Redox Properties of Human Transferrin Bound to Its Receptor

Abstract

Virtually all organisms require iron, and iron-dependent cells of vertebrates (and some more ancient species) depend on the Fe(3+)-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 Fe(2+), but the reduction potential of ferric iron in free transferrin at endosomal pH (approximately 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 Fe(2+) very weakly, is therefore physiologically feasible, a further indication that the transferrin receptor is more than a passive conveyor of transferrin and its iron.

Human iron transporters

“…because the reduction potential of the iron is more within a range where intracellular reductants can drive the reaction when Fe 3? is associated with Tf-TfR1 [9]. Unless the sequence is as now suggested, there is a need to find a physiological reductant although proof that reduction occurs when the iron is still associated with Tf-TfR1 remains to be supplied.…”

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

“…The endosomal ferrireductase STEAP3 (six-transmembrane epithelial antigen of the prostate 3) reduces the liberated Fe 3ϩ to Fe 2ϩ (39), which is subsequently transported into the cytosol via DMT1 (9,40). Although it is generally accepted that endosomal Fe 3ϩ is reduced after it is released from transferrin, thermodynamic and kinetic considerations suggest that reduction occurs (via STEAP3 or otherwise) while Fe 3ϩ is still bound to transferrin (41). Interestingly, mice deficient in either STEAP3 or DMT1 (in the hematopoietic compartment) become anemic, but hemoglobin levels can be maintained at ϳ8 g/dl (10, 39), suggesting that erythrocyte precursors may have alternative, although less efficient, means of endosomal ferrireduction and iron transport.…”

EPR and semi-empirical studies as tools to assign the geometric structures of FeIII isomer models for transferrins

“…Abbreviations 6 , tetra-n-butylamonium hexafluorophosphate; ESI-MS, electrospray ionization mass spectrometry; CV, cyclic voltammetry; IR, infrared spectroscopy; EPR, electron paramagnetic resonance spectroscopy; SCE, standard calomel electrode; Fc, ferrocene; Fc + , ferrocenium ion; NHE, normal hydrogen electrode.…”

“…This then leaves the endosome via a membrane metal ion transporter (DMT). 6 In order to better understand this process, the full characterization of transferrins is of fundamental importance. The structures of human lactoferrin, 7 serum transferrin, 8,9 and duck ovotransferrin 10 have all been well studied using X-ray crystallography and are quite similar.…”

“…However, it has recently been demonstrated that the interaction of the Fe III -Tf complex with the membrane transferrin receptor (TfR) raises the potential by more than 200 mV, explaining the Fe III →Fe II reduction in physiological medium. 6 Based on these studies, several articles have been published reporting Fe III complexes with phenolate-and pyridine/imidazole-containing ligands as models for Fe- Figure 1. Graphic representation of the active site of human lactoferrin based on coordinates from the PDB file from reference 9 (1D3K).…”