Neurotoxicity of clostridium toxins (Homo sapiens)

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3, 12, 23, 24, 29...30, 49, 51, 5518, 22, 46302930, 38, 49, 552726, 30, 37, 42, 5530296, 8, 3111, 3229, 33, 41, 5230, 42, 55307, 30, 45, 5515, 30, 38, 48, 5518, 193024, 39, 4330, 42, 55305, 17, 313012304, 24, 3929, 33, 412935, 362, 107, 34, 5029, 33351, 21, 30, 5516, 24, 3929, 33, 411, 21, 28, 3015, 30, 48, 5526, 30, 37, 42, 5529, 33, 41endocytic vesiclecytosolsynaptic vesicle lumenclathrin-coated endocytic vesiclesynaptic vesicle lumencytosolBoNT/A:SV2:GT1bZn2+ Zn2+ VAMP2(59-116)SNAP25(1-198)TeNT:gangliosidesSTX1(1-?)GT1b SV2B VAMP2(2-76)GT1b BoNT/F HC disulfide bonded VAMP2(2-81)TeNT LC disulfide bonded BoNT/F LC disulfide bonded SNAP25(199-206)Zn2+ BoNT/B HC disulfide bonded GT1b SYT2 TeNT LC disulfide bonded SNAP25(1-197)GD3 GT1b BoNT/G HCha70VAMP2(2-58)VAMP1GM1a GT1bSV2A GT1b BoNT/A:SV2:GT1bSV2B BoNT/E LC:Zn2+SYT1 Zn2+ VAMP2(2-76)SV2A BoNT/E HC disulfide bonded H+BoNT/B HC disulfide bonded BoNT/G LC disulfide bonded BoNT/B:SYT:GT1bGT1bBoNT/A HC:LC dimerBoNT/E LC disulfide bonded SV2A SV2B SYT1 VAMP2(77-116)SNAP25(1-198)TeNT LC SYT1,2GT1bSNAP25(199-206)Zn2+ BoNT/G HC disulfide bonded GT1b TeNT:gangliosidesSTX1B(1-?) BoNT/F HC disulfide bonded SV2B GD3 BoNT/B LC SV2A,B,CSV2A Zn2+ GM1a SYT2 VAMP1(1-60)BoNT/B HC:LC dimerBoNT/D HC:LC dimerha70 BoNT/D LC:Zn2+VAMP2BoNT/D LC BoNT/A LC disulfide bonded SV2C BoNT/B HC disulfide bonded Zn2+ Zn2+ GD3SV2B BoNT/B LC disulfide bonded BoNT/E:SV2:GT1bZn2+ SV2C BoNT/G:SYT1:GT1bZn2+ GT1b GT1b Zn2+ BoNT/F LC:Zn2+NTNHA VAMP1(62-118)SYT1BoNT/A LC disulfide bonded TeNT LC disulfide bonded H+Zn2+ Zn2+ Zn2+ BoNT/A HC disulfide bonded Zn2+ ha17GD2 SV2B ha33BoNT/A LC disulfide bonded BoNT/C HC disulfide bonded BoNT/G HC disulfide bonded BoNT/C LC disulfide bonded BoNT/G HC:LC dimerTeNT:gangliosidesH+SYT1 SV2B SNAP25BoNT/F:SV2:GT1bBoNT/E:NTNHAZn2+ GT1bSYT2 BoNT/B HC disulfide bonded SYT2 SV2A,BBoNT/G LC BoNT/E LC disulfide bonded BoNT/C HC disulfide bonded BoNT/F HC disulfide bonded NTNHA Zn2+ VAMP2VAMP1(1-61)SNAP25GT1bZn2+ BoNT/C HCBoNT/D LC disulfide bonded BoNT/A HC disulfide bonded VAMP1(84-118)VAMP2SV2C NTNHA GT1bSV2C SV2B H+TeNT LC:Zn2+VAMP2(77-116)BoNT/C LC:Zn2+GT1b VAMP1(61-118)BoNT/B:NTNHA:HASTX1(?-288)SV2A BoNT/B LC disulfide bonded GM1aBoNT/D:SV2:GD2BoNT/F HC:LC dimerSV2C BoNT/B LC:Zn2+ha70 SV2C BoNT/C HC:LC dimerGD2Zn2+ VAMP2(60-116)BoNT/B LC disulfide bonded BoNT/E HC disulfide bonded SNAP25BoNT/A LC disulfide bonded BoNT/F LC disulfide bonded SV2C SYT1,2STX1A BoNT/A LC:Zn2+BoNT/G HC disulfide bonded TeNT HC disulfide bonded BoNT/E LC disulfide bonded SV2B SYT1 NTNHABoNT/D HC disulfide bonded Zn2+ SV2A,B,Cha33 BoNT/C LC disulfide bonded SV2C GD2 GT1b SV2B ha17 BoNT/G LC disulfide bonded ha17 SYT1 SV2C BoNT/F LC TeNT HC disulfide bonded H+TeNT HCTeNT LC disulfide bonded SV2A GT1b SV2A BoNT/C LC Zn2+ BoNT/E LC H+GT1bBoNT/A HC disulfide bonded SV2A,B,CBoNT/C LC disulfide bonded STX1B SV2C Zn2+ STX1A(?-288) VAMP1Zn2+ GD3BoNT/A LC VAMP1(1-83)STX1A(1-?) H+H+BoNT/C HC disulfide bonded BoNT/A HCSV2A SV2A SV2B GM1a SV2A BoNT/E HCNTNHAVAMP2STX1B(?-288) BoNT/C:GT1bBoNT/B:SYT:GT1bGT1bGT1bBoNT/A HC disulfide bonded GD2SV2B SV2A SV2A,B,CSV2A BoNT/G LC disulfide bonded SV2A Zn2+ Zn2+ SV2B GD3 VAMP2(82-116)SYT1Zn2+ TeNT HC disulfide bonded BoNT/D LC disulfide bonded BoNT/E HC:LC dimerZn2+ BoNT/G LC:Zn2+Zn2+ BoNT/E LC disulfide bonded SV2A,BSV2A,B,CBoNT/G:SYT1:GT1bGM1aSV2A ha33 Zn2+ GT1bVAMP2(2-59)SV2B BoNT/D HCSV2B BoNT/B HCBoNT/E HC disulfide bonded SV2C BoNT/F HCBoNT/E:SV2:GT1bGT1b BoNT/E HC disulfide bonded STX1Zn2+ Zn2+ TeNT HC disulfide bonded BoNT/C:GT1bBoNT/F LC disulfide bonded SV2A BoNT/D:SV2:GD2Zn2+ SNAP25(198-206)SV2A,B,CTeNT HC:LC dimerBoNT/D LC disulfide bonded Zn2+ SV2B SYT1 Zn2+ BoNT/B LC disulfide bonded Zn2+ BoNT/F:SV2:GT1bZn2+ BoNT/D HC disulfide bonded GT1bBoNT/A:NTNHA:HASV2C BoNT/D HC disulfide bonded SV2A 2740, 4614, 473792220938, 4838385514, 4742272, 101337, 424094037, 42139422014, 4720, 36, 507, 45131, 211, 21204014, 47131, 21137, 45402914, 477, 4584014, 4720, 36, 5020, 501620, 35, 36, 50202014, 474313404019, 4217, 311398132592038, 481320133814, 4740813207, 45139449, 5111, 32134414, 4740994025, 5049, 5113403842421, 216, 31937


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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