Redox Properties of Human Transferrin Bound to Its Receptor

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Abstract
Virtually all organisms require iron, and iron-dependent cells of vertebrates (and some more ancient species) depend on the Fe3+-binding protein of the circulation, transferrin, to meet their needs. In its iron-donating cycle, transferrin is first captured by the transferrin receptor on the cell membrane, and then internalized to a proton-pumping endosome where iron is released. Iron exits the endosome to enter the cytoplasm via the ferrous iron transporter DMT1, a molecule that accepts only Fe2+, but the reduction potential of ferric iron in free transferrin at endosomal pH (∼5.6) is below −500 mV, too low for reduction by physiological agents such as the reduced pyridine nucleotides with reduction potentials of −284 mV. We now show that in its complex with the transferrin receptor, which persists throughout the transferrin-to-cell cycle of iron uptake, the potential is raised by more than 200 mV. Reductive release of iron from transferrin, which binds Fe2+ very weakly, is therefore physiologically feasible, a further indication that the transferrin receptor is more than a passive conveyor of transferrin and its iron.