The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin

Anthony M. Giannetti, Peter J. Halbrooks, Anne B. Mason, Todd M. Vogt, Caroline A. Enns, Pamela J. Björkman

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1613-1623
Number of pages11
JournalStructure
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2005

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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