, Botulinum neurotoxin type C
Enzyme Classification 18.104.22.168
Also Known as
Botulinum neurotoxin type C: 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)., Botulinum neurotoxin C light chain: 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)., Botulinum neurotoxin C heavy chain: 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 Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC) (PubMed:16252491). The LC has the proteolytic/pharmacological activity (PubMed:7901002, PubMed:7737992, 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.