AB toxins are a distinct class of bacterial poisons responsible for many severe symptoms in infectious diseases. Their unique architecture allows them to specifically target and disrupt host cell functions. Understanding these toxins provides insight into how bacteria cause illness and how their effects might be countered.
Understanding AB Toxin Structure
AB toxins are named for their two-part structure: an “A” subunit and a “B” subunit. The B subunit recognizes and binds to specific receptors on host cell surfaces, directing the toxin to its target. This subunit often consists of multiple identical protein molecules, frequently forming a pentamer.
The A subunit typically consists of a single polypeptide chain and possesses the enzymatic activity that damages the host cell. While the B subunit acts as the delivery vehicle, the A subunit carries out the harmful cellular modifications. These two subunits are linked, either non-covalently or sometimes through disulfide bonds, forming a functional complex.
How AB Toxins Work
AB toxins begin their action with the B subunit’s interaction with the host cell. The B subunit specifically binds to carbohydrate or lipid receptors on the host cell membrane, ensuring the toxin targets particular cell types. Following binding, the entire toxin complex is often internalized into the host cell via receptor-mediated endocytosis.
Once inside the cell, often within an endosome, the environment becomes more acidic. This pH change triggers a conformational shift in the toxin, leading to the separation of the A and B subunits. The active A subunit is then translocated from the endosome into the host cell’s cytoplasm. This allows it to access its intracellular targets.
Within the cytoplasm, the A subunit acts as an enzyme, modifying or inactivating specific host cell proteins. A common activity is ADP-ribosylation, where the A subunit transfers an ADP-ribose group from NAD+ to a target protein. This modification can lead to the inactivation of enzymes, disruption of signaling pathways, or inhibition of protein synthesis, causing cellular dysfunction or death. The B subunit remains associated with the cell membrane or within the endosomal compartment, having completed its delivery role.
Common AB Toxins and Their Impact
Cholera toxin, produced by Vibrio cholerae, causes severe diarrheal disease. Its A subunit ADP-ribosylates a G-protein regulating adenylate cyclase, leading to excessive cyclic AMP production and massive fluid and electrolyte secretion into the intestine. Diphtheria toxin, from Corynebacterium diphtheriae, disrupts protein synthesis in host cells. Its A subunit directly inactivates elongation factor 2 (eEF2) through ADP-ribosylation, leading to cell death in various tissues, including the heart and nervous system.
Shiga toxin, produced by Shigella dysenteriae and certain E. coli strains like O157:H7, causes bloody diarrhea and can lead to hemolytic-uremic syndrome. The A subunit of Shiga toxin acts as an N-glycosidase, cleaving a specific adenine residue from the 28S ribosomal RNA within the 60S ribosomal subunit. This action inhibits protein synthesis, particularly in intestinal epithelial and kidney endothelial cells. Pertussis toxin, from Bordetella pertussis, is responsible for many symptoms of whooping cough. Its A subunit ADP-ribosylates an inhibitory G-protein, disrupting cellular signaling pathways and affecting immune cell function, which contributes to the characteristic cough and lymphocytosis.
AB Toxins in Medicine
Despite their pathogenic nature, AB toxins have found utility in biological research and medicine due to their highly specific cellular targeting and enzymatic activities. Scientists have repurposed these toxins as valuable tools to investigate various cellular processes, such as protein trafficking, signal transduction, and gene regulation. The precise way the B subunit binds to specific receptors makes them useful probes for studying cell surface molecules.
The distinct A and B subunit functions have also been harnessed for therapeutic applications. The B subunit can be engineered to deliver various payloads, including drugs or diagnostic agents, to specific cell types, acting as a targeted delivery system. The A subunit, when separated from its binding partner, can be modified and used in targeted therapies, such as in certain anti-cancer strategies. For example, modified Diphtheria toxin A subunit has been explored to selectively kill cancer cells by inhibiting their protein synthesis without affecting healthy cells.