Recombinant Clostridium botulinum C phage Botulinum neurotoxin type C, partial

Function

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:21542861, PubMed:23027864). 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:19650874, PubMed:20731382, PubMed:23027864). 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:21542861, PubMed:23027864). 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)

Subcellular Location

Secreted

Subunit

Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC) (PubMed:16252491). The LC has the proteolytic/pharmacological activity (PubMed:7737992, PubMed:7901002, PubMed:8611567). The N- and C-terminal of the HC mediate channel formation and toxin binding, respectively. Can also be purified in complex with a non-toxic component that is larger than the HC (PubMed:16252491, PubMed:7802661). The stoichiometry of the whole complex has been modeled as one BoNT/C, one NTNHA, three HA-70, six HA-33 and three HA-17 (By similarity)

• Hauser D. et al. Nucleotide sequence of Clostridium botulinum C1 neurotoxin. — Nucleic Acids Res. (1990)
• Kimura K. et al. The complete nucleotide sequence of the gene coding for botulinum type C1 toxin in the C-ST phage genome. — Biochem. Biophys. Res. Commun. (1990)
• Takeda M. et al. Characterization of the neurotoxin produced by isolates associated with avian botulism. — Avian Dis. (2005)
• Tsuzuki K. et al. 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)
• Donovan J.J. et al. Ion-conducting channels produced by botulinum toxin in planar lipid membranes. — Biochemistry (1986)
• Oguma K. et al. Infant botulism due to Clostridium botulinum type C toxin. — Lancet (1990)
• Blasi J. et al. Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. — EMBO J. (1993)
• Fujinaga Y. et al. Molecular construction of Clostridium botulinum type C progenitor toxin and its gene organization. — Biochem. Biophys. Res. Commun. (1994)