Mechanism for Multiple Ligand Recognition by the Human Transferrin Receptor
Open accessAbstract
Transferrin receptor 1 (TfR) plays a critical role in cellular iron import for most higher organisms. Cell surface TfR binds to circulating iron-loaded transferrin (Fe-Tf) and transports it to acidic endosomes, where low pH promotes iron to dissociate from transferrin (Tf) in a TfR-assisted process. The iron-free form of Tf (apo-Tf) remains bound to TfR and is recycled to the cell surface, where the complex dissociates upon exposure to the slightly basic pH of the blood. Fe-Tf competes for binding to TfR with HFE, the protein mutated in the iron-overload disease hereditary hemochromatosis. We used a quantitative surface plasmon resonance assay to determine the binding affinities of an extensive set of site-directed TfR mutants to HFE and Fe-Tf at pH 7.4 and to apo-Tf at pH 6.3. These results confirm the previous finding that Fe-Tf and HFE compete for the receptor by binding to an overlapping site on the TfR helical domain. Spatially distant mutations in the TfR protease-like domain affect binding of Fe-Tf, but not iron-loaded Tf C-lobe, apo-Tf, or HFE, and mutations at the edge of the TfR helical domain affect binding of apo-Tf, but not Fe-Tf or HFE. The binding data presented here reveal the binding footprints on TfR for Fe-Tf and apo-Tf. These data support a model in which the Tf C-lobe contacts the TfR helical domain and the Tf N-lobe contacts the base of the TfR protease-like domain. The differential effects of some TfR mutations on binding to Fe-Tf and apo-Tf suggest differences in the contact points between TfR and the two forms of Tf that could be caused by pH-dependent conformational changes in Tf, TfR, or both. From these data, we propose a structure-based model for the mechanism of TfR-assisted iron release from Fe-Tf.
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Regulation of ferritin synthesis by iron is mainly due to posttranscriptional regulation through binding of IRP1 and IRP2 to an IRE in the 5′ UTR of ferritin mRNA.
“The regulation of ferritin synthesis by iron is mainly due to posttranscriptional regulation (107, 129, 262) through the binding of IRP1 and IRP2 to an IRE located in the 5′ UTR of ferritin mRNA (41)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [107]
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- Authors
- Giannetti, A. M., Snow, P. M., Zak, O., & Björkman, P. J.
- Affiliations
- California Institute of Technology (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Björkman, Pamela J
- ORCID
- Björkman, Pamela J
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2003-12-22
- Volume
- 1
- Issue
- 3
- Pages
- e51
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC300677
- OpenAlex
- W2031856351
- Cited by
- 122
- References
- 47
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 8 · 2018: 2 · 2017: 1 · 2016: 6 · 2015: 2 · 2014: 2 · 2013: 4 · 2012: 7
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- California Institute of Technology
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007616, 5T32-GM-7616)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK15056, 1 R01 DK60770, R01DK015056, R01DK060770)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Keywords
- transferrin receptor 1, transferrin, apotransferrin, HFE gene, iron imports, ligand binding, receptor mutants, binding affinity, hereditary hemochromatosis, pH-dependent conformational change, site-directed mutagenesis
- MeSH terms
- Hemochromatosis Protein, Epitopes, Binding Sites, Hemochromatosis, Humans, Hydrogen-Ion Concentration, Iron, Ligands, Membrane Proteins, Models, Chemical, Molecular Sequence Data, Mutation, Protein Binding, Protein Conformation, Receptors, Transferrin, Regression Analysis, Thermodynamics, Transferrin, Histocompatibility Antigens Class I, Gene Library, Mutagenesis, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Surface Plasmon Resonance
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