Abstract
To intoxicate cells, pore-forming bacterial toxins are evolved to allow for the transmembrane traffic of different substrates, ranging from small inorganic ions to cell-specific polypeptides. Recent developments in single-channel electrical recordings, X-ray crystallography, protein engineering, and computational methods have generated a large body of knowledge about the basic principles of channel-mediated molecular transport. These discoveries provide a robust framework for expansion of the described principles and methods toward use of biological nanopores in the growing field of nanobiotechnology. This article, written for a special volume on “Intracellular Traffic and Transport of Bacterial Protein Toxins”, reviews the current state of applications of pore-forming bacterial toxins in small- and macromolecule-sensing, targeted cancer therapy, and drug delivery. We discuss the electrophysiological studies that explore molecular details of channel-facilitated protein and polymer transport across cellular membranes using both natural and foreign substrates. The review focuses on the structurally and functionally different bacterial toxins: gramicidin A of Bacillus brevis, α-hemolysin of Staphylococcus aureus, and binary toxin of Bacillus anthracis, which have found their “second life” in a variety of developing medical and technological applications.
Highlights
Channel-Forming Bacterial ToxinsDuring intoxication or internalization, many bacterial exotoxins form ion-conducting channels in membranes of the targeted cells or intracellular organelles
Gramicidin A can serve as an ideal single molecule on/off switch reacting to different stimuli and as a sensor for lipid membranes properties
The crystal structure of αHL was solved at a 1.9-Å resolution more than 15 years ago and the protein could be genetically or chemically modified in a number of ways. αHL was recently reengineered to form a functional bottom-up dimeric pore than spans two adjacent lipid bilayers [335]
Summary
Many bacterial exotoxins form ion-conducting channels in membranes of the targeted cells or intracellular organelles. We highlight the applications where bacterial toxin pores were used to probe mechanisms of molecule detection and macromolecule transport Some of these applications, for instance those that develop the targeted toxin therapies to battle cancer, directly employ the unique ability of these proteins to intoxicate cells, whereas many other approaches use the channel-forming bacterial toxins as suitable tools able to respond to electrical, chemical or mechanical stimuli [19]. Note that the channel-forming proteins play quite distinct roles in the cell intoxication by PFTs and AB-type bacterial toxins. For the practical purpose of this review, we will use the term ―channel-forming bacterial toxins‖ when referring to any of these types of toxins
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