Scientific article on anthrax edema factor structure, undated

NYC 9/11 Public Portal Document

Experts Dissect Last Layer of Anthrax Toxin By NICHOLAS WADE Activating a Toxin Scientists have worked out the exact Edema factor, an anthrax toxin, changes CELL PROTEIN three-dimensional structure of the edema shape when it reacts with a common cell CALMODULIN factor, the last of three components in the protein. The shape change activates the deadly toxin produced by the anthrax bacte­ toxin, and it deranges the cell's internal rium. The knowledge should help in imder- signaling process. Art standing how the edema factor works and in devising drugs to block it. ■ The structures of the other two, known as lethal factor and protective antigen, have already been worked out by the same tech­ nique, known as X-ray crystallography, an arduous way of visualizing structures too EDEMA FACTOR small to be picked up by light. (ACTIVE) With the three toxin components deci­ phered, biologists are beginning to under­ stand the extraordinary cunning with which the anthrax bacterium first stifles the EDEMA FACTOR EDEMA FACTOR (INERT) CHANGING SHAPE body’s immune system by blocking the sig­ Illustration by Chester L. Drum nals that coordinate its usual defense I * against bacterial invasion. The structure of the edema factor, so seem to be their principal target Mr. Drum macrophages are suddenly killed, releasing called because it causes swelling, was and his colleagues have found that the ede­ a flood of pent-up cytokines. The cytokines, worked out by Chester L.' Drum of the ma factor, which is harmless while inside which cause a useful inflammatory re­ University of Chicago, working with Dr. the bacterium, is activated as soon as it sponse in small doses, are lethal en masse. • Wei-Jen Tang, also at the university, and Dr. bumps into a common component of cells. Vessels leak, blood pressure drops, organs Andrew Bohm of Tufts University. They known as calmodulin. It grabs both ends of fail and the victim dies from septic shock. . describe their work in the current issue of the calmodulin, changing shape as it does But another anthrax expert. Dr. John the journal Nature. so. The activated edema factor is able to Collier of Harvard Medical School, said it Anthrax spends most of its time as an generate a small messenger chemical wide­ was not yet clear that the macrophages invisible spore, lurking in soil. When a spore ly used within cells, synthesizing it a thou­ produced cytokines, and that anthrax might is inhaled by a grazing animal, or slips sand times as fast as the cell itself does. kiU by some other means. through a break in the skin, it is swiftly The messenger, known as cyclic AMP, With the victim’s death, the immune sys­ engulfed by a macrophage, a type of cell quickly reaches abnormally high levels, tem is immobilized. The anthrax bacteria . that patrols the body surfaces for invaders. which derange the macrophages and block are free to grow and devour the body’s ■ The anthrax spores, however, are special­ them from performing their usual role of nutrients until they run out of food. Their ized to destroy their captors. They germi­ sending out cytokines to alert the immune lethal orgy ended, they turn back into spores nate into bacteria, burst out into the blood­ system to a bacterial invasion. and wait patiently to repeat the cycle. stream, and flood the body with their three Lethal factor, the other anthrax toxin, Dr. Drum said it took him nearly four toxins. Protective antigen, so named before also inhibits cytokine production, though years to work out the structure of the edema its true role was understood, serves as the through a different mechanism. “The bacte­ factor, a protein he said some ancestral attack vehicle for the other two toxins. The rium is stifling the immune response com­ anthrax bacterium may have hijacked from protective antigen proteins assemble in pletely, so that the body doesn’t know it is an animal cell many millennia ago. , clusters of seven, forming a barrel-shaped being infected,’’ said Dr. Robert C. Lidding- Knowledge of the exact structure of the structure with a docking site for either ton of the Bumham Institute in Torrey three toxins should speed the search for new edema factor or lethal factor, the other two Pines, Calif. Dr. Liddington worked out the drugs, which are likely to be used in combi­ members of the toxic troika. structure of lethal factor last year. nation with antibiotics. Dr. Liddington said The toxin-laden barrels seek and enter Experts are uncertain how anthrax deliv­ drugs against lethal factor might be ready many kinds of ceU, but macrophages again ers its coup de grace. One idea is that the to test in 18 months.

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