The Anthrax Toxin: A Molecular Trojan Horse

Abstract

Anthrax is a three protein component exotoxin released by the virulent bacterium Bacillus anthracis that causes cell lethality in its host. In humans and many animals, Bacillus anthracis can enter the body through the lungs, skin, intestines, or bloodstream. Symptoms of Anthrax poisoning are commonly displayed between one day to two months after initial contact. Once the bacterium spores enter the host organism, the spores germinate and the bacterium synthesizes and releases the anthrax endotoxin protein molecules in response to elevated CO2 levels. Anthrax toxin is composed of three protein molecules: protective antigen, edema factor, and the lethal factor. The protective antigen is released by the bacterium as an 83 kDa protein single chain, and then binds to the host cell receptors. It is then cleaved by proteases on the host cell into a smaller 63 kDa assembly competent monomer which assembles on the cell surface as a heptamer. This heptameric ring binds to edema factor and lethal factor. The pre pore three component complex is then endocytosed into the host cell. As the endosome acidifies to pH 5.0, the prepore protective antigen changes shape, and inserts into the endosomal lipid membrane. The bound edema factor and the lethal factor are gradually unfolded and threaded through the protective antigen pore translocon injection system. The translocated edema and lethal factors then refold in the cytoplasm. This threading is facilitated by a pH gradient. During the threading of the lethal and edema factors, the acidic residues of these proteins are first protonated, resulting in a positive charged state. As these enzymatic proteins are threaded through the pore, the proton is lost after crossing a critical phenylalanine clamp loop region and the protein continues to thread in a unidirectional manner into the cytoplasm. Once the translocated enzymes refold in the cytoplasm, the lethal factor disrupts cell signaling and the edema factor disrupts cell homeostasis. To study this translocation mechanism, one can use the 20 kDa N terminal portion of the lethal factor (called LFN) that binds to the pore and removes the enzymatic portion of the protein. Research is progressing where this translocation system is used to deliver drugs that are attached onto the LFN and be transported into cells in a very specific manner. Thus the understanding of this transport mechanism may be important for engineered drug delivery systems. The Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine structure‐function relationships of anthrax.Support or Funding InformationThe Olathe North SMART Team is joint venture between the Medical Professions Academy and the Milwaukee School of Engineering.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.