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  • 1
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    Common architecture of Tc toxins from human and insect pathogenic bacteria (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉Tc toxins use a syringe-like mechanism to penetrate the membrane and translocate toxic enzymes into the host cytosol. They are composed of three components: TcA, TcB, and TcC. Low-resolution structures of TcAs from different bacteria suggest a considerable difference in their architecture and possibly in their mechanism of action. Here, we present high-resolution structures of five TcAs from insect and human pathogens, which show a similar overall composition and domain organization. Essential structural features, including a trefoil protein knot, are present in all TcAs, suggesting a common mechanism of action. All TcAs form functional pores and can be combined with TcB-TcC subunits from other species to form active chimeric holotoxins. We identified a conserved ionic pair that stabilizes the shell, likely operating as a strong latch that only springs open after destabilization of other regions. Our results provide new insights into the architecture and mechanism of the Tc toxin family.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    A syringe-like injection mechanism in Photorhabdus luminescens toxins (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-22
    Description: Photorhabdus luminescens is an insect pathogenic bacterium that is symbiotic with entomopathogenic nematodes. On invasion of insect larvae, P. luminescens is released from the nematodes and kills the insect through the action of a variety of virulence factors including large tripartite ABC-type toxin complexes (Tcs). Tcs are typically composed of TcA, TcB and TcC proteins and are biologically active only when complete. Functioning as ADP-ribosyltransferases, TcC proteins were identified as the actual functional components that induce actin-clustering, defects in phagocytosis and cell death. However, little is known about the translocation of TcC into the cell by the TcA and TcB components. Here we show that TcA in P. luminescens (TcdA1) forms a transmembrane pore and report its structure in the prepore and pore state determined by cryoelectron microscopy. We find that the TcdA1 prepore assembles as a pentamer forming an alpha-helical, vuvuzela-shaped channel less than 1.5 nanometres in diameter surrounded by a large outer shell. Membrane insertion is triggered not only at low pH as expected, but also at high pH, explaining Tc action directly through the midgut of insects. Comparisons with structures of the TcdA1 pore inserted into a membrane and in complex with TcdB2 and TccC3 reveal large conformational changes during membrane insertion, suggesting a novel syringe-like mechanism of protein translocation. Our results demonstrate how ABC-type toxin complexes bridge a membrane to insert their lethal components into the cytoplasm of the host cell. We believe that the proposed mechanism is characteristic of the whole ABC-type toxin family. This explanation of toxin translocation is a step towards understanding the host-pathogen interaction and the complex life cycle of P. luminescens and other pathogens, including human pathogenic bacteria, and serves as a strong foundation for the development of biopesticides.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gatsogiannis, Christos -- Lang, Alexander E -- Meusch, Dominic -- Pfaumann, Vanda -- Hofnagel, Oliver -- Benz, Roland -- Aktories, Klaus -- Raunser, Stefan -- England -- Nature. 2013 Mar 28;495(7442):520-3. doi: 10.1038/nature11987. Epub 2013 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23515159" target="_blank"〉PubMed〈/a〉
    Keywords: ADP Ribose Transferases/chemistry/metabolism/ultrastructure ; Animals ; Bacterial Proteins/chemistry/*metabolism/ultrastructure ; Bacterial Toxins/chemistry/*metabolism ; Cell Membrane/metabolism ; Cryoelectron Microscopy ; Cytoplasm/metabolism ; Host-Pathogen Interactions ; Insects/cytology/metabolism/microbiology ; Models, Biological ; Models, Molecular ; Photorhabdus/*metabolism/pathogenicity/ultrastructure ; Pore Forming Cytotoxic Proteins/chemistry/*metabolism/ultrastructure ; Protein Conformation ; Protein Transport
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Mechanism of Tc toxin action revealed in molecular detail (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-02-28
    Description: Tripartite Tc toxin complexes of bacterial pathogens perforate the host membrane and translocate toxic enzymes into the host cell, including in humans. The underlying mechanism is complex but poorly understood. Here we report the first, to our knowledge, high-resolution structures of a TcA subunit in its prepore and pore state and of a complete 1.7 megadalton Tc complex. The structures reveal that, in addition to a translocation channel, TcA forms four receptor-binding sites and a neuraminidase-like region, which are important for its host specificity. pH-induced opening of the shell releases an entropic spring that drives the injection of the TcA channel into the membrane. Binding of TcB/TcC to TcA opens a gate formed by a six-bladed beta-propeller and results in a continuous protein translocation channel, whose architecture and properties suggest a novel mode of protein unfolding and translocation. Our results allow us to understand key steps of infections involving Tc toxins at the molecular level.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meusch, Dominic -- Gatsogiannis, Christos -- Efremov, Rouslan G -- Lang, Alexander E -- Hofnagel, Oliver -- Vetter, Ingrid R -- Aktories, Klaus -- Raunser, Stefan -- England -- Nature. 2014 Apr 3;508(7494):61-5. doi: 10.1038/nature13015. Epub 2014 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany [2]. ; Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany. ; Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany. ; Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany. ; 1] Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universitat Freiburg, 79104 Freiburg, Germany. ; 1] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany [2] Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Thielallee 63, 14195 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572368" target="_blank"〉PubMed〈/a〉
    Keywords: ADP Ribose Transferases/metabolism ; Bacterial Toxins/*chemistry/*metabolism ; Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Host Specificity ; Hydrogen-Ion Concentration ; Models, Molecular ; Neuraminidase/chemistry ; Photorhabdus/*chemistry ; Porosity ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Protein Transport ; Protein Unfolding ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Common architecture of Tc toxins from human and insect pathogenic bacteria (2019)
    American Association for the Advancement of Science
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    Publication Date: 2019-10-16
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science
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