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This volume focuses on the transport of medically relevant bacterial protein toxins into mammalian cells, and on novel pharmacological strategies to inhibit toxin uptake. The first chapters review our current understanding of the cell-surface receptors and cellular transport processes of Clostridium botulinum neurotoxins, Clostridium botulinum C3 toxin, Clostridium difficile toxins, binary clostridial enterotoxins, anthrax toxins and diphtheria toxin. In brief, specific binding/transport (B) subunits deliver the enzyme (A) subunits into the cytosol, where the latter modify their substrates, producing cytotoxic effects and the characteristic toxin-associated diseases. Key mechanisms for the transport of the A subunits from endosomes into the cytosol and the role of trans-membrane pores formed by the B subunits and host cell chaperones for this process are reviewed. The book’s closing chapters focus on compounds which inhibit the transport of the A subunits from endosomes into the cytosol and therefore might lead to novel therapeutic strategies for toxin-associated diseases. These substances include pharmacological inhibitors of the host cell chaperones involved, as well as multivalent and heterocyclic molecules that specifically block the toxins’ translocation channels. This volume offers an up-to-date resource for scientists.

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This volume focuses on the transport of medically relevant bacterial protein toxins into mammalian cells, and on novel pharmacological strategies to inhibit toxin uptake. The first chapters review our current understanding of the cell-surface receptors and cellular transport processes of Clostridium botulinum neurotoxins, Clostridium botulinum C3 toxin, Clostridium difficile toxins, binary clostridial enterotoxins, anthrax toxins and diphtheria toxin. In brief, specific binding/transport (B) subunits deliver the enzyme (A) subunits into the cytosol, where the latter modify their substrates, producing cytotoxic effects and the characteristic toxin-associated diseases. Key mechanisms for the transport of the A subunits from endosomes into the cytosol and the role of trans-membrane pores formed by the B subunits and host cell chaperones for this process are reviewed. The book’s closing chapters focus on compounds which inhibit the transport of the A subunits from endosomes into the cytosol and therefore might lead to novel therapeutic strategies for toxin-associated diseases. These substances include pharmacological inhibitors of the host cell chaperones involved, as well as multivalent and heterocyclic molecules that specifically block the toxins’ translocation channels. This volume offers an up-to-date resource for scientists.

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Intro -- Preface -- Contents -- 48 Two Feet on the Membrane: Uptake of Clostridial Neurotoxins -- Abstract -- 1 Introduction -- 2 How to Categorise CNT Variants: Serotypes and Subtypes -- 3 How Are CNT Molecules Structured? -- 4 How Do Complex Polysialo Gangliosides Accumulate CNT on the Neuronal Membrane? -- 5 How Do CNT Bind to Complex Gangliosides? -- 6 Which Synaptic Vesicle Proteins Are Receptors of CNT? -- 7 How Do CNT Bind to Synaptotagmin and SV2? -- 8 How Does BoNT Approach the Membrane? -- 9 Outlook -- References -- 50 Uptake of Clostridial Neurotoxins into Cells and Dissemination -- Abstract -- 1 Introduction -- 2 Clostridial Neurotoxins -- 2.1 Botulinum Neurotoxins and Tetanus Neurotoxin Share a Common Structure -- 2.2 Botulinum Neurotoxin Diversity -- 2.3 Botulinum Neurotoxin Complexes -- 2.4 Tetanus Neurotoxin Forms No Complex -- 3 Transport of Botulinum Neurotoxins Through the Intestinal Epithelial Barrier -- 3.1 BoNT Passage Through the Intestinal Epithelial Cell Barrier -- 3.2 BoNT Entry into Intestinal Epithelial Cells -- 3.3 Role of ANTPs in BoNT Passage Through Intestinal Epithelial Barrier -- 4 Dissemination of Botulinum Neurotoxins to the Central Nervous System -- 5 Transport of Tetanus Neurotoxin to the Central Nervous System -- 6 Entry of Clostridial Neurotoxins into Target Neuronal Cells -- 6.1 Binding to Receptors -- 6.2 Endocytosis into Neuronal Cells -- 7 Concluding Remarks -- References -- 17 Receptors and Binding Structures for Clostridium difficile Toxins A and B -- Abstract -- 1 Receptor-Binding Domains of TcdA and TcdB -- 1.1 A/B-Type Structure of Toxins -- 1.2 Functional Characterization of the Receptor-Binding Domains -- 1.2.1 The Combined Repetitive Oligopeptides -- 1.2.2 Additional Receptor-Binding Domains -- 2 Functional Receptors for Binding and Uptake -- 2.1 Carbohydrates and Lipid Structures -- 2.2 Receptors for TcdA -- 2.3 Receptors for TcdB -- 3 Further Toxin Interacting Structures -- 3.1 Ligand Effect of TcdB -- 4 Conclusion -- References -- 44 Cell Entry of C3 Exoenzyme from Clostridium botulinum -- Abstract -- 1 Introduction -- 2 C3 Exoenzyme from Clostridium Botulinum -- 2.1 C3 Exoenzyme as Virulence Factor -- 2.2 C3 Exoenzyme as Cell Biological Tool -- 2.3 C3 Exoenzyme and Enzyme-Independent Effects on Neuronal Function -- 3 Binding and Uptake of C3 Exoenzyme -- 3.1 Effect of Posttranslational Modifications on the Binding of C3 -- 3.2 Uptake of C3 Exoenzyme into Cells -- 3.3 Classical Endocytosis Mechanism and Internalization of C3 Exoenzyme -- 4 Vimentin Mediates Binding and Uptake of C3 -- 4.1 Identification of Vimentin as Binding Partner of C3 -- 4.2 Role of Vimentin in the Uptake of C3 -- 4.3 Significance of Vimentin as a Binding Partner of C3 -- 5 Conclusion -- References -- 46 Receptor-Binding and Uptake of Binary Actin-ADP-Ribosylating Toxins -- Abstract -- 1 Introduction -- 2 Binary Actin-ADP-Ribosylating Toxins -- 2.1 Structure of Binary Toxins -- 2.2 Functions of Binary Actin-ADP-Ribosylat.