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Substrates and catalytic mechanism of clostridial neurotoxins


Binz T (2013): Clostridial neurotoxin light chains: devices for SNARE cleavage mediated blockade of neurotransmission. Curr Top Microbiol Immunol 364, 139-157.



Binz T, Sikorra S, and Mahrhold S (2010): Clostridial Neurotoxins: mechanism of SNARE cleavage and outlook on potential substrate specificity reengineering. Toxins 2, 665-682.



Sikorra S, Henke T, Galli T, and Binz T (2008): Substrate recognition mechanism of VAMP/synaptobrevin cleaving clostridial neurotoxins. J Biol Chem 283, 21145-21152.


Jin R, Sikorra S, Stegmann CM, Pich A, Binz T, and Brunger AT (2007): Structural and biochemical studies of botulinum neurotoxin serotype C1 light chain protease: implications for dual substrate specificity. Biochemistry 46, 10685-10693.


Sikorra S, Henke T, Swaminathan S, Galli T, and Binz T (2006): Identification of the amino acid residues rendering TI-VAMP resistant towards botulinum neurotoxin B. J Mol Biol 357, 574-582.


Agarwal R, Binz T, and Swaminathan S (2005): Structural analysis of botulinum neurotoxin serotype F light chain: implications on substrate binding and inhibitor design. Biochemistry 44, 11758-11765.


Agarwal R, Binz T, and Swaminathan S (2005): Analysis of active site residues of botulinum neurotoxin E by mutational, functional and structural studies: Glu335Gln is an apoenzyme. Biochemistry 44, 8291-8302.


Rao KN, Kumaran D, Binz T, and Swaminathan S (2005): Structural analysis of the catalytic domain of tetanus neurotoxin. Toxicon 45, 929-939.


Agarwal R, Eswaramoorthy S, Kumaran D, Binz T, and Swaminathan S (2004): Structural analysis of botulinum neurotoxin type E catalytic domain and its mutant Glu212→Gln reveals the pivotal role of the Glu212 carboxylate in the catalytic pathway.

Biochemistry 43, 6637-6644.


Binz T, Bade S, Rummel A, Kollewe A, and Alves J (2002): Arg-362 and Tyr-365 of Botulinum Neurotoxin Type A Light Chain Are Involved in Transition State Stabilization.

Biochemistry 41, 1717-23.


Li L, Binz T, Niemann H, and Singh BR (2000): Probing the mechanistic role of glutamate residue in the zinc-binding motif of type A botulinum neurotoxin light chain. Biochemistry 39, 2399-405.


Vaidyanathan VV, Jahnz M, Dörries C, Bade S, Nauenburg S, Niemann H, and Binz T (1999): Proteolysis of SNAP-25 isoforms by Botulinum neurotoxin types A, C, and E: domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage. J Neurochem 72, 327-37.


Binz T Blasi J, Yamasaki S, Baumeister A, Link E, Südhof TC, Jahn R, and Niemann H (1994): Proteolysis of SNAP-25 by types E and A botulinal neurotoxins. J Biol Chem 269, 1617-1620.


Blasi J, Binz T, Yamasaki S, Link E, Niemann H, and Jahn R (1994): Inhibition of neurotransmitter release by clostridial neurotoxins correlates with specific proteolysis of synaptosomal proteins. J Physiol (Paris) 88, 235-241.


Dayanithi G, Stecher B, Höhne-Zell B, Yamasaki S, Binz T, Weller U, Niemann H, and Gratzl M (1994): Exploring the functional domain and the target of the tetanus toxin light chain in neurohypophysial terminals. Neuroscience 58, 423-431.


Yamasaki S, Baumeister A, Binz T, Blasi J, Link E, Cornille F, Roques B, Fykse EM, Südhof TC, Jahn R, and Niemann H (1994): Cleavage of members of the synaptobrevin/VAMP family by types D and F botulinal neurotoxins and tetanus toxin. J Biol Chem 269, 12764-12772.


Yamasaki S, Binz T, Hayashi T, Szabo L, Yamasaki N, Eklund M, Jahn R, and Niemann H (1994): Botulinum neurotoxin type G proteolyses the Ala81-Ala82 bond of rat synaptobrevin 2. Biochem Biophys Res Commun 200, 829-835.


Yamasaki S, Hu Y, Binz T, Kalkuhl A, Kurazono H, Tamura T, Jahn R, Kandel E, and Niemann H (1994): Synaptobrevin of Aplysia californica: structure and degradation by tetanus toxin and botulinal neurotoxins type D and F. Proc Natl Acad Sci USA 91, 4688-4692.

Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, DeCamilli P, Südhof TC, Niemann H, and Jahn R (1993): Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365, 160-163.


Blasi J, Chapman ER, Yamasaki S, Binz T, Niemann H, and Jahn R (1993): Botulinum neurotoxin C blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. EMBO J 12, 4821-4828.


Link E, Edelmann L, Chou J, Binz T, Yamasaki S, Eisel U, Baumert M, Südhof TC, Niemann H, and Jahn R (1992): Tetanus toxin action: inhibiton of neurotransmitter release linked to synaptobrevin proteolysis. Biochem Biophys Res Commun 189, 1017-1023.


Kurazono H, Mochida S, Binz T, Eisel U, Quanz M, Grebenstein O, Wernars K, Poulain B, Tauc L, and Niemann H (1992): Minimal essential domains specifying toxicity of the light chains of tetanus toxin and botulinum neurotoxin type A. J Biol Chem 267, 14721-14729.



Translocation of clostridial neurotoxin catalytic domains


Pirazzini M, Azarnia Tehran D, Zanetti G, Megighian A, Scorzeto M, Fillo S, Shone CC, Binz T, Rossetto O, Lista F, and Montecucco C(2014): Thioredoxin and its reductase are present on synaptic vesicles, and their inhibition prevents the paralysis induced by botulinum neurotoxins. Cell Reports 8, 1–9.


Pirazzini M, Henke T, Rossetto O, Mahrhold S, Krez N, Rummel A, Montecucco C, and Binz T (2013): Neutralisation of specific surface carboxylates speeds up translocation of botulinum neurotoxin type B enzymatic domain. FEBS Lett 587, 3831-3836.


Pirazzini M, Rossetto O, Bertasio C, Bordin F, Shone CC, Binz T, and Montecucco C (2013): 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.


Pirazzini M, Bordin F, Rossetto O, Shone CC, Binz T, and Montecucco C (2013): 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.

Bade S, Rummel A, Reisinger C, Karnath T, Ahnert-Hilger G, Bigalke H, and Binz T (2004): Botulinum neurotoxin type D enables cytosolic delivery of enzymatically active cargo proteins to neurons via unfolded translocation intermediates. J Neurochem 91, 1461-1472.



Nerve cell receptors of clostridial neurotoxins


Strotmeier J, Mahrhold S, Krez N, Janzen C, Lou J, Marks JD, Binz T, and Rummel A (2014): Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A. FEBS Lett 588, 1087-1093.


Höltje M, Schulze S, Strotmeier J, Mahrhold S, Richter K, Binz T, Bigalke H, Ahnert-Hilger G, and Rummel A (2013): Exchanging the minimal cell binding fragments of tetanus neurotoxin in botulinum neurotoxin A and B impacts their toxicity at the neuromuscular junction and central neurons. Toxicon 75, 108-121.


Willjes G, Mahrhold S, Strotmeier J, Eichner T, Rummel A, and Binz T (2013): Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: tyrosine 1186 and lysine 1191 cause its lower affinity. Biochemistry 52, 3930-3938.


Mahrhold S, Strotmeier J, Garcia-Rodriguez C, Lou J, Marks, JD, Rummel A, and Binz T (2013): Identification of the SV2-Protein Receptor Binding Site of Botulinum Neurotoxin Type E. Biochem J 453, 37-47.


Strotmeier J, Willjes G, Binz T, and Rummel A (2012): Human synaptotagmin-II is not a high affinity receptor for botulinum neurotoxin B and G: increased therapeutic dosage and immunogenicity. FEBS Lett 586, 310-313.


Rummel A, Mahrhold S, Bigalke H, and Binz T (2011): Exchange of the HCC domain mediating the double receptor recognition improves the pharmacodynamic properties of botulinum neurotoxin. FEBS J 278, 4506-4515.


Strotmeier J, Gu S, Jutzi S, Mahrhold S, Zhou J, Pich A, Eichner T, Bigalke H, Rummel A, Jin R, and Binz T (2011): The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites. Mol Microbiol 81, 143-156.


Strotmeier J, Lee K, Völker AK, Mahrhold S, Zong Y, Zeiser J, Zhou J, Pich A, Bigalke H, Binz T, Rummel A, Jin R (2010): Botulinum neurotoxin serotype D attacks neurons via two carbohydrate binding sites in a ganglioside dependent manner. Biochem J 431, 207-216.


Binz T and Rummel A (2009): Cell entry strategy of clostridial neurotoxins. J Neurochem 109, 1584-1595.



Rummel A, Häfner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, and Binz T (2009): Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J Neurochem 110, 1942-1954.


Rummel A, Eichner T, Weil T, Karnath T, Gutcaits A, Mahrhold S, Sandhoff K, Proia R, Acharya K R, Bigalke H, and Binz T (2007): 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.


Jin R, Rummel A, Binz T, and Brunger AT (2006): Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 444, 1092-1095.


Mahrhold S, Rummel A, Bigalke H, Davletov B, and Binz T (2006): The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 580, 2011-2014.


Rummel A, Karnath T, Henke T, Bigalke H, and Binz T (2004): Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J Biol Chem 279, 30865-30870.


Rummel A, Mahrhold S, Bigalke H, and Binz T (2004): The HCC-domain of botulinum neurotoxins A and B exhibits a singular ganglioside binding site displaying serotype specific carbohydrate interaction. Mol Microbiol 51, 631-643.


Rummel A, Bade S, Alves J, Bigalke H, and Binz T (2003): Two carbohydrate binding sites in the HCC-domain of tetanus neurotoxin are required for toxicity. J Mol Biol 326, 835-847.



Clostridial neurotoxins as tools to study vesicular fusion


Arsenault J, Cuijpers SA, Ferrari E, Niranjan D, Rust A, Leese C, O'Brien JA, Binz T, and Davletov B (2014): Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells. J Neurochem 129, 781-791.


Zylbersztejn K, Petkovic M, Burgo A, Deck M, Garel S, Marcos S, Bloch-Gallego E, Nothias F, Serini G, Bagnard D, Binz T, and Galli T (2012): The vesicular SNARE Synaptobrevin is required for Semaphorin 3A axonal repulsion. J Cell Biol 196, 37-46.


Gutierrez-Martin Y, Bustillo D, Gomez-Villafuertes R, Sanchez-Nogueiro J, Torregrosa-Hetland C, Binz T, Gutierrez LM, Miras-Portugal MT, and Artalejo AR (2011): P2X7 receptors trigger ATP exocytosis and modify secretory vesicle dynamics in neuroblastoma cells. J Biol Chem 286, 11370-11381.


Nouvian R, Neef J, Bulankina AV, Reisinger E, Pangrsic T, Frank T, Sikorra S, Brose N, Binz T, and Moser T (2011): Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins. Nat Neurosci 14, 411-413.


Darios F, Niranjan D, Ferrari E, Zhang F, Soloviev M, Rummel A, Bigalke H, Suckling J, Ushkaryov Y, Naumenko N, Shakirzyanova A, Giniatullin R, Maywood E, Hastings M, Binz T, and Davletov B (2010): SNARE tagging allows stepwise assembly of a multimodular medicinal toxin. Proc Natl Acad Sci USA 107, 18197-18201.


Darios F, Wasser C, Shakirzyanova A, Giniatullin A, Goodman K, Munoz-Bravo JL, Raingo J, Jorgačevski J, Kreft M, Zorec R, Rosa JM, Gandia L, Gutiérrez LM, Binz T, Giniatullin R, Kavalali ET, and Davletov B (2009): Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis. Neuron 62, 683-694.


Sedej S, Gurung, IS, Binz T, and Rupnik M (2009): Phosphatidylinositol-4,5-bisphosphate-dependent facilitation of the ATP-dependent secretory activity in mouse pituitary cells. Ann N Y Acad Sci 1152, 165-173.


Scheuber A, Rudge R, Danglot L, Raposo G, Binz T, Poncer JC, and Galli T (2006): Loss of AP3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses. Proc Natl Acad Sci USA 103, 16562-16567.


Davletov B, Bajohrs M, and Binz T (2005): Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins. Trends Neurosci 28, 446-452.



Yelamanchili SV, Reisinger C, Becher A, Sikorra S, Bigalke H, Binz T, and Ahnert-Hilger G (2005): The C-terminal transmembrane region of synaptobrevin binds synaptophysin from adult synaptic vesicles. Eur J Cell Biol 84, 467-475.


Bajohrs M, Rickman C, Binz T, and Davletov B (2004): A molecular basis underlying differences in the toxicity of botulinum serotypes A and E. EMBO Rep 5, 1090-1095.


Nagy G, Reim K, Matti U, Brose N, Binz T, Rettig J, Neher E, and Sørensen JB (2004): Regulation of releasable vesicle pool sizes by protein kinase A-dependent phosphorylation of SNAP-25. Neuron 41, 351-365.


Rickman C, Meunier FA, Binz T, and Davletov B (2004): High affinity interaction of syntaxin and SNAP-25 on the plasma membrane is abolished by botulinum toxin E. J Biol Chem 279, 644-651.


Nagy G, Matti U, Nehring RB., Binz T, Rettig J, Neher E, and Sørensen JB (2002): Protein kinase C dependent phosphorylation of SNAP-25 at Ser187 potentiates vesicle recruitment. J Neurosci 22, 9278-9286.


Sørensen JB, Matti U, Wei SH, Nehring RB, Voets T, Ashery U, Binz T, Neher E, and Rettig J (2002): The SNARE protein SNAP-25 is linked to fast calcium triggering of exocytosis. Proc Natl Acad Sci USA 99, 1627-32.


Xu T, Binz T, Niemann H, and Neher E (1998): Multiple kinetic components of exocytosis distinguished by neurotoxin sensitivity.

Nature Neurosci 1, 192-200.


Hayashi T, Yamasaki S, Nauenburg S, Binz T, and Niemann H (1995): Disassembly of the reconstituted synaptic vesicle membrane fusion complex in vitro. EMBO J 14, 2317-2325.


Galli T, Chilcote T, Mundigl O, Binz T, Niemann H, and DeCamilli P (1994): Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor containing vesicles in CHO cells. J Cell Biol 125, 1015-1024.


Hayashi T, McMahon H, Yamasaki S, Binz T, Hata Y, Südhof TC, and Niemann H (1994): Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J 13, 5051-5061.


Link E, Blasi J, Chapman ER, Edelmann L, Baumeister A, Binz T, Yamasaki S, Niemann H, and Jahn R (1994): Tetanus and botulinal neurotoxins: tools to understand exocytosis in neurons. Adv. Second Messenger & Phoshoprotein Res 29, 47-58.



McMahon HT, Ushkaryov YA, Edelmann L, Link E, Binz T, Niemann H, Jahn R, and Südhof TC (1993): Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein. Nature 364, 346-349.


Mochida S, Poulain B, Eisel U, Binz T, Kurazono H, Niemann H, and Tauc L (1990): Molecular biology of clostridial toxins: expression of mRNAs encoding tetanus and botulinum neurotoxins in Aplysia neurons. J Physiol (Paris) 84, 278-284.


Mochida S, Poulain B, Eisel U, Binz T, Kurazono H, Niemann H, and Tauc L (1990): Exogenous mRNA encoding tetanus or botulinum neurotoxins expressed in Aplysia neurons. Proc Natl Acad Sci USA 87, 7844-7848.



Genetics and immunology of clostridial neurotoxins


Marvaud JC, Eisel U, Binz T, Niemann H, and Popoff MR (1998): TetR is a positive regulator of the Tetanus toxin gene in Clostridium tetani and is homolgous to BotR. Infect Immun 66, 5698-702.


Niemann H, Binz T, Grebenstein O, Kurazono H, Thierer J, Mochida S, Poulain B, and Tauc L (1991): Clostridial neurotoxins: from toxins to therapeutic tools? Behring Inst Mitt 89, 153-162.



Binz T, Kurazono H, Popoff MR, Eklund MW, Sakaguchi G, Kozaki S, Kriegelstein K, Henschen A, Gill DM, and Niemann H (1990): Nucleotide sequence of the gene encoding Clostridium botulinum neurotoxin type D. Nucl Acids Res 18, 5556.


Binz T, Kurazono H, Wille M, Frevert J, Wernars K, and Niemann H (1990): The complete sequence of botulinum neurotoxin type A and comparison with other clostridial neurotoxins. J Biol Chem 265, 9153-9158.


Hauser D, Eklund MW, Kurazono H, Binz T, Niemann H, Gill DM, Boquet P, and Popoff MR (1990): Nucleotide sequence of Clostridium botulinum C1 neurotoxin. Nucl Acids Res 18, 4924.


Andersen-Beckh B, Binz T, Kurazono H, Mayer T, Eisel U, and Niemann H (1989): Expression of tetanus toxin subfragments in vitro and characterization of epitopes. Infect Immun 57, 3498-3505.



Borna Disease Virus


Kliche S, Stitz L, Mangalam H, Shi L, Binz T, Niemann H, Briese T, and Lipkin WI (1996): Characterization of the Borna disease virus phosphoprotein, p23. J Virol 70, 8133-8137.


Binz T, Lebelt J, Niemann H, and Hagenau K (1994): Sequence analyses of the p24 gene of Borna disease virus in naturally infected horse, donkey and sheep. Virus Res 34, 281-289.


Thierer J, Riehle H, Grebenstein O, Binz T, Herzog S, Thiedemann N, Stitz L, Rott R, Lottspeich F, and Niemann H (1992): The 24K protein of Borna disease virus. J Gen Virol 73, 413-416.


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