ADP-ribosylating toxins modifying the actin cytoskeleton

Barth, Holger; Stiles, Bradley G.; Popoff, Michel R.

doi:10.1016/b978-0-12-800188-2.00014-8

Cited by 4 publications

(1 citation statement)

References 166 publications

(236 reference statements)

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“…A group of clostridial binary channel-forming toxins (Knapp et al 2015a): C2 (Ohishi and Odagiri 1984; Aktories et al 1986; Simpson 1984), iota (Simpson et al 1987; Stiles and Wilkins 1986), and CDT (Popoff et al 1988) are related both structurally and functionally. They are made of two components where the A subunit acts through mono-ADP-ribosylation of G-actins (Aktories and Wegner 1989; Barth et al 2015) and the B subunit binds and mediates delivery of the A subunit into the cytosol (Barth and Stiles 2008). PA and clostridial binary toxin B subunits have high degrees (from 27 to 38 %) of amino acid homology and are made of four distinct domains, each involved in the host receptor interaction, oligomerization, channel formation, and binding of the A subunits (Petosa et al 1997; Schleberger et al 2006).…”

Section: Multivalent Inhibitors Of Channel-forming Bacterial Exotoxinsmentioning

confidence: 99%

Multivalent Inhibitors of Channel-Forming Bacterial Toxins

Yamini

Nestorovich

2016

Current Topics in Microbiology and Immunology

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Rational design of multivalent molecules represents a remarkable modern tool to transform weak non-covalent interactions into strong binding by creating multiple finely-tuned points of contact between multivalent ligands and their supposed multivalent targets. Here, we describe several prominent examples where the multivalent blockers were investigated for their ability to directly obstruct oligomeric channel-forming bacterial exotoxins, such as the pore-forming bacterial toxins and B component of the binary bacterial toxins. We address problems related to the blocker/target symmetry match and nature of the functional groups, as well as chemistry and length of the linkers connecting the functional groups to their multivalent scaffolds. Using the anthrax toxin and AB5 toxin case studies, we briefly review how the oligomeric toxin components can be successfully disabled by the multivalent non-channel-blocking inhibitors, which are based on a variety of multivalent scaffolds.

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Section: Multivalent Inhibitors Of Channel-forming Bacterial Exotoxinsmentioning

confidence: 99%

Multivalent Inhibitors of Channel-Forming Bacterial Toxins

Yamini

Nestorovich

2016

Current Topics in Microbiology and Immunology

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Clostridial Binary Toxins: Basic Understandings that Include Cell Surface Binding and an Internal “Coup de Grâce”

Stiles

2016

Current Topics in Microbiology and Immunology

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Clostridium species can make a remarkable number of different protein toxins, causing many diverse diseases in humans and animals. The binary toxins of Clostridium botulinum, C. difficile, C. perfringens, and C. spiroforme are one group of enteric-acting toxins that attack the actin cytoskeleton of various cell types. These enterotoxins consist of A (enzymatic) and B (cell binding/membrane translocation) components that assemble on the targeted cell surface or in solution, forming a multimeric complex. Once translocated into the cytosol via endosomal trafficking and acidification, the A component dismantles the filamentous actin-based cytoskeleton via mono-ADP-ribosylation of globular actin. Knowledge of cell surface receptors and how these usurped, host-derived molecules facilitate intoxication can lead to novel ways of defending against these clostridial binary toxins. A molecular-based understanding of the various steps involved in toxin internalization can also unveil therapeutic intervention points that stop the intoxication process. Furthermore, using these bacterial proteins as medicinal shuttle systems into cells provides intriguing possibilities in the future. The pertinent past and state-of-the-art present, regarding clostridial binary toxins, will be evident in this chapter.

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