STRUCTURE AND FUNCTION OF DIPHTHERIA TOXIN: FROM PATHOLOGY TO ENGINEERING

Among bacterial protein toxins with an intracellular target, diphtheria toxin is one of the most studied. Since the first publication of its crystal structure in 1992, tremendous progress has been made describing the molecular events involved in its toxicity. However, the precise mechanism of translocation is not fully understood yet. The diphtheria toxin contains three structural domains, each carrying a distinct biological function implicated in the intoxication of the cell. The receptor-binding domain mediates the recognition of a specific receptor on the surface of targeted cells. This binding event allows the internalization of the toxin by the cells and its routing towards acidic intracellular compartments. The translocation (or transmembrane) domain, reacting to the low pH, penetrates the membrane and assists the transport of the catalytic domain through this membrane into the cytoplasm. There, the catalytic domain transfers an ADP-ribose from cytosolic NAD to its substrate, the elongation factor 2. This activity blocks the synthesis of cellular proteins, leading to cell death. All three domains of the diphtheria toxin, isolated or combined with other proteins, are now exploited for their biological properties to design new biotechnological tools and new therapeutics.