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Showing Protein Botulinum neurotoxin type C (HMDBP13988)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 0 metabolites
Identification
HMDB Protein ID HMDBP13988
Secondary Accession Numbers None
Name Botulinum neurotoxin type C
Synonyms
  1. BoNT/C
  2. Bontoxilysin-C1
  3. Botulinum neurotoxin type C1
  4. BoNT/C1
Gene Name (REFSEQ) CLOSTRIDIUM PHAGE C-ST; BOTULINUM NEUROTOXIN TYPE C1 PRECURSOR
Protein Type Unknown
Biological Properties
General Function Not Available
Specific 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:16252491, PubMed:7901002, PubMed:8611567). Is unique among characterized BoNTs in having 2 substrates, syntaxin (STX) and SNAP25 (PubMed:7901002, PubMed:7737992, PubMed:8611567, PubMed:9886085, PubMed:17718519). Precursor of botulinum neurotoxin C which unlike most BoNTs seems not to have a proteinaceous coreceptor, and instead recognizes 2 different complex polysialylated gangliosides found on neural tissue probably found in synaptic vesicles (PubMed:21483489, PubMed:23027864). 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 heavy chain (HC) forms pores that allows the light chain (LC) to translocate into the cytosol (By similarity). 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). In vitro the whole toxin only has protease activity after reduction (PubMed:8611567). Electrical stimulation increases uptake of toxin, presumably by transiently exposing a receptor usually found in eukaryotic target synaptic vesicles (PubMed:19650874). Forms ion-conducting channels at around pH 6.1 (PubMed:2424493). Requires complex eukaryotic host polysialogangliosides for full neurotoxicity (PubMed:19650874, PubMed:21483489). Synaptic vesicle glycoproteins (SV2) do not seem to act as its receptor (PubMed:21483489).Has proteolytic activity. After translocation into the eukaryotic host cytosol, inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves syntaxin-1A/STX1A and syntaxin-1B/STX1B (PubMed:7901002, PubMed:7737992, PubMed:8611567). Cleaves the '253-Arg-|-Ala-254' bond of STX1 and the '252-Arg-|-Ala-253' bond of STX2; also acts on syntaxin 3 (STX3) but not 4 (STX4) (PubMed:7737992). Cleaves the '198-Arg-|-Ala-199' bond of SNAP25 (PubMed:8611567, PubMed:9886085, PubMed:17718519). Recognizes the '93-Asn--Met-202' region of SNAP25 (PubMed:9886085).Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into eukaryotic host cytosol. 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 eukaryotic target cell surface. It simultaneously recognizes 2 polysialated gangliosides coreceptors in close proximity on host synaptic vesicles (PubMed:23027864, PubMed:21542861). 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 (Probable). The C-terminal half of the HC (residues 864-1291) binds neurons in a dose-dependent manner (PubMed:20731382). The C-terminal half of the HC (residues 863-1291) binds eukaryotic host gangliosides in the order GD1b > GT1b > GD1a > GM1a (PubMed:16115873, PubMed:20731382, PubMed:23027864, PubMed:19650874). Has 2 ganglioside binding sites; Sia-1 prefers a sia7 sialic acid and sugars within the ganglioside (GD1b > GT1b), whereas GBP2 recognizes a sia5 sialic acid (GT1b and GD1a) (PubMed:23027864, PubMed:21542861). Both sites are required for HC to enter neurons, acting via different gangliosides (PubMed:23027864). This suggests that 2 gangliosides serve as toxin receptors (PubMed:16115873, PubMed:20731382, PubMed:21542861, PubMed:23027864). Synaptic activity (depolarization with K(+)) increases uptake by neurons (PubMed:23027864). Treatment of synaptosomes with proteinase K does not reduce HC binding, suggesting there is no protein receptor or it is protected from extracellular proteases (PubMed:16115873). Decreases uptake and toxicity of whole BoNT/A, but also interferes with uptake of BoNT/E and BoNT/F (PubMed:19650874). HC also binds phosphoinositides, which might play a role in membrane-binding (PubMed:22120109).
Pathways Not Available
Reactions Not Available
GO Classification
Biological Process
pathogenesis
negative regulation of neurotransmitter secretion
membrane protein proteolysis
negative regulation of calcium ion-dependent exocytosis
Cellular Component
extracellular region
Molecular Function
zinc ion binding
metalloendopeptidase activity
toxin activity
ganglioside binding
protein transmembrane transporter activity
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 1291
Molecular Weight 148868.56
Theoretical pI 5.642
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID P18640
UniProtKB/Swiss-Prot Entry Name BXC_CBCP
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Fujinaga Y, Inoue K, Shimazaki S, Tomochika K, Tsuzuki K, Fujii N, Watanabe T, Ohyama T, Takeshi K, Inoue K, et al.: Molecular construction of Clostridium botulinum type C progenitor toxin and its gene organization. Biochem Biophys Res Commun. 1994 Dec 15;205(2):1291-8. doi: 10.1006/bbrc.1994.2805. [PubMed:7802661 ]
  2. Hauser D, Eklund MW, Kurazono H, Binz T, Niemann H, Gill DM, Boquet P, Popoff MR: Nucleotide sequence of Clostridium botulinum C1 neurotoxin. Nucleic Acids Res. 1990 Aug 25;18(16):4924. doi: 10.1093/nar/18.16.4924. [PubMed:2204031 ]
  3. Kimura K, Fujii N, Tsuzuki K, Murakami T, Indoh T, Yokosawa N, Takeshi K, Syuto B, Oguma K: The complete nucleotide sequence of the gene coding for botulinum type C1 toxin in the C-ST phage genome. Biochem Biophys Res Commun. 1990 Sep 28;171(3):1304-11. doi: 10.1016/0006-291x(90)90828-b. [PubMed:2222445 ]
  4. Takeda M, Tsukamoto K, Kohda T, Matsui M, Mukamoto M, Kozaki S: Characterization of the neurotoxin produced by isolates associated with avian botulism. Avian Dis. 2005 Sep;49(3):376-81. doi: 10.1637/7347-022305R1.1. [PubMed:16252491 ]
  5. Tsuzuki K, Yokosawa N, Syuto B, Ohishi I, Fujii N, Kimura K, Oguma K: Establishment of a monoclonal antibody recognizing an antigenic site common to Clostridium botulinum type B, C1, D, and E toxins and tetanus toxin. Infect Immun. 1988 Apr;56(4):898-902. doi: 10.1128/iai.56.4.898-902.1988. [PubMed:2450068 ]
  6. Donovan JJ, Middlebrook JL: Ion-conducting channels produced by botulinum toxin in planar lipid membranes. Biochemistry. 1986 May 20;25(10):2872-6. doi: 10.1021/bi00358a020. [PubMed:2424493 ]
  7. 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. EMBO J. 1993 Dec;12(12):4821-8. [PubMed:7901002 ]
  8. Schiavo G, Shone CC, Bennett MK, Scheller RH, Montecucco C: Botulinum neurotoxin type C cleaves a single Lys-Ala bond within the carboxyl-terminal region of syntaxins. J Biol Chem. 1995 May 5;270(18):10566-70. doi: 10.1074/jbc.270.18.10566. [PubMed:7737992 ]
  9. 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. Biochemistry. 1996 Feb 27;35(8):2630-6. doi: 10.1021/bi9519009. [PubMed:8611567 ]
  10. Eleopra R, Tugnoli V, Rossetto O, Montecucco C, De Grandis D: Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy in human. Neurosci Lett. 1997 Mar 14;224(2):91-4. doi: 10.1016/s0304-3940(97)13448-6. [PubMed:9086464 ]
  11. Vaidyanathan VV, Yoshino K, Jahnz M, Dorries 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. J Neurochem. 1999 Jan;72(1):327-37. doi: 10.1046/j.1471-4159.1999.0720327.x. [PubMed:9886085 ]
  12. Rummel A, Hafner 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. J Neurochem. 2009 Sep;110(6):1942-54. doi: 10.1111/j.1471-4159.2009.06298.x. Epub 2009 Jul 23. [PubMed:19650874 ]
  13. Peng L, Tepp WH, Johnson EA, Dong M: Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS Pathog. 2011 Mar;7(3):e1002008. doi: 10.1371/journal.ppat.1002008. Epub 2011 Mar 31. [PubMed:21483489 ]
  14. Zhang Y, Varnum SM: The receptor binding domain of botulinum neurotoxin serotype C binds phosphoinositides. Biochimie. 2012 Mar;94(3):920-3. doi: 10.1016/j.biochi.2011.11.004. Epub 2011 Nov 18. [PubMed:22120109 ]
  15. Pirazzini M, Rossetto O, Eleopra R, Montecucco C: Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. Pharmacol Rev. 2017 Apr;69(2):200-235. doi: 10.1124/pr.116.012658. [PubMed:28356439 ]
  16. Jin R, Sikorra S, Stegmann CM, Pich A, Binz T, Brunger AT: Structural and biochemical studies of botulinum neurotoxin serotype C1 light chain protease: implications for dual substrate specificity. Biochemistry. 2007 Sep 18;46(37):10685-93. doi: 10.1021/bi701162d. Epub 2007 Aug 24. [PubMed:17718519 ]
  17. Karalewitz AP, Kroken AR, Fu Z, Baldwin MR, Kim JJ, Barbieri JT: Identification of a unique ganglioside binding loop within botulinum neurotoxins C and D-SA . Biochemistry. 2010 Sep 21;49(37):8117-26. doi: 10.1021/bi100865f. [PubMed:20731382 ]
  18. Strotmeier J, Gu S, Jutzi S, Mahrhold S, Zhou J, Pich A, Eichner T, Bigalke H, Rummel A, Jin R, Binz T: The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites. Mol Microbiol. 2011 Jul;81(1):143-56. doi: 10.1111/j.1365-2958.2011.07682.x. Epub 2011 Jun 2. [PubMed:21542861 ]