

Type A polypeptide

ProteinP10845 (Uniprot-TrEMBL)
BoNT Light chain Type AComplexREACT_11247 (Reactome)
BoNT Light chain

Type B polypeptide

ProteinP10844 (Uniprot-TrEMBL)
BoNT Light chain Type BComplexREACT_11746 (Reactome)
BoNT Light chain

Type C1 polypeptide

ProteinP18640 (Uniprot-TrEMBL)
BoNT Light chain Type C1 polypeptideProteinP18640 (Uniprot-TrEMBL)
BoNT Light chain Type C1ComplexREACT_11290 (Reactome)
BoNT Light chain

Type D polypeptide

ProteinP19321 (Uniprot-TrEMBL)
BoNT Light chain Type DComplexREACT_11845 (Reactome)
BoNT Light chain

Type E polypeptide

ProteinQ00496 (Uniprot-TrEMBL)
BoNT Light chain Type EComplexREACT_11278 (Reactome)
BoNT Light chain

Type F polypeptide

ProteinP30996 (Uniprot-TrEMBL)
BoNT Light chain Type FComplexREACT_11984 (Reactome)
BoNT Light chain Types A,C and EComplexREACT_11662 (Reactome)
BoNT Light chain Types B,D,F,GComplexREACT_11940 (Reactome)
BoNT bound to membrane receptorComplexREACT_11594 (Reactome)
BoNT with

conformational change in Heavy

chain N-terminal
ComplexREACT_11938 (Reactome)
BoNT with Heavy

chain N-terminal inserted into

endosomal membrane
ComplexREACT_11623 (Reactome)
Gangliosides:SynaptogaminComplexREACT_11246 (Reactome)
Gangliosides:SynaptotagminComplexREACT_11647 (Reactome)
SNAP25(1-180)ProteinP60880 (Uniprot-TrEMBL)
SNAP25(1-197)ProteinP60880 (Uniprot-TrEMBL)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
Syntaxin fragmentProteinREACT_11762 (Reactome)
SyntaxinsProteinREACT_11590 (Reactome)
VAMP/SynaptobrevinProteinREACT_11688 (Reactome)
VAMP2(1-76)ProteinP63027 (Uniprot-TrEMBL)
VAMP2ProteinP63027 (Uniprot-TrEMBL)
Zn2+ [cytosol]MetaboliteCHEBI:29105 (ChEBI)
internalized BoNTComplexREACT_11848 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
Activated BoNTREACT_11084 (Reactome)
BoNT D cleaved VAMP/SynaptobrevinArrowREACT_11179 (Reactome)
BoNT F cleaved VAMP/SynaptobrevinArrowREACT_11158 (Reactome)
BoNT Light chain Type Amim-catalysisREACT_11146 (Reactome)
BoNT Light chain Type Bmim-catalysisREACT_11165 (Reactome)
BoNT Light chain Type C1 polypeptideArrowREACT_11226 (Reactome)
BoNT Light chain Type C1mim-catalysisREACT_11130 (Reactome)
BoNT Light chain Type C1mim-catalysisREACT_11195 (Reactome)
BoNT Light chain Type Dmim-catalysisREACT_11179 (Reactome)
BoNT Light chain Type Emim-catalysisREACT_11089 (Reactome)
BoNT Light chain Type Fmim-catalysisREACT_11158 (Reactome)
BoNT Light chain Types A,C and EArrowREACT_11226 (Reactome)
BoNT Light chain Types B,D,F,GArrowREACT_11226 (Reactome)
BoNT bound to membrane receptorArrowREACT_11084 (Reactome)
BoNT bound to membrane receptorREACT_11086 (Reactome)
BoNT with

conformational change in Heavy

chain N-terminal
ArrowREACT_11131 (Reactome)
BoNT with

conformational change in Heavy

chain N-terminal
REACT_11217 (Reactome)
BoNT with Heavy

chain N-terminal inserted into

endosomal membrane
ArrowREACT_11217 (Reactome)
BoNT with Heavy

chain N-terminal inserted into

endosomal membrane
ArrowREACT_11226 (Reactome)
BoNT with Heavy

chain N-terminal inserted into

endosomal membrane
REACT_11226 (Reactome)
Gangliosides:SynaptogaminArrowREACT_11217 (Reactome)
Gangliosides:SynaptotagminREACT_11084 (Reactome)
REACT_11084 (Reactome) Botulinum neurotoxins (BoNTs) bind to polysialogangliosides, including GT1b, GD1b and GQ1b and synaptotagmin polypeptides on the neuronal plasma membrane (Verderio et al., 2006). In the body, this dual binding may have the effect of targeting BoNTs to specific regions of the neuromuscular junction for endocytosis. Different serotypes are known to bind to different receptors: Bont/A to SV2, Bont/B and G to Syt1 and Syt2 with different affinities.
REACT_11086 (Reactome) Once BoNT molecules are bound to the host cell surface via their HC domains, they undergo transcytosis which include sorting and endocytosis into an acidic vesicular compartment within the cytosol. As a result of endocytosis, the toxin becomes resistant to neutralization by antisera. Endocytosis is temperature and energy-dependent. In the body, endocytosed BoNT molecules remain associated with the neuromuscular junction which they finally reach by transcytosis.
REACT_11089 (Reactome) BoNT Light Chain type E protein cleaves SNAP-25 protein of human SNARE complex.
REACT_11130 (Reactome) BoNT Light Chain type C1 protein cleaves SNAP-25 protein of human SNARE complex.
REACT_11131 (Reactome) The N-terminal half of the BoNT Heavy Chain undergoes conformational changes effected by endosomal pH resulting in ion channel formation (Blaustein et al., 1987). This process has been demonstrated experimentally for BoNT serotypes A and B, but all serotypes are thought to have this property (Pellizzari et al. 1999).
REACT_11146 (Reactome) BoNT Light Chain type A protein cleaves SNAP-25 protein of human SNARE complex.
REACT_11158 (Reactome) BoNT Light Chain type F protein cleaves VAMP proteins of human SNARE complex.
REACT_11165 (Reactome) BoNT Light Chain type B protein cleaves Vamp-2 protein, a member of SNARE complex.
REACT_11179 (Reactome) BoNT Light Chain type D protein cleaves VAMP proteins of human SNARE complex.
REACT_11195 (Reactome) Syntaxins are involved in the localization (docking) of both synaptic vesicles and calcium channels to the presynaptic active zone. Syntaxin 1A interacts with SNAP-25 in forming t-SNARE part of SNARE complex. BoNT Type C specifically cleaves Syntaxin 1A although a broader target spectrum is suspected.
REACT_11217 (Reactome) Acidic pH triggers a conformation change in the Heavy chain N-terminal domain leading to its insertion into the lipid bilayer and formation of a trans-membrane channel large enough to accommodate the unfolded Light chain. It has been observed that in the closely related Diptheria toxin, a 10-aa motif is critical for pore formation. Ratts et al. identified this motif in some of the virulent BoNTs (Ratts et al., 2005).
REACT_11226 (Reactome) The BoNT L chain traverses the H chain channel into the cytosol, refolds, and is released into the cytosol. The complete molecular details of cleavage of the L- H disulfide bond and L chain refolding are not yet known (Pellizzari et al.,1999). The cleavage of host proteins may require the toxins binding to specific recogntion sites as well as cleavage sites (Rossetto et al., 1994).
SNAP25(1-180)ArrowREACT_11089 (Reactome)
SNAP25(1-197)ArrowREACT_11146 (Reactome)
SNAP25ArrowREACT_11130 (Reactome)
SNAP25REACT_11089 (Reactome)
SNAP25REACT_11130 (Reactome)
SNAP25REACT_11146 (Reactome)
Syntaxin fragmentArrowREACT_11195 (Reactome)
SyntaxinsREACT_11195 (Reactome)
VAMP/SynaptobrevinREACT_11158 (Reactome)
VAMP/SynaptobrevinREACT_11179 (Reactome)
VAMP2(1-76)ArrowREACT_11165 (Reactome)
VAMP2REACT_11165 (Reactome)
internalized BoNTArrowREACT_11086 (Reactome)
internalized BoNTREACT_11131 (Reactome)
Personal tools