Molecular Model of AB5 Toxin A Subunit Translocation into the Target Cells

摘要

AB5 toxins are pore-forming protein complexes, which destroy eukaryotic target cells through ADP-ribosylation or N-glycosylation of intracellular enzyme complexes by A_1 subunits. In this paradigm, B subunit pentamer interacts with the target-cell receptors and forms a pore in the cell membrane. Then receptor-mediated endocytosis is induced, and A subunit is translocated into the cytosol. In the present article, we propose a new model of A_1 subunit translocation as a globular structure. It is based on those endosome properties that present it as a phospholipid bilayer “ball” with 3D structure as opposed to planar “unfolding folding” 2D model. Furthermore, the proposed model accounts for membrane phospholipid physical and chemical properties and the activity of membrane-bound K~+/Na~+-and H~+-ATPases. A subunit translocation (together with the B subunit) from the endosome to the cytosol is driven by the proton potential difference generated by H~+-ATPases. This is followed by the reduction of A_1-A_2 disulphide bond by intracellular enzymes, and subunits B and A_2 return back into the endosome, where they are destroyed by endosomal/lysosomal proteases; the membrane pore is closed. Endosome integrates into the cellular membrane (endosome recycling), and membrane-bound enzymatic complexes (ATPases and others) return back to their initial position. The proposed model of receptor-mediated endocytosis is a universal mechanism of membrane reparation and translocation of effector toxin subunits or any other pore-forming proteins into the target cell.