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| Figure 1. Fully assembled anthrax toxin ready for attack |
Letters containing anthrax spores were mailed to several news media offices and two Democratic U.S. Senators, killing five people and infecting 17 others. The ensuing investigation became "one of the largest and most complex in the history of law enforcement.1 Anthrax is well known for its thorn than its structural beauty which is often underappreciated due to its infamous connection with biological terrorism.
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| Figure 2. Anthrax toxin side view |
Anthrax toxin is a three-protein virulence factor secreted by Bacillus anthracis, and is composed of two A components (also known as lethal factor-LF, a cytotoxic enzyme), one B component (protective antigen-PA), and edema factor (EF). It is an example of a transmembrane protein-delivery system. The toxic complexes form lethal toxin (LT) that consists of protective antigen and lethal factor. Endocytosis of this LT complex causes the protein to unfold and PA region of the toxin to form a B-barrel so that lethal factor can be translocated into the cell similar to a virus inserting its genome into the host cell. The translocated LF then disrupts normal cellular physiology by cleaving mitogen-activated kinases. The mechanism of protein transport in mammalian systems require auxiliary proteins such as ATPases to provide energy to drive translocation. Similar mechanism is employed by the mechanism of protein transport through the anthrax channel which is a self-sufficient protein-translocating machine.2
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| Figure 3. Structural basis for anthrax lethal factor unfolding |
Interestingly, unfolding of this protein is central for translocation into the host cell. Because folded proteins are thermodynamically stable under normal physiological conditions, the unfolding process requires complex and energy-consuming molecular mechanisms. The structural basis for the unfolding of anthrax lethal factor involves dimeric protective antigen oligomers. This structure contains a PA octamer bound to four LF PA-binding domains. The first α-helix and β-strand of each LF(N) unfold and dock into a deep amphipathic cleft on the surface of the PA octamer, which is called the α clamp. The α clamp possesses nonspecific polypeptide binding activity and is functionally relevant to efficient holotoxin assembly, PA.3 This crystal structure of this toxin was obtained and explored to provide insight into the mechanism of translocation-coupled protein unfolding. Though beautiful, each of the subunits seen in the complete assembly of the toxin dissociates and unfolds to burrow their way inside the cell. Like Angel hair in Christmas ornaments, anthrax toxin is beautiful to look at but one should not be in contact with it.
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2. Blaustein, O. Robert. The anthrax toxin channel: a barrel of LFs. The Journal of Cell Biology, 2011.
3. Feld, Geoffrey, Katie Thoren, Alexander, Kintzer, et al. Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers. Nature Structural & Molecular Biology 17(11): 1383-1391, 2010.
