The Molecular Mechanism for Receptor-Stimulated Iron Release from the Plasma Iron Transport Protein Transferrin

• Published in: Structure (London) 2005-11, Vol.13 (11), p.1613-1623
• Main Authors: Giannetti, Anthony M., Halbrooks, Peter J., Mason, Anne B., Vogt, Todd M., Enns, Caroline A., Björkman, Pamela J.
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Antigens, CD - metabolism; Binding Sites; Electron Spin Resonance Spectroscopy; Histidine - metabolism; Humans; Iron - blood; Iron - metabolism; Mutation; Phenylalanine - metabolism; Protein Transport; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Transferrin - metabolism; Tryptophan - metabolism
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2005.07.016

Human transferrin receptor 1 (TfR) binds iron-loaded transferrin (Fe-Tf) and transports it to acidic endosomes where iron is released in a TfR-facilitated process. Consistent with our hypothesis that TfR binding stimulates iron release from Fe-Tf at acidic pH by stabilizing the apo-Tf conformation, a TfR mutant (W641A/F760A-TfR) that binds Fe-Tf, but not apo-Tf, cannot stimulate iron release from Fe-Tf, and less iron is released from Fe-Tf inside cells expressing W641A/F760A-TfR than cells expressing wild-type TfR (wtTfR). Electron paramagnetic resonance spectroscopy shows that binding at acidic pH to wtTfR, but not W641A/F760A-TfR, changes the Tf iron binding site ≥30 Å from the TfR W641/F760 patch. Mutation of Tf histidine residues predicted to interact with the W641/F760 patch eliminates TfR-dependent acceleration of iron release. Identification of TfR and Tf residues critical for TfR-facilitated iron release, yet distant from a Tf iron binding site, demonstrates that TfR transmits long-range conformational changes and stabilizes the conformation of apo-Tf to accelerate iron release from Fe-Tf.