botA, Botulinum neurotoxin type A
Enzyme Classification 22.214.171.124
Also Known as
BXA1_CLOBH, botA, bna
Botulinum neurotoxin type A: 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:8103915). Precursor of botulinum neurotoxin A which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins of synaptic vesicles (By similarity). Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them (PubMed:19476346). Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway (By similarity). When the pH of the toxin-containing endosome drops a structural rearrangement occurs so that the N-terminus of the 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., Botulinum neurotoxin A light chain: Has proteolytic activity (PubMed:8103915, PubMed:8294407). In vitro the whole toxin is reduced to release LC (PubMed:8103915, PubMed:8294407). After translocation into the eukaryotic host cytosol, LC hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP25, blocking neurotransmitter release (PubMed:8103915, PubMed:8294407)., Botulinum neurotoxin A heavy chain: Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into host cytosol. Composed of 3 subdomains; the translocation domain (TD), and N-terminus and C-terminus of the receptor-binding domain (RBD) (PubMed:9783750, PubMed:17173035). The RBD is responsible for the adherence of the toxin to the cell surface. It simultaneously recognizes 2 coreceptors; polysialated gangliosides and synaptic vesicle glycoproteins SV2A, SV2B and SV2C in close proximity on host synaptic vesicles (By similarity). The RBD specifically recognizes the N-linked glycan on 'Asn-559' of SV2A, SV2B and SV2C (By similarity). Isolated HC binds to host synaptosomes, significantly decreases uptake and toxicity of whole BoNT/A (PubMed:19476346). Binds ganglioside GD1a in vitro (PubMed:21849494). 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 to protect toxin prior to translocation (PubMed:9783750). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol. Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC) (PubMed:9783750, PubMed:17173035). Interacts with host synaptic vesicle glycoproteins SV2A, SV2B and SV2C which serve as coreceptors (By similarity). Glycosylation of 'Asn-559' in SV2C probably contributes a 12-fold increase in affinity to this interaction (By similarity). Depolarization of target tissue with high levels of K(+) leads to greater levels of receptor exposure (PubMed:19476346).