Botulinum neurotoxins: genetic, structural and mechanistic insights
Tóm tắt
Từ khóa
Tài liệu tham khảo
Popoff, M. R. & Bouvet, P. Genetic characteristics of toxigenic Clostridia and toxin gene evolution. Toxicon 75, 63–89 (2013).
Johnson, E. A. & Montecucco, C. in Handbook of Clinical Neurology Vol. 91, 333–368 (ed. Engel, A. G.) (Elsevier, 2008).
Schiavo, G., Matteoli, M. & Montecucco, C. Neurotoxins affecting neuroexocytosis. Physiol. Rev. 80, 717–766 (2000).
Centers for Disease Control and Prevention, Department of Health and Human Services. Possession, use, and transfer of select agents and toxins; biennial review. Final rule. Fed. Regist. 77, 61083–61115 (2012).
Arnon, S. S. et al. Botulinum toxin as a biological weapon: medical and public health management. J. Am. Med. Ass. 285, 1059–1070 (2001).
Lim, E. C. & Seet, R. C. Use of botulinum toxin in the neurology clinic. Nature Rev. Neurol. 6, 624–636 (2010).
Smith, L. D. S. & Sugiyama, H. Botulism: the Organism, its Toxins, the Disease (Charles C. Thomas Publisher, 1988).
Hill, K. K. & Smith, T. J. Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes. Curr. Top. Microbiol. Immunol. 364, 1–20 (2013).
Rocke, E. T. & Samuel, M. D. Water and sediment characteristics associated with avian botulism outbreaks in wetlands. J. Wildl. Management 63, 1249–1260 (1999).
Aureli, P. et al. Two cases of type E infant botulism caused by neurotoxigenic Clostridium butyricum in Italy. J. Infect. Dis. 154, 207–211 (1986). This is the first report of botulism caused by a clostridial species other than C. botulinum.
Koepke, R., Sobel, J. & Arnon, S. S. Global occurrence of infant botulism, 1976–2006. Pediatrics 122, e73–e82 (2008).
Chertow, D. S. et al. Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. J. Am. Med. Ass. 296, 2476–2479 (2006).
Dover, N., Barash, J. R., Hill, K. K., Xie, G. & Arnon, S. S. Molecular characterization of a novel botulinum neurotoxin type H gene. J. Infect. Dis. 209, 192–202 (2014).
Lacy, D. B., Tepp, W., Cohen, A. C., DasGupta, B. R. & Stevens, R. C. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nature Struct. Biol. 5, 898–902 (1998). This study reports the first crystal structure of a BoNT and provides the molecular basis for understanding the mechanism of neuron intoxication.
Swaminathan, S. & Eswaramoorthy, S. Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nature Struct. Biol. 7, 693–699 (2000).
Kumaran, D. et al. Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation. J. Mol. Biol. 386, 233–245 (2009).
Gu, S. et al. Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science 335, 977–981 (2012). This study reports the unexpected finding that NTNHA adopts a similar fold to BoNT and that together, the two proteins form an interlocked complex, which suggests that NTNHA stabilizes BoNT and protects the toxin against proteolytic cleavage.
Bonventre, P. F. Absorption of botulinal toxin from the gastrointestinal tract. Rev. Infect. Dis. 1, 663–667 (1979).
Ohishi, I. & Sakaguchi, G. Oral toxicities of Clostridium botulinum type C and D toxins of different molecular sizes. Infect. Immun. 28, 303–309 (1980).
Lee, K. et al. Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog. 9, e1003690 (2013).
Benefield, D. A., Dessain, S. K., Shine, N., Ohi, M. D. & Lacy, D. B. Molecular assembly of botulinum neurotoxin progenitor complexes. Proc. Natl Acad. Sci. USA 110, 5630–5635 (2013).
Sugawara, Y. et al. Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin. J. Cell Biol. 189, 691–700 (2010).
Fujinaga, Y., Sugawara, Y. & Matsumura, T. Uptake of botulinum neurotoxin in the intestine. Curr. Top. Microbiol. Immunol. 364, 45–59 (2013).
Couesnon, A., Molgo, J., Connan, C. & Popoff, M. R. Preferential entry of botulinum neurotoxin A H domain through intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine. PLoS Pathog. 8, e1002583 (2012).
Maksymowych, A. B. et al. Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade. Infect. Immun. 67, 4708–4712 (1999).
Restani, L. et al. Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog. 8, e1003087 (2012).
Sheth, A. N. et al. International outbreak of severe botulism with prolonged toxemia caused by commercial carrot juice. Clin. Infect. Dis. 47, 1245–1251 (2008).
Fagan, R. P., McLaughlin, J. B. & Middaugh, J. P. Persistence of botulinum toxin in patients' serum: Alaska, 1959–2007. J. Infect. Dis. 199, 1029–1031 (2009).
Dolly, J. O., Black, J., Williams, R. S. & Melling, J. Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature 307, 457–460 (1984). This study provides the first evidence that BoNTs bind specifically to the presynaptic membrane before entering the nerve terminal.
Montecucco, C. How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem. Sci. 11, 314–317 (1986). This paper proposes that dual receptor binding could account for the high specificity and affinity of tetanus toxin and BoNTs for the presynaptic membrane.
Rummel, A. Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity. Curr. Top. Microbiol. Immunol. 364, 61–90 (2013).
Chai, Q. et al. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444, 1096–1100 (2006).
Jin, R., Rummel, A., Binz, T. & Brunger, A. T. Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 444, 1092–1095 (2006).
Berntsson, R. P., Peng, L., Dong, M. & Stenmark, P. Structure of dual receptor binding to botulinum neurotoxin B. Nature Commun. 4, 2058 (2013). References 35, 36 and 37 describe the crystallographic structure of BoNT/B in complex with both its protein receptor and glycolipid receptor, which provides experimental evidence for the dual receptor binding model.
Montecucco, C., Rossetto, O. & Schiavo, G. Presynaptic receptor arrays for clostridial neurotoxins. Trends Microbiol. 12, 442–446 (2004).
Muraro, L., Tosatto, S., Motterlini, L., Rossetto, O. & Montecucco, C. The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane. Biochem. Biophys. Res. Commun. 380, 76–80 (2009).
Zhang, Y. et al. Structural insights into the functional role of the Hn sub-domain of the receptor-binding domain of the botulinum neurotoxin mosaic serotype C/D. Biochimie 95, 1379–1385 (2013).
Van Heyningen, W. E. Tentative identification of the tetanus toxin receptor in nervous tissue. J. Gen. Microbiol. 20, 310–320 (1959). This paper provides the first experimental evidence that a ganglioside is involved in the neurospecific binding of a clostridial neurotoxin.
Simpson, L. L. & Rapport, M. M. The binding of botulinum toxin to membrane lipids: sphingolipids, steroids and fatty acids. J. Neurochem. 18, 1751–1759 (1971).
Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nature Rev. Mol. Cell Biol. 1, 31–39 (2000).
Prinetti, A., Loberto, N., Chigorno, V. & Sonnino, S. Glycosphingolipid behaviour in complex membranes. Biochim. Biophys. Acta 1788, 184–193 (2009).
Chiba, A., Kusunoki, S., Shimizu, T. & Kanazawa, I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann. Neurol. 31, 677–679 (1992).
Bullens, R. W. et al. Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. J. Neurosci. 22, 6876–6884 (2002).
Fogolari, F., Tosatto, S. C., Muraro, L. & Montecucco, C. Electric dipole reorientation in the interaction of botulinum neurotoxins with neuronal membranes. FEBS Lett. 583, 2321–2325 (2009).
Black, J. D. & Dolly, J. O. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J. Cell Biol. 103, 535–544 (1986).
Strotmeier, J. et al. Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner. Biochem. J. 431, 207–216 (2010).
Karalewitz, A. P., Fu, Z., Baldwin, M. R., Kim, J. J. & Barbieri, J. T. Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry. J. Biol. Chem. 287, 40806–40816 (2012).
Strotmeier, J. et al. The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites. Mol. Microbiol. 81, 143–156 (2011).
Pirazzini, M., Rossetto, O., Bolognese, P., Shone, C. C. & Montecucco, C. Double anchorage to the membrane and intact inter-chain disulfide bond are required for the low pH induced entry of tetanus and botulinum neurotoxins into neurons. Cell. Microbiol. 13, 1731–1743 (2011).
Kitamura, M., Takamiya, K., Aizawa, S. & Furukawa, K. Gangliosides are the binding substances in neural cells for tetanus and botulinum toxins in mice. Biochim. Biophys. Acta 1441, 1–3 (1999).
Yowler, B. C., Kensinger, R. D. & Schengrund, C. L. Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I. J. Biol. Chem. 277, 32815–32819 (2002).
Jacky, B. P. S. et al. Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A). PLoS Pathog. 9, e1003369 (2013).
Nishiki, T. et al. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J. Biol. Chem. 269, 10498–10503 (1994). This study is the first to identify a synaptic vesicle protein receptor for a BoNT by showing that BoNT/B binds to Syt.
Dong, M. et al. Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J. Cell. Biol. 162, 1293–1303 (2003).
Rummel, A. et al. Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. Proc. Natl Acad. Sci. USA 104, 359–364 (2007).
Peng, L. et al. Botulinum neurotoxin D-C uses synaptotagmin I and II as receptors, and human synaptotagmin II is not an effective receptor for type B, D–C and G toxins. J. Cell Sci. 125, 3233–3242 (2012).
Berntsson, R. P., Peng, L., Svensson, L. M., Dong, M. & Stenmark, P. Crystal structures of botulinum neurotoxin dc in complex with its protein receptors synaptotagmin I and II. Structure 21, 1602–1611 (2013).
Dong, M. et al. SV2 is the protein receptor for botulinum neurotoxin A. Science. 312, 592–596 (2006).
Dong, M. et al. Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol. Biol. Cell 19, 5226–5237 (2008).
Mahrhold, S., Rummel, A., Bigalke, H., Davletov, B. & Binz, T. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett. 580, 2011–2014 (2006). References 61, 62 and 63 report that the synaptic vesicle protein SV2 functions as a protein receptor for BoNT/A1 and BoNT/E1.
Mahrhold, S. et al. Identification of the SV2 protein receptor-binding site of botulinum neurotoxin type E. Biochem. J. 453, 37–47 (2013).
Benoit, R. M. et al. Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A. Nature 505, 108–111 (2014).
Colasante, C. et al. Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction. Mol. Neurobiol. 48, 120–127 (2013).
Harper, C. B. et al. Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. J. Biol. Chem. 286, 35966–35976 (2011).
Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006). This paper provides a landmark analysis of the fine structure and molecular composition of synaptic vesicles.
Saheki, Y. & De Camilli, P. Synaptic vesicle endocytosis. Cold Spring Harb. Perspect. Biol. 4, a005645 (2012).
Wohlfarth, K., Goschel, H., Frevert, J., Dengler, R. & Bigalke, H. Botulinum A toxins: units versus units. Naunyn. Schmiedebergs. Arch. Pharmacol. 355, 335–340 (1997).
Rasetti-Escargueil, C., Liu, Y., Rigsby, P., Jones, R. G. & Sesardic, D. Phrenic nerve hemidiaphragm as a highly sensitive replacement assay for determination of functional botulinum toxin antibodies. Toxicon 57, 1008–1016 (2011).
Sun, S., Tepp, W. H., Johnson, E. A. & Chapman, E. R. Botulinum neurotoxins B and E translocate at different rates and exhibit divergent responses to GT1b and low pH. Biochemistry 51, 5655–5662 (2012).
Ahnert-Hilger, G., Holtje, M., Pahner, I., Winter, S. & Brunk, I. Regulation of vesicular neurotransmitter transporters. Rev. Physiol. Biochem. Pharmacol. 150, 140–160 (2003).
Simpson, L. L., Coffield, J. A. & Bakry, N. Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins. J. Pharmacol. Exp. Ther. 269, 256–262 (1994).
Williamson, L. C. & Neale, E. A. Bafilomycin A1 inhibits the action of tetanus toxin in spinal cord neurons in cell culture. J. Neurochem. 63, 2342–2345 (1994). References 75 and 76 show that the acidification of an intracellular compartment by the vesicular ATPase proton pump is a necessary step in nerve intoxication by clostridial neurotoxins.
Sun, S. et al. Receptor binding enables botulinum neurotoxin B to sense low pH for translocation channel assembly. Cell Host Microbe 10, 237–247 (2011).
Montal, M. Botulinum neurotoxin: a marvel of protein design. Annu. Rev. Biochem. 79, 591–617 (2010).
Fischer, A. Synchronized chaperone function of botulinum neurotoxin domains mediates light chain translocation into neurons. Curr. Top. Microbiol. Immunol. 364, 115–137 (2013).
Hoch, D. H. et al. Channels formed by botulinum, tetanus, and diphtheria toxins in planar lipid bilayers: relevance to translocation of proteins across membranes. Proc. Natl Acad. Sci. USA 82, 1692–1696 (1985). This is the first study to describe the formation of ion channels by clostridial neurotoxins in planar lipid bilayers.
Donovan, J. J. & Middlebrook, J. L. Ion-conducting channels produced by botulinum toxin in planar lipid membranes. Biochemistry 25, 2872–2876 (1986).
Blaustein, R. O., Germann, W. J., Finkelstein, A. & DasGupta, B. R. The N-terminal half of the heavy chain of botulinum type A neurotoxin forms channels in planar phospholipid bilayers. FEBS Lett. 226, 115–120 (1987).
Koriazova, L. K. & Montal, M. Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nature Struct. Biol. 10, 13–18 (2003).
Fischer, A. & Montal, M. Crucial role of the disulfide bridge between botulinum neurotoxin light and heavy chains in protease translocation across membranes. J. Biol. Chem. 282, 29604–29611 (2007). This study shows that the disulphide bond that connects the L chain and H chain of BoNT/A1 and BoNT/E1 must be reduced on the cytosolic side of the synaptic vesicle to release the L chain metalloprotease into the cytosol.
Fischer, A. & Montal, M. Single molecule detection of intermediates during botulinum neurotoxin translocation across membranes. Proc. Natl Acad. Sci. USA 104, 10447–10452 (2007).
Sheridan, R. E. Gating and permeability of ion channels produced by botulinum toxin types A and E in PC12 cell membranes. Toxicon 36, 703–717 (1998).
Dalla Serra, M. et al. Conductive properties and gating of channels formed by syringopeptin 25A, a bioactive lipodepsipeptide from Pseudomonas syringae pv. syringae, in planar lipid membranes. Mol. Plant. Microbe Interact. 12, 401–409 (1999).
Fischer, A. et al. Molecular architecture of botulinum neurotoxin E revealed by single particle electron microscopy. J. Biol. Chem. 283, 3997–4003 (2008).
Bade, S. et al. Botulinum neurotoxin type D enables cytosolic delivery of enzymatically active cargo proteins to neurones via unfolded translocation intermediates. J. Neurochem. 91, 1461–1472 (2004).
Galloux, M. et al. Membrane Interaction of botulinum neurotoxin A translocation (T) domain. The belt region is a regulatory loop for membrane interaction. J. Biol. Chem. 283, 27668–27676 (2008).
Fischer, A. et al. Bimodal modulation of the botulinum neurotoxin protein-conducting channel. Proc. Natl Acad. Sci. USA 106, 1330–1335 (2009).
Pirazzini, M. et al. Neutralisation of specific surface carboxylates speeds up translocation of botulinum neurotoxin type B enzymatic domain. FEBS Lett. 587, 3831–3836 (2013).
Schiavo, G. et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992). This study shows that VAMP has an essential role in neurotransmitter release and that both tetanus toxin and BoNT/B cleave the same protein at the same site, despite the different clinical symptoms that they cause.
Schiavo, G., Papini, E., Genna, G. & Montecucco, C. An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin. Infect. Immun. 58, 4136–4141 (1990).
de Paiva, A. et al. A role for the interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that binds to ecto-acceptors and inhibits transmitter release intracellularly. J. Biol. Chem. 268, 20838–20844 (1993).
Eswaramoorthy, S., Kumaran, D., Keller, J. & Swaminathan, S. Role of metals in the biological activity of Clostridium botulinum neurotoxins. Biochemistry 43, 2209–2216 (2004).
Fu, F. N., Busath, D. D. & Singh, B. R. Spectroscopic analysis of low pH and lipid-induced structural changes in type A botulinum neurotoxin relevant to membrane channel formation and translocation. Biophys. Chem. 99, 17–29 (2002).
Puhar, A., Johnson, E. A., Rossetto, O. & Montecucco, C. Comparison of the pH-induced conformational change of different clostridial neurotoxins. Biochem. Biophys. Res. Commun. 319, 66–67 (2004).
Pirazzini, M. et al. Time course and temperature dependence of the membrane translocation of tetanus and botulinum neurotoxins C and D in neurons. Biochem. Biophys. Res. Commun. 430, 38–42 (2013).
Miesenbock, G., De Angelis, D. A. & Rothman, J. E. Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394, 192–195 (1998).
Sankaranarayanan, S. & Ryan, T. A. Real-time measurements of vesicle-SNARE recycling in synapses of the central nervous system. Nature Cell Biol. 2, 197–204 (2000).
Eisenberg, M., Gresalfi, T., Riccio, T. & McLaughlin, S. Adsorption of monovalent cations to bilayer membranes containing negative phospholipids. Biochemistry 18, 5213–5223 (1979).
Nordera, P., Serra, M. D. & Menestrina, G. The adsorption of Pseudomonas aeruginosa exotoxin A to phospholipid monolayers is controlled by pH and surface potential. Biophys. J. 73, 1468–1478 (1997).
Deutsch, J. W. & Kelly, R. B. Lipids of synaptic vesicles: relevance to the mechanism of membrane fusion. Biochemistry 20, 378–385 (1981).
Ledeen, R. W., Diebler, M. F., Wu, G., Lu, Z. H. & Varoqui, H. Ganglioside composition of subcellular fractions, including pre- and postsynaptic membranes, from Torpedo electric organ. Neurochem. Res. 18, 1151–1155 (1993).
Bychkova, V. E., Pain, R. H. & Ptitsyn, O. B. The 'molten globule' state is involved in the translocation of proteins across membranes. FEBS Lett. 238, 231–234 (1988).
Ptitsyn, O. B., Pain, R. H., Semisotnov, G. V., Zerovnik, E. & Razgulyaev, O. I. Evidence for a molten globule state as a general intermediate in protein folding. FEBS Lett. 262, 20–24 (1990).
van der Goot, F. G., Gonzalez-Manas, J. M., Lakey, J. H. & Pattus, F. A 'molten-globule' membrane-insertion intermediate of the pore-forming domain of colicin A. Nature 354, 408–410 (1991). This paper provides the first evidence that a bacterial toxin adopts a molten globular state during membrane translocation.
Kukreja, R. & Singh, B. Biologically active novel conformational state of botulinum, the most poisonous poison. J. Biol. Chem. 280, 39346–39352 (2005).
Meyer, Y., Buchanan, B. B., Vignols, F. & Reichheld, J. P. Thioredoxins and glutaredoxins: unifying elements in redox biology. Annu. Rev. Genet. 43, 335–367 (2009).
Hanschmann, E. M., Godoy, J. R., Berndt, C., Hudemann, C. & Lillig, C. H. Thioredoxins, glutaredoxins, and peroxiredoxins — molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxid. Redox Signal. 19, 1539–1605 (2013).
Berndt, C., Lillig, C. H. & Holmgren, A. Thioredoxins and glutaredoxins as facilitators of protein folding. Biochim. Biophys. Acta 1783, 641–650 (2008).
Pirazzini, M. et al. The thioredoxin reductase–thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals. FEBS Lett. 587, 150–155 (2013). This study provides the first evidence that the thioredoxin reductase–thioredoxin protein disulphide-reducing system reduces the inter-chain disulphide bond of clostridial neurotoxins in the neuronal cytosol.
Dekker, C., Willison, K. R. & Taylor, W. R. On the evolutionary origin of the chaperonins. Proteins 79, 1172–1192 (2011).
Sudhof, T. C. & Rizo, J. Synaptic vesicle exocytosis. Cold Spring Harb. Perspect. Biol. 3, a005637 (2011).
Pantano, S. & Montecucco, C. The blockade of the neurotransmitter release apparatus by botulinum neurotoxins. Cell. Mol. Life Sci. 71, 793–811 (2014).
Binz, T. Clostridial neurotoxin light chains: devices for SNARE cleavage mediated blockade of neurotransmission. Curr. Top. Microbiol. Immunol. 364, 139–157 (2013).
Hayashi, T. et al. Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J. 13, 5051–5061 (1994). This study shows that VAMP, SNAP25 and syntaxin form a tight coiled-coil complex that is resistant to proteolysis by tetanus and botulinum neurotoxins and to SDS.
Sutton, R. B., Fasshauer, D., Jahn, R. & Brunger, A. T. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395, 347–353 (1998). This fundamental paper describes the atomic coiled-coil structure of the SNARE complex and its importance for neurotransmitter release.
Megighian, A. et al. Evidence for a radial SNARE super-complex mediating neurotransmitter release at the Drosophila neuromuscular junction. J. Cell Sci. 126, 3134–3140 (2013).
Kalb, S. R. et al. Discovery of a novel enzymatic cleavage site for botulinum neurotoxin F5. FEBS Lett. 586, 109–115 (2012).
Schiavo, G., Shone, C. C., Rossetto, O., Alexander, F. C. & Montecucco, C. Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J. Biol. Chem. 268, 11516–11519 (1993).
Whitemarsh, R. C. et al. Characterization of botulinum neurotoxin a subtypes1 through 5 by investigation of activities in mice, in neuronal cell cultures, and in vitro. Infect. Immun. 81, 3894–3902 (2013).
Wang, D. et al. Comparison of the catalytic properties of the botulinum neurotoxin subtypes A1 and A5. Biochim. Biophys. Acta 1834, 2722–2728 (2013).
Shoemaker, C. B. & Oyler, G. A. Persistence of botulinum neurotoxin inactivation of nerve function. Curr. Top. Microbiol. Immunol. 364, 179–196 (2013).
Whitemarsh, R. C., Tepp, W. H., Johnson, E. A. & Pellett, S. Persistence of botulinum neurotoxin A subtypes 1–5 in primary rat spinal cord cells. PLoS ONE. 9, e90252 (2014).
Naumann, M. et al. Evidence-based review and assessment of botulinum neurotoxin for the treatment of secretory disorders. Toxicon 67, 141–152 (2013).
Wang, J. et al. A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. J. Biol. Chem. 286, 6375–6385 (2011).
Guo, J., Pan, X., Zhao, Y. & Chen, S. Engineering clostridia neurotoxins with elevated catalytic activity. Toxicon 74c, 158–166 (2013).
Ma, L. et al. Single application of A2 NTX, a botulinum toxin A2 subunit, prevents chronic pain over long periods in both diabetic and spinal cord injury-induced neuropathic pain models. J. Pharmacol. Sci. 119, 282–286 (2012).
Chen, S. & Barbieri, J. T. Engineering botulinum neurotoxin to extend therapeutic intervention. Proc. Natl Acad. Sci. USA 106, 9180–9184 (2009).
Wang, D. et al. Syntaxin requirement for Ca2+-triggered exocytosis in neurons and endocrine cells demonstrated with an engineered neurotoxin. Biochemistry 50, 2711–2713 (2011).
Franciosa, G., Ferreira, J. L. & Hatheway, C. L. Detection of type A, B, and E botulism neurotoxin genes in Clostridium botulinum and other Clostridium species by PCR: evidence of unexpressed type B toxin genes in type A toxigenic organisms. J. Clin. Microbiol. 32, 1911–1917 (1994).
Luquez, C., Raphael, B. H. & Maslanka, S. E. Neurotoxin gene clusters in Clostridium botulinum type Ab strains. Appl. Environ. Microbiol. 75, 6094–6101 (2009).
Carter, A. T., Stringer, S. C., Webb, M. D. & Peck, M. W. The type F6 neurotoxin gene cluster locus of group II Clostridium botulinum has evolved by successive disruption of two different ancestral precursors. Genome Biol. Evol. 5, 1032–1037 (2013).
Dover, N. et al. Clostridium botulinum strain Af84 contains three neurotoxin gene clusters: BoNT/A2, BoNT/F4 and BoNT/F5. PLoS ONE 8, e61205 (2013).
Jahn, R. & Fasshauer, D. Molecular machines governing exocytosis of synaptic vesicles. Nature 490, 201–207 (2012).
Harlow, M. L. et al. Alignment of synaptic vesicle macromolecules with the macromolecules in active zone material that direct vesicle docking. PLoS ONE 8, e69410 (2013).
Zhai, R. G. & Bellen, H. J. The architecture of the active zone in the presynaptic nerve terminal. Physiol. (Bethesda) 19, 262–270 (2004).
Kasai, H., Takahashi, N. & Tokumaru, H. Distinct initial SNARE configurations underlying the diversity of exocytosis. Physiol. Rev. 92, 1915–1964 (2012).
Chernomordik, L. V. & Kozlov, M. M. Mechanics of membrane fusion. Nature Struct. Mol. Biol. 15, 675–683 (2008).
Middlebrook, J. L. & Brown, J. E. Immunodiagnosis and immunotherapy of tetanus and botulinum neurotoxins. Curr. Top. Microbiol. Immunol. 195, 89–122 (1995).
Fairweather, N. F., Lyness, V. A. & Maskell, D. J. Immunization of mice against tetanus with fragments of tetanus toxin synthesized in Escherichia coli. Infect. Immun. 55, 2541–2545 (1987).
Byrne, M. P. & Smith, L. A. Development of vaccines for prevention of botulism. Biochimie 82, 955–966 (2000).
Karalewitz, A. P.-A. & Barbieri, J. T. Vaccines against botulism. Curr. Opin. Microbiol. 15, 317–324 (2012).
Arnon, S. S., Schechter, R., Maslanka, S. E., Jewell, N. P. & Hatheway, C. L. Human botulism immune globulin for the treatment of infant botulism. N. Engl. J. Med. 354, 462–471 (2006).
Garcia-Rodriguez, C. et al. Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nature Biotech. 25, 107–116 (2007).
Lou, J. et al. Affinity maturation of human botulinum neurotoxin antibodies by light chain shuffling via yeast mating. Protein Eng. Des. Sel. 23, 311–319 (2010).
Cheng, L. W., Stanker, L. H., Henderson, T. D., Lou, J. & Marks, J. D. Antibody protection against botulinum neurotoxin intoxication in mice. Infect. Immun. 77, 4305–4313 (2009).
Conway, J. O., Sherwood, L. J., Collazo, M. T., Garza, J. A. & Hayhurst, A. Llama single domain antibodies specific for the 7 botulinum neurotoxin serotypes as heptaplex immunoreagents. PLoS ONE 5, e8818 (2010).
Thanongsaksrikul, J. & Chaicumpa, W. Botulinum neurotoxins and botulism: a novel therapeutic approach. Toxins (Basel) 3, 469–488 (2011).
Li, B. et al. Small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication. Molecules 16, 202–220 (2011).