The mechanism of diphtheria toxin translocation across membranes

This chapter discusses the protein diphtheria toxin because it is concerned with membrane translocation. Diphtheria toxin is a protein secreted by Corynebacterium diphtheriae. It is synthesized as a single polypeptide, but at a site that loops out into solution, it can be readily cleaved by proteolysis into A and B chains. The structure of the toxin in its native conformation at neutral pH has been solved by X-ray crystallography. The crystal structure shows the protein has three domains of roughly equal size. Much progress has been made in understanding the translocation of diphtheria toxin. This progress has been made possible by the elucidation of the cellular entry pathway, in particular the role of low pH in translocation. Studies of the structure of membrane-inserted toxin allow the formulation of a detailed model for the translocation process in the not too-far distant future. The most important role for toxin binding to its receptor is probably to allow the toxin to be taken into the cell by receptor-mediated endocytosis. There is a great deal of evidence that upon endocytosis the toxin reaches the lumen of the endosomal vacuole system.