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 Enns, Pamela J. Björkman

Research output: Contribution to journalArticle

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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 2005

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Transferrin Receptors
Transferrin
Carrier Proteins
Iron
Binding Sites
Endosomes
Electron Spin Resonance Spectroscopy
Histidine
Spectrum Analysis
holotransferrin

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin. / Giannetti, Anthony M.; Halbrooks, Peter J.; Mason, Anne B.; Vogt, Todd M.; Enns, Caroline; Björkman, Pamela J.

In: Structure, Vol. 13, No. 11, 11.2005, p. 1613-1623.

Research output: Contribution to journalArticle

Giannetti, Anthony M. ; Halbrooks, Peter J. ; Mason, Anne B. ; Vogt, Todd M. ; Enns, Caroline ; Björkman, Pamela J. / The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin. In: Structure. 2005 ; Vol. 13, No. 11. pp. 1613-1623.
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