Clostridial neurotoxins, when taken up by human neurons, block synaptic transmission by cleaving proteins required for the fusion of synaptic vesicles with the plasma membrane. They are remarkably efficient so that very small doses cause paralysis of an affected person (Lalli et al. 2003; Turton et al. 2002). All characterized clostridial neurotoxins are synthesized as products of chromosomal, plasmid or prophage-borne bacterial genes. The nascent toxin may be cleaved into light (LC) and heavy (HC) chain moieties that remain attached by noncovalent interactions and a disulfide bond (Turton et al. 2002).
Strains of Clostridium botulinum produce seven serologically distinct toxins, BoNT/A, B, C, D, E, F, and G. An eighth toxin, BoNT/H has recently been identified (Barash & Arnon 2014) but its molecular properties have not yet been described. Human poisoning most commonly result from ingestion of toxin contaminated food. More rarely, it is due to wound infection or clostridial colonization of the gut of an infant whose own gut flora have not yet developed or of an older individual whose flora have been suppressed. While all seven characterized toxins can cleave human target proteins, three, BoNT/A, B, and E, are most commonly associated with human disease (Hatheway 1995; Sakaguchi 1982). BoNT/F is also able to cause human botulism.<p>Once ingested, the botulinum toxin must be taken up from the gut lumen into the circulation, a process mediated by four accessory proteins. These proteins form a complex that mediates transcytosis of the toxin molecule across the gut epithelium, allowing its entry into the circulation. The accessory proteins produced by different C. botulinum strains differ in their affinities for polarized epithelia of different species (e.g., human versus canine), and may thus be a key factor in human susceptibility to the toxins of strains A, B, and E and resistance to the others (Simpson 2004).<p>Clostridium tetani produces TeNT toxin. Human poisoning is the result of toxin secretion by bacteria growing in an infected wound and the toxin is released directly into the circulation.<p>Circulating clostridial toxins are taken up by neurons at neuromuscular junctions. They bind to specific gangliosides (BoNT/C, TeNT) or to both gangliosides and synaptic vesicle proteins (BoNT/A, B, D G) exposed on the neuronal plasma membrane during vesicle exocytosis (Montal 2010). All seven characterized forms of BoNT are thought to be taken up into synaptic vesicles as these re-form at the neuromuscular junction. These vesicles remain close to the site of uptake and are rapidly re-loaded with neurotransmitter and acidified (Sudhoff 2004). TeNT, in contrast, is taken up into clathrin coated vesicles that reach the neuron cell body by retrograde transport and then possibly other neurons before undergoing acidification. Vesicle acidification causes a conformational change in the toxin, allowing its HC part to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved and the cytosolic LC functions as a zinc metalloprotease to cleave specific bonds in proteins on the cytosolic faces of synaptic vesicles and plasma membranes that normally mediate exocytosis (Lalli et al. 2003; Montal 2010).
View original pathway at Reactome.</div>
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Botulinum toxin type C light chain (botC LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from syntaxin 1 (STX1). botC LC is a zinc metalloprotease (Blasi et al. 1993; Foran et al. 1994). STX1 is associated with the cytosolic face of the target cell plasma membrane where it forms part of a complex required for synaptic vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type C light chain (botC LC), in the cytosol of a target cell, catalyzes the removal of a carboxyterminal peptide from synaptosomal associated protein 25 (SNAP25). botC LC is a zinc metalloprotease (Foran et al. 1994; Vaidyanathan et al. 1999). SNAP25 is associated with the cytosolic face of the target cell plasma membrane where it forms part of a complex required for synaptic vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type B light chain (botB LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 2 (VAMP2). botB LC is a zinc metalloprotease (Foran et al. 1994; Schiavo et al. 1992). VAMP2 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release and in vivo leads to a long lasting flaccid paralysis (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type E light chain (botE LC), in the cytosol of a target cell, catalyzes the removal of a carboxyterminal peptide from synaptosomal-associated protein 25 (SNAP25). botE LC is a zinc metalloprotease (Binz et al. 1994; Schiavo et al. 1993; Vaidyanathan et al. 1999). SNAP25 is associated with the cytosolic face of the target cell plasma membrane where it forms part of a complex required for synaptic vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release and in vivo leads to a long lasting flaccid paralysis (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type F light chain (botF LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 1 (VAMP1). botF LC is a zinc metalloprotease (Yamasaki et al. 1994). VAMP1 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type D light chain (botD LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 1 (VAMP1). botD LC is a zinc metalloprotease (Arndt et al. 2006; Schiavo et al. 1993; Yamasaki et al. 1994). VAMP1 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type A light chain (botA LC), in the cytosol of a target cell, catalyzes the removal of a carboxyterminal peptide from synaptosomal-associated protein 25 (SNAP25). botA LC is a zinc metalloprotease (Binz et al. 1994; Schiavo et al. 1993). SNAP25 is associated with the cytosolic face of the target cell plasma membrane where it forms part of a complex required for synaptic vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release and in vivo leads to a long lasting flaccid paralysis (Sudhof et al, 1993; Sudhof 2004).
Acidification of the vesicle containing tetanus toxin disulfide-bonded heavy chain - light chain dimer (tetX HC:LC) is inferred to cause a conformational change in the toxin dimer, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol (Montal 2010).
Tetanus toxin disulfide-bonded heavy chain - light chain dimer (tetX HC:LC) binds gangliosides on the plasma membrane of a human target cell (Chen et al. 2009; Deinhardt et al. 2006).
Vesicles containing ganglioside-bound tetanus toxin disulfide-bonded heavy chain - light chain dimer (tetX HC:LC) are transported in a retrograde fashion away from the target cell synapse where they were formed into the cell body (Lalli et al. 2003).
Ganglioside-bound tetanus toxin disulfide-bonded heavy chain - light chain dimer (tetX HC:LC) is taken up into the target cell by clathrin-mediated endocytosis (Deinhardt et al. 2006).
Tetanus toxin light chain (tetX LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 2 (VAMP2). tetX LC is a zinc metalloprotease (Foran et al. 1994; Schiavo et al. 1992). VAMP2 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks exocytosis and in vivo leads to a long-lasting spastic paralysis (Link et al. 1992).
The bacterial botB:NTNHA:HA (BoNT/B:NTNHA:HA) complex,, consisting of a Botulinum toxin type B (botB) disulfide bonded heavy chain (HC) - light chain (LC) dimer associated with nontoxic nonhemagglutinin protein (NTNHA), three molecules of hemagglutinin (ha) 17, six of ha33, and three of ha70 (Amatsu et al. 2013), associates with the plasma membrane of a human cell (in vivo, the apical surface of a gut epithelial cell) and undergoes transcytosis. While the molecular details of transcytosis remain to be established definitively, the process enables the toxin heterodimer to cross the epithelial cell layer and enter the circulation (Fujinaga et al. 2013; Simpson 2004).
The bacterial botE:NTNHA complex, consisting of a Botulinum toxin type E (botE, also known as BoNT/E) disulfide bonded heavy chain (HC) - light chain (LC) heterodimer (“dichain�) associated with nontoxic nonhemagglutinin protein (NTNHA) (Benefield et al. 2013), associates with the plasma membrane of a human cell (in vivo, the apical surface of a gut epithelial cell) and undergoes transcytosis. While the molecular details of transcytosis remain to be established definitively, the process enables the toxin heterodimer to cross the epithelial cell layer and enter the circulation (Fujinaga et al. 2013; Simpson 2004).
The bacterial botA:NTNHA:HA (BoNT/A:NTNHA:HA) complex, consisting of a Botulinum toxin type A (botA) disulfide bonded heavy chain (HC) - light chain (LC) heterodimer ("dichain") associated with nontoxic nonhemagglutinin protein (NTNHA), three molecules of hemagglutinin (ha) 17, six of ha33, and three of ha70 (Lee et al. 2013), associates with the plasma membrane of a human cell (in vivo, the apical surface of a gut epithelial cell) and undergoes transcytosis. While the molecular details of transcytosis remain to be established definitively, the process enables the toxin heterodimer to cross the epithelial cell layer and enter the circulation (Fujinaga et al. 2013; Simpson 2004).
The Botulinum toxin type B disulfide-bonded heavy chain - light chain dimer (botB HC:LC, encoded by the C. botulinum botB gene) (Swaminathan & Eswaramoorthy 2000) binds ganglioside GT1b and syntagmin 1 or 2 (SYT1 or 2) on the plasma membrane of a human target cell. In vivo, this process specifically targets synapses at neuromuscular junctions, where toxin association with ganglioside may position it to bind efficiently to SYT1 or 2 when those proteins are exposed at the cell surface by exocytosis (Dong et al. 2003). In vitro, botB HC:LC can bind gangliosides in addition to GT1b but with lower affinity (Kozaki et al. 1998). Only GT1b binding is annotated here.
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type B disulfide bonded heavy chain - light chain heterodimer (botB HC:LC dimer) bound to ganglioside GT1b and syntagmin 1 or 2 (SYT) is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
By analogy to the process described for botulinum toxin type A (Koriazova and Montal 2003; Montal 2010), acidification, a normal step in synaptic vesicle recycling, is inferred to cause a conformational change in the botulinum toxin type B disulfide bonded heavy chain - light chain dimer (botB HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved. Recent studies in vitro suggest that GT1b ganglioside associated with the toxin may play a role in this process (Sun et al. 2011, 2012).
The Botulinum toxin type A disulfide bonded heavy chain - light chain heterodimer (botA HC:LC, encoded by the C. botulinum botA gene) (Lacy et al. 1998) binds ganglioside GT1b and synaptic vesicle protein 2A (SV2A) on the plasma membrane of a human target cell. In vivo, this process specifically targets synapses at neuromuscular junctions, where toxin association with ganglioside may position it to bind efficiently to SV2A, SV2B, or SV2C when those proteins are exposed at the cell surface by exocytosis (Dong et al. 2006). In vitro, botA HC:LC can bind gangliosides in addition to GT1b but with lower affinity (Kozaki et al. 1998). Only GT1b binding is annotated here.
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type A disulfide bonded heavy chain - light chain heterodimer (“dichain�) (botA HC:LC) bound to ganglioside GT1b and synaptic vesicle protein 2A, 2B, or 2C (SV2A, B, or C) is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
Acidification, a normal step in endocytosis causes a conformational change in the botulinum toxin type A disulfide bonded heavy chain - light chain heterodimer (“dichain�) (botA HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved (Koriazova & Montal 2003; Montal 2010). Recent studies in vitro suggest that GT1b ganglioside associated with the toxin may play a role in this process (Sun et al. 2012).
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type E disulfide bonded heavy chain - light chain heterodimer (botE HC:LC) bound to ganglioside GT1b and synaptic vesicle protein 2A (SV2A) or 2B (SV2B) is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
The Botulinum toxin type E disulfide bonded heavy chain - light chain heterodimer (botE HC:LC, encoded by the C. botulinum botE gene) (Kumaran et al. 2009) binds ganglioside GT1b and synaptic vesicle protein 2A (SV2A) or 2B (SV2B) on the plasma membrane of a human target cell. In vivo, this process specifically targets synapses at neuromuscular junctions, where toxin association with ganglioside may position it to bind efficiently to SV2A or B when those proteins are exposed at the cell surface by exocytosis (Dong et al. 2008; Rummel et al. 2009).
By analogy to the process described for botulinum toxin type A (Koriazova and Montal 2003; Montal 2010), acidification, a normal step in synaptic vesicle recycling, is inferred to cause a conformational change in the botulinum toxin type E disulfide bonded heavy chain - light chain dimer (botE HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved. Recent studies in vitro suggest that GT1b ganglioside associated with the toxin may play a role in this process (Sun et al. 2012).
The botulinum toxin type C disulfide-bonded heavy chain - light chain heterodimer (“dichain�) (botC HC:LC, encoded by the C. botulinum botC1 gene) binds two molecules of GT1b ganglioside on the plasma membrane of a human target cell (Karalewitz et al. 2012).
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type C disulfide-bonded heavy chain - light chain heterodimer (botC HC:LC) bound to ganglioside GT1b is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
By analogy to the process described for botulinum toxin type A (Koriazova and Montal 2003; Montal 2010), acidification, a normal step in synaptic vesicle recycling, is inferred to cause a conformational change in the botulinum toxin type C disulfide-bonded heavy chain - light chain dimer (botC HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved. Recent studies in vitro suggest that GT1b ganglioside associated with the toxin may play a role in this process (Sun et al. 2012).
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type D disulfide-bonded heavy chain - light chain heterodimer (botD HC:LC) bound to ganglioside GD2 and synaptic vesicle protein 2A, 2B, or 2C (SV2A, B, or C) is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
Botulinum toxin type D light chain (botD LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 2 (VAMP2). botD LC is a zinc metalloprotease (Arndt et al. 2006; Schiavo et al. 1993; Yamasaki et al. 1994). VAMP2 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
The botulinum toxin type D disulfide-bonded heavy chain - light chain heterodimer ("dichain") (botD HC:LC, encoded by the C. botulinum botD gene) binds ganglioside GD2 and synaptic vesicle proteins 2A (SV2A), 2B (SV2B), or 2C (SV2C) on the plasma membrane of a human target cell. In vivo, this process specifically targets synapses at neuromuscular junctions, where toxin association with ganglioside may position it to bind efficiently to SV2A, SV2B, or SV2C when those proteins are exposed at the cell surface by exocytosis (Kroken et al. 2011; Peng et al. 2011).
By analogy to the process described for botulinum toxin type A (Koriazova and Montal 2003; Montal 2010), acidification, a normal step in synaptic vesicle recycling, is inferred to cause a conformational change in the botulinum toxin type D disulfide-bonded heavy chain - light chain dimer (botD HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol where the HC - LC disulfide bond is cleaved.
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type F disulfide-bonded heavy chain - light chain heterodimer ("dichain") (botF HC:LC) bound to ganglioside GT1b and synaptic vesicle protein 2A (SV2A), 2B (SV2B), or 2C (SV2C) is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
The botulinum toxin type F disulfide-bonded heavy chain - light chain heterodimer ("dichain") (botF HC:LC, encoded by the C. botulinum botF gene) binds ganglioside GT1b and synaptic vesicle protein 2A (SV2A), B (SV2B), or C (SV2C) on the plasma membrane of a human target cell. In vivo, this process specifically targets synapses at neuromuscular junctions, where toxin association with ganglioside may position it to bind efficiently to SV2A, B, or C when those proteins are exposed at the cell surface by exocytosis (Fu et al. 2009; Rummel et al. 2009).
By analogy to the process described for botulinum toxin type A (Koriazova and Montal 2003; Montal 2010), acidification, a normal step in synaptic vesicle recycling, is inferred to cause a conformational change in the botulinum toxin type F disulfide-bonded heavy chain - light chain heterodimer (botF HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol.The HC - LC disulfide bond is cleaved. Recent studies in vitro suggest that GT1b ganglioside associated with the toxin may play a role in this process (Sun et al. 2012).
Botulinum toxin type F light chain (botF LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 2 (VAMP2). botF LC is a zinc metalloprotease (Yamasaki et al. 1994). VAMP2 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
Botulinum toxin type G light chain (botG LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 2 (VAMP2). botG LC is a zinc metalloprotease (Schiavo et al. 1994; Yamasaki et al. 1994). VAMP2 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis. Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
By analogy to the process described for botulinum toxin type A (Koriazova and Montal 2003; Montal 2010), acidification, a normal step in synaptic vesicle recycling, is inferred to cause a conformational change in the botulinum toxin type G disulfide-bonded heavy chain - light chain dimer (BoNT/G HC:LC) it contains, allowing the HC part of the toxin to function as a channel through which its LC part is extruded into the neuronal cytosol. The HC - LC disulfide bond is cleaved. Recent studies in vitro suggest that GT1b ganglioside associated with the toxin may play a role in this process (Sun et al. 2012).
Botulinum toxin type G light chain (botG LC), in the cytosol of a target cell, catalyzes the removal of an aminoterminal peptide from vesicle-associated membrane protein 1 (VAMP1). botG LC is a zinc metalloprotease (Schiavo et al. 1994; Yamasaki et al. 1994). VAMP1 is associated with the cytosolic face of the target cell synaptic vesicle and is required for vesicle docking and exocytosis.Its cleavage by botulinum toxin blocks synaptic vesicle fusion with the plasma membrane and neurotransmitter release (Sudhof et al, 1993; Sudhof 2004).
Synaptic vesicles re-form rapidly after exocytosis, carrying vesicle membrane proteins that had been exposed on the cell surface by exocytosis back into the cell (Sudhoff 2004). The botulinum toxin type G disulfide-bonded heavy chain - light chain heterodimer (botG HC:LC) bound to ganglioside GT1b and syntagmin 1 (SYT1) is inferred to be taken up as well, delivering it to the re-formed synaptic vesicle.
The botulinum toxin type G disulfide-bonded heavy chain - light chain heterodimer ("dichain") (botG HC:LC) binds ganglioside GT1b and synaptotagmin-1 (SYT1) on the plasma membrane of a human target cell. In vivo, this process specifically targets synapses at neuromuscular junctions, where toxin association with ganglioside may position it to bind efficiently to SYT1 when that protein is exposed at the cell surface by exocytosis (Peng et al. 2012; Willjes et al. 2013).
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