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From Proteopedia

THE ANTHRAX PROTECTIVE ANTIGEN

                                --Student 04:53, 28 April 2013 (IDT)by Matt Wier

Anthrax is a rapid onset disease that comes from the anthrax toxin, which is produced by the bacteria Bacillus anthracis. The toxin consists of three parts: the protective antigen (PA), the lethal factor (LF), and the edema factor (EF). Apart, the components are harmless, but when they are together, they produce a toxin that can be very harmful to the host's intracellular pathways and can inhibit cell signaling.

Tetrameric Structure

The is a tetrameric protein that functions to bind to host receptors on the plasma membrane to translocate the anthrax toxin factors into the host cell. The monomer form contains (1 is red, 2 is yellow, 3 is green, and 4 is blue) that each serve unique functions. The contains a enzyme cleavage site, the binding site for the toxin factors, and two Calcium ions (green) for stabilizaion. The contains a flexible loop to aid in plasma membrane insertion. The interacts with other PA's in the heptamer form. The is the most important domain because it can undergo a conformational change to allow heptamerization to occur. Monomer PA's must oligomerize to form a before it can translocate the toxin into the cell.

Receptor Binding

The two cellular receptors that the PA binds to for translocation are the and plasma membrane receptors. induces a conformational change allowing the PA to form a heptamer and for toxin factors to bind to Domain-1. This conformational change induces receptor-mediated endocytosis to occur. This process forms a vesicle that engulfs the PA heptamer and translocates it across the plasma membrane and into the cytosol where it can then release its anthrax toxic factors to interfere with cellular signaling pathways.

Anthrax Toxin Factors

The two toxin factors that bind to Domain 1 of the PA are the and the . These two factors differ from each other structurally, which allows them to bind to different cellular components and carry out different functions to impair cellular signaling pathways. The LF binds to the of cells and cleaves its . This cleavage releases the phosphorylase kinase domain, which results in blocked MAPKK signaling. MAPKK functions to activate several vital cellular processes, such as cell growth and differentiation, so when the LF inhibits MAPKK, these process do not occur and the cell eventually dies from lack of signaling.

The EF is a continuously active bacterial Adenylate Cyclase that binds to host and produces from the host's ATP. cAMP functions to activate , which functions to activate several cellular pathways, such as glycogen metabolism and urea transportation. cAMP binds to the of PKA on the orange residues to activate it. The overproduction of cAMP from the EF causes PKA to be continuously be activated, which results in the activation of pathways that do not need to be activated. This disrupts the normal functions of the cell and inhibit its intracellular signaling pathways.

Treatment

There are several methods available to treat anthrax. One drug known as inhibits the of the Bacillus anthracis by binding to the active site of the gyrase. This inhibits the gyrase from reannealing the DNA (red, blue, grey), resulting in broken DNA that cannot be replicated. This inhibits the bacteria from multiplying in the host. There is also an anthrax vaccine available that is very effective in providing immunity from the disease.