Iron is normally transported in plasma and other extracellular fluids bound to transferrin, a bilobal protein which can bind two Fe3+ ions, in octahedral coordination, with four protein ligands and a bidentate carbonate anion . It is taken up by cells via the transferrin-to-cell cycle (Figure 3), which begins with the binding of the holo(diferric)-transferrin molecule (HOLO-TF) to transferrin receptors at the cell surface. The complexes localize to clathrin-coated pits, which pinch off from the membrane to form coated vesicles, initiating the process of endocytosis. After budding is complete, the clathrin coat is removed, and smooth-surfaced endosomes are formed. The pH of the endosome is acidified by the action of an ATP-dependent proton pump. At the acidic pH, the holotransferrin undergoes a conformational change, releasing iron from transferrin as Fe3+, presumably accompanied by protonation of the bound carbonate.
Acidification facilitates proton-coupled transport of iron transport out of the endosomes through the action of the divalent metal transporter, DMT1, a member of the SLC11 family of H+-coupled metal ion transporters . However, the ferric reductase, which is assumed to reduce the iron, prior to its transport out of the endosome by DMT1, has not yet been identified. Apotransferrin (APO-TF) bound to its receptor, returns to the plasma membrane, where, at neutral pH, the complex dissociates. The two proteins can then participate in further rounds of iron delivery. This transferrin-to-cell cycle ensures iron uptake by cells that have transferrin receptors.
Certain specialized cells obtain additional iron by other pathways. The cells of the reticuloendothelial system acquire significant amounts of iron from the phagocytosis and catabolism of red blood cells. And, when there is iron overload, and transferrin is iron-saturated, non-transferrin bound iron, attached to a variety of ligands, is taken up mostly by liver hepatocytes.
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