Botulinum toxin type B (BoNT/B), a disulfide-bonded heavy chain (HC) - light chain (LC) heterodimer, enters the gut typically as a result of consuming contaminated food (Hatheway 1995), as a complex with nontoxic nonhemagglutinin protein (NTNHA, encoded by the C. botulinum ntnha gene) and multiple copies of three hemagglutinin proteins (HA, encoded by the C. botulinum ha17, ha34, and ha70 genes) (Amatsu et al. 2013). The complex protects the toxin from degradation in the gut and mediates its association with the gut epithelium and transcytosis to enter the circulation (Fujinaga et al. 2013). Circulating toxin molecules associate with gangliosides and synaptotagmin (SYT) proteins exposed by exocytosis at a synapse of a target neuron (Dong et al. 2003; Yowler & Schengrund 2004). Vesicle recycling brings the toxin into the neuron where the vesicle is acidified (Sudhoff 2004). The lowered pH induces a conformational change in the toxin: its HC forms a passage in the vesicle membrane through which its LC is extruded into the neuronal cytosol. Tthe HC - LC disulfide bond is reduced (Montal 2010). The LC then catalyzes the cleavage of vesicle-associated membrane protein 2 (VAMP2) on the cytosolic face of synaptic vesicle membranes (Foran et al. 1994; Schiavo et al. 1992), thereby inhibiting synaptic vesicle fusion with the plasma membrane and exocytosis.
Fujinaga, Y, Sugawara, Y, Matsumura, T
Schiavo, G, Benfenati, F, Poulain, B, Rossetto, O, Polverino de Laureto, P, DasGupta, BR, Montecucco, C
Dong, M, Richards, DA, Goodnough, MC, Tepp, WH, Johnson, EA, Chapman, ER
Amatsu, S, Sugawara, Y, Matsumura, T, Kitadokoro, K, Fujinaga, Y
Foran, P, Shone, CC, Dolly, JO
Montal, M
Yowler, BC, Schengrund, CL
Südhof, TC
Hatheway, CL
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