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

Giannetti, Anthony M. and Halbrooks, Peter J. and Mason, Anne B. and Vogt, Todd M. and Enns, Caroline A. and Bjorkman, Pamela J. (2005) The Molecular Mechanism for Receptor-Stimulated Iron Release from the Plasma Iron Transport Protein Transferrin. Structure, 13 (11). pp. 1613-1623. ISSN 0969-2126. doi:10.1016/j.str.2005.07.016.

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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.

Item Type:Article
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URLURL TypeDescription ItemSupplemental Data
Mason, Anne B.0000-0003-3097-4589
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2005 Elsevier Ltd. Received 14 June 2005, Revised 19 July 2005, Accepted 23 July 2005, Available online 8 November 2005. Published: November 8, 2005. We thank Peter Snow and Inderjit Nangiana (Caltech Protein Expression Facility) for expression of TfR constructs, Ross MacGillivray for Tf constructs, Angel J. Di Bilio for help with EPR spectroscopy, members of the Björkman, Mason, and Enns labs for critical reading of the manuscript, and Dr. Dennis Chasteen for helpful discussions. This work was supported by the National Institutes of Health (R01 DK60770 [P.J.B.], R01 DK21739 [A.B.M.], R01 DK54488 [C.A.E.]), the Howard Hughes Medical Institute (P.J.B.), a National Research Service Award (5T32-GM-7616 [A.M.G.]), and USDOE DE-FG02-00ER45828 Graduate Assistantship (P.J.H.).
Funding AgencyGrant Number
NIHR01 DK60770
NIHR01 DK21739
NIHR01 DK54488
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Predoctoral Fellowship5T32-GM-7616
Department of Energy (DOE)DE-FG02-00ER45828
Issue or Number:11
Record Number:CaltechAUTHORS:20170327-143107189
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Official Citation:Anthony M. Giannetti, Peter J. Halbrooks, Anne B. Mason, Todd M. Vogt, Caroline A. Enns, Pamela J. Björkman, The Molecular Mechanism for Receptor-Stimulated Iron Release from the Plasma Iron Transport Protein Transferrin, Structure, Volume 13, Issue 11, November 2005, Pages 1613-1623, ISSN 0969-2126, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75433
Deposited By: Ruth Sustaita
Deposited On:28 Mar 2017 18:45
Last Modified:15 Nov 2021 16:33

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