Binary Bacterial Toxins: Biochemistry, Biology, and Applications of CommonClostridiumandBacillusProteins

Abstract

Certain pathogenic species of Bacillus and Clostridium have developed unique methods for intoxicating cells that employ the classic enzymatic “A-B” paradigm for protein toxins. The binary toxins produced by B. anthracis, B. cereus, C. botulinum, C. difficile, C. perfringens, and C. spiroforme consist of components not physically associated in solution that are linked to various diseases in humans, animals, or insects. The “B” components are synthesized as precursors that are subsequently activated by serine-type proteases on the targeted cell surface and/or in solution. Following release of a 20-kDa N-terminal peptide, the activated “B” components form homoheptameric rings that subsequently dock with an “A” component(s) on the cell surface. By following an acidified endosomal route and translocation into the cytosol, “A” molecules disable a cell (and host organism) via disruption of the actin cytoskeleton, increasing intracellular levels of cyclic AMP, or inactivation of signaling pathways linked to mitogen-activated protein kinase kinases. Recently, B. anthracis has gleaned much notoriety as a biowarfare/bioterrorism agent, and of primary interest has been the edema and lethal toxins, their role in anthrax, as well as the development of efficacious vaccines and therapeutics targeting these virulence factors and ultimately B. anthracis. This review comprehensively surveys the literature and discusses the similarities, as well as distinct differences, between each Clostridium and Bacillus binary toxin in terms of their biochemistry, biology, genetics, structure, and applications in science and medicine. The information may foster future studies that aid novel vaccine and drug development, as well as a better understanding of a conserved intoxication process utilized by various gram-positive, spore-forming bacteria

Alternative Splicing in Class V Myosins Determines Association with Rab10

“…Channels formed by toxin A in lipid bilayers had a single-channel conductance of about 1 to 2 nanosiemens in 1 M KCl. This result suggests that toxin A-induced channels have approximately the same dimensions as channels formed by porins (57) or by the binding components of C2 and anthrax toxins (53,58). It is noteworthy that toxin A and toxin B insert into artificial bilayers in the absence of any specific receptors.…”

Synergistic allelochemicals from a freshwater cyanobacterium

“…A similar situation was described in the synergistic antifungal activity of two classes of cyclic peptides obtained from the freshwater cyanobacterium Anabaena laxa (48). Other examples include the proteic "binary toxin" systems of several gram-positive bacteria, most notably the anthrax toxin (49). In such systems, proteins are structurally different and play distinct roles and in combination result in the toxic effect.…”

Microsphere‐based protease assays and screening application for lethal factor and factor Xa

“…HyperCyt Ò , combined with our protease assay system, will enable us to screen for inhibitors of LF and other medically relevant proteases in a low cost high-throughput fashion. Inhibition of LF itself has been implicated to be a better pharmaceutical target than the LF protective antigen interaction (28), which is currently under intense investigation as a pharmaceutical and second generation vaccine target (34).…”