HFE and Transferrin Directly Compete for Transferrin Receptor in Solution and at the Cell Surface
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Transferrin receptor (TfR) is a dimeric cell surface protein that binds both the serum iron transport protein transferrin (Fe-Tf) and HFE, the protein mutated in patients with the iron overload disorder hereditary hemochromatosis. HFE and Fe-Tf can bind simultaneously to TfR to form a ternary complex, but HFE binding to TfR lowers the apparent affinity of the Fe-Tf/TfR interaction. This apparent affinity reduction could result from direct competition between HFE and Fe-Tf for their overlapping binding sites on each TfR polypeptide chain, from negative cooperativity, or from a combination of both. To explore the mechanism of the affinity reduction, we constructed a heterodimeric TfR that contains mutations such that one TfR chain binds only HFE and the other binds only Fe-Tf. Binding studies using a heterodimeric form of soluble TfR demonstrate that TfR does not exhibit cooperativity in heterotropic ligand binding, suggesting that some or all of the effects of HFE on iron homeostasis result from competition with Fe-Tf for TfR binding. Experiments using transfected cell lines demonstrate a physiological role for this competition in altering HFE trafficking patterns.
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In humans, deficiency in Cp results in aceruloplasminemia, which leads to late-onset degeneration of the retina and basal ganglia because of pathologic accumulation of iron in various tissues, including liver, spleen, and pancreas.
“In humans, deficiency in Cp results in a disease called aceruloplasminemia, which leads to late-onset degeneration of the retina and basal ganglia because of the pathologic accumulation of iron in various tissues, including the aforementioned affected tissues as well as the liver, spleen, and pancreas (106).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [106]
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- Authors
- Giannetti, A. M., & Björkman, P. J.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Björkman, Pamela J.
- ORCID
- Björkman, Pamela J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 279
- Issue
- 24
- Pages
- 25866-25875
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2009542872
- Cited by
- 143
- References
- 52
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 1 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 6 · 2012: 7
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- 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 (1 R01 DK60770, R01DK060770)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- transferrin receptor, HFE gene, transferrin, hereditary hemochromatosis, iron homeostasis, ligand competition, ternary complex, negative cooperativity, protein trafficking, cell surface binding
- MeSH terms
- Hemochromatosis Protein, Binding, Competitive, Humans, Membrane Proteins, Receptors, Transferrin, Solutions, Transferrin, Histocompatibility Antigens Class I, Dimerization
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