Neurotoxicity of clostridium toxins (Homo sapiens)

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3, 12, 23, 24, 29...24, 39, 433016, 24, 3935, 363029, 33, 41, 52302929, 33, 4129301230, 49, 51, 5515, 30, 38, 48, 5530357, 30, 45, 5530, 38, 49, 556, 8, 3129, 3330, 42, 553026, 30, 37, 42, 557, 34, 502, 10301, 21, 30, 552929, 33, 415, 17, 3126, 30, 37, 42, 5515, 30, 48, 5518, 1918, 22, 464, 24, 39271, 21, 28, 3029, 33, 4111, 3230, 42, 55synaptic vesicle lumensynaptic vesicle lumenendocytic vesicleclathrin-coated endocytic vesiclecytosolcytosolha33SV2A BoNT/B HC disulfide bonded GT1b BoNT/B:NTNHA:HASTX1B(1-?) SV2A BoNT/B LC disulfide bonded BoNT/F HC disulfide bonded Zn2+ BoNT/E HC:LC dimerBoNT/G LC disulfide bonded BoNT/A:NTNHA:HABoNT/D HC disulfide bonded BoNT/C LC:Zn2+SNAP25(1-198)Zn2+ BoNT/E:SV2:GT1bZn2+ Zn2+ BoNT/B HC disulfide bonded BoNT/E LC:Zn2+STX1(1-?)TeNT HC:LC dimerSNAP25(199-206)STX1B(?-288) STX1(?-288)STX1A(?-288) SV2B H+BoNT/G LC:Zn2+BoNT/B:SYT:GT1bha70 SV2C TeNT HC disulfide bonded TeNT:gangliosidesBoNT/D LC disulfide bonded SV2B SV2A,BZn2+ GD3 VAMP2(60-116)Zn2+ SNAP25Zn2+ TeNT LC:Zn2+SV2C TeNT LC disulfide bonded BoNT/D LC:Zn2+SV2B SV2A VAMP1(62-118)SV2B SV2A BoNT/G HC disulfide bonded SV2A SV2A BoNT/E LC GT1bBoNT/A HC disulfide bonded GT1bZn2+ Zn2+ BoNT/E:SV2:GT1bZn2+ Zn2+ BoNT/E:NTNHAGT1b SV2C BoNT/B HCBoNT/A:SV2:GT1bSYT2 BoNT/D:SV2:GD2Zn2+ SV2C SV2B BoNT/B LC H+GM1a BoNT/F HC:LC dimerGT1b BoNT/C LC disulfide bonded BoNT/D:SV2:GD2BoNT/B LC disulfide bonded SV2C BoNT/A LC disulfide bonded VAMP2(77-116)GT1bSV2A GD2SNAP25(199-206)Zn2+ H+SV2A GD3 H+ha70Zn2+ BoNT/C LC disulfide bonded SYT1 BoNT/F HC disulfide bonded SV2B STX1A(1-?) BoNT/C HC disulfide bonded SV2C BoNT/D HC disulfide bonded SV2B TeNT LC VAMP1(1-83)SV2C VAMP1(1-61)BoNT/A LC disulfide bonded SYT2 VAMP2(2-59)SV2A,B,CSNAP25(1-198)BoNT/D LC disulfide bonded BoNT/B HC disulfide bonded SYT1 TeNT LC disulfide bonded GT1b BoNT/B HC disulfide bonded BoNT/A LC TeNT HC disulfide bonded BoNT/B LC:Zn2+SNAP25(1-197)H+SV2B GT1bBoNT/F:SV2:GT1bZn2+ BoNT/G HCSV2B VAMP2(77-116)BoNT/F LC disulfide bonded SYT1 TeNT LC disulfide bonded BoNT/E LC disulfide bonded SV2A SV2A SYT1,2BoNT/G LC disulfide bonded BoNT/A:SV2:GT1bGT1b BoNT/F LC:Zn2+BoNT/G:SYT1:GT1bBoNT/A LC:Zn2+Zn2+ ha17 Zn2+ Zn2+ VAMP2(2-76)BoNT/C:GT1bGM1a GT1b BoNT/A LC disulfide bonded BoNT/C HC disulfide bonded TeNT HCVAMP2(59-116)SYT1 GM1aSV2C SV2A,B,CBoNT/F HC disulfide bonded BoNT/A HC disulfide bonded VAMP1Zn2+ GD3Zn2+ SV2C VAMP1(61-118)BoNT/C:GT1bZn2+ STX1A SV2A BoNT/D HC:LC dimerBoNT/E LC disulfide bonded GT1bVAMP1(1-60)BoNT/G LC SV2A BoNT/F LC SV2B VAMP2(2-76)Zn2+ SV2B SNAP25GM1a VAMP2SV2A,B,CSV2B BoNT/E HC disulfide bonded NTNHA SNAP25VAMP2Zn2+ SYT2 ha33 BoNT/D LC disulfide bonded GD3GD2 TeNT HC disulfide bonded SV2B NTNHA BoNT/C HCNTNHASYT1TeNT HC disulfide bonded BoNT/D HC disulfide bonded SV2A Zn2+ VAMP2(82-116)Zn2+ H+SNAP25(198-206)SV2A VAMP2(2-81)ha17GT1b GT1b Zn2+ BoNT/A HC:LC dimerZn2+ Zn2+ VAMP1BoNT/G:SYT1:GT1bH+BoNT/E LC disulfide bonded SV2A SV2A,B,CH+GT1bVAMP1(84-118)BoNT/D HCSV2B BoNT/F HCSV2A STX1B Zn2+ GM1aBoNT/D LC BoNT/G HC:LC dimerNTNHA Zn2+ BoNT/E HC disulfide bonded GD3 SYT1,2GT1bBoNT/E LC disulfide bonded GT1b SV2A,B,CTeNT:gangliosidesBoNT/G HC disulfide bonded GT1bBoNT/B:SYT:GT1bZn2+ TeNT:gangliosidesSV2A,BBoNT/C LC disulfide bonded BoNT/A LC disulfide bonded BoNT/E HC disulfide bonded ha33 BoNT/A HC disulfide bonded BoNT/F LC disulfide bonded BoNT/E HCBoNT/F LC disulfide bonded SYT2 BoNT/A HC disulfide bonded GD2BoNT/C HC:LC dimerVAMP2(2-58)VAMP2GT1b VAMP2BoNT/B LC disulfide bonded ha70 BoNT/C LC GT1b NTNHAGD2 Zn2+ GT1bZn2+ SV2B SV2B SV2C BoNT/G HC disulfide bonded BoNT/F:SV2:GT1bBoNT/B LC disulfide bonded GT1b SV2C Zn2+ SV2A,B,CZn2+ BoNT/E HC disulfide bonded Zn2+ ha17 GT1bBoNT/B HC:LC dimerSYT1STX1BoNT/C HC disulfide bonded SYT1 TeNT LC disulfide bonded SYT1 BoNT/G LC disulfide bonded SV2C BoNT/A HCGT1b4340849, 511382, 10401314, 4737204013201, 21131337404011, 3240, 469227, 4514, 4719, 421, 21272038, 4820938, 481620, 36, 5013291, 2117, 313814, 4738134020, 5014, 47134014, 4737, 42421, 2114, 477, 457, 452513201314, 4746, 319914, 474098914, 474238134420424020, 35, 36, 503852797, 459421337, 4249, 51920, 36, 5020135925, 5013204040


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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