Abstract
Pore-forming toxins (PFTs) form nanoscale pores across target membranes causing cell death. The pore-forming cytolysins of the RTX (repeats in toxin) family belong to a steadily increasing family of proteins characterized by having in their primary sequences a number of glycine- and aspartate-rich nonapeptide repeats. They are secreted by a variety of Gram-negative bacteria and form ion-permeable pores in several cell types, such as immune cells, epithelial cells, or erythrocytes. Pore-formation by RTX-toxins leads to the dissipation of ionic gradients and membrane potential across the cytoplasmic membrane of target cells, which results in cell death. The pores formed in lipid bilayers by the RTX-toxins share some common properties such as cation selectivity and voltage-dependence. Hemolytic and cytolytic RTX-toxins are important virulence factors in the pathogenesis of the producing bacteria. And hence, understanding the function of these proteins at the molecular level is critical to elucidating their role in disease processes. In this review we summarize the current state of knowledge on pore-formation by RTX toxins, and include recent results from our own laboratory regarding the pore-forming activity of adenylate cyclase toxin (ACT or CyaA), a large protein toxin secreted by Bordetella pertussis, the bacterium causative of whooping cough.
Highlights
Proteins that share the ability of creating hydrophilic “holes” that allow the passage of solutes through a wide variety of target membranes are called pore-forming proteins (PFPs); they are found in all kingdoms of life, from bacteria to humans [1,2,3]
In the case of adenylate cyclase toxin, Votjova-Vodolanova et al solved by blue native polyacrylamide gel electrophoresis (BN–PAGE), in erythrocytes membranes, protein bands of ≈400 and 470 kDa, which might correspond to dimers of the 200 kDa toxin polypeptide [69]
After more than thirty years our knowledge on the pore structure that adenylate cyclase toxin (ACT) or other repeat in toxins (RTX) toxins create in the plasma membrane to induce target cell permeabilization remains very limited, and though the abundant mutagenesis studies have resulted in valuable tools to define segments important for pore-forming activity, we still lack a precise delineation of the structural elements directly involved in ACT toxin pores
Summary
Proteins that share the ability of creating hydrophilic “holes” that allow the passage of solutes (water, ions, or other biomolecules) through a wide variety of target membranes are called pore-forming proteins (PFPs); they are found in all kingdoms of life, from bacteria to humans [1,2,3]. PFPs are produced by their originating organisms usually as water-soluble units (generally monomers, dimers in some cases) and bind the target cell through sugars, lipids, or proteins present in the membrane that act as specific receptors. For example Staphylococcus aureus α-hemolysin, Aeromonas hydrophila aerolysin, or lysenin produced by the earthworm Eisenia fetida, among others, were reported for their potential use as single molecule sensors [12,13,14] Such investigations that started in the 1990s by using pore-forming toxins as sensing elements have led to the development of a new, distinct, and highly relevant subfield in nanobiotechnology. We summarize recent information from our own laboratory on pore formation by one such RTX toxin, namely, the adenylate cyclase toxin (ACT or CyaA) secreted by Bordetella pertussis
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