Transferrin receptor 1

doi:10.1016/j.biocel.2004.02.007

The International Journal of Biochemistry & Cell Biology

Volume 36, Issue 11, November 2004, Pages 2137-2143

https://doi.org/10.1016/j.biocel.2004.02.007 Get rights and content

Abstract

With the discovery that transferrin serves as the iron source for hemoglobin-synthesizing immature red blood cells came the demonstration that a cell surface receptor, now known as transferrin receptor 1, is required for iron delivery from transferrin to cells. (A recently described second transferrin receptor, with as yet poorly understood function, will not be discussed in this brief review.) In succeeding years transferrin receptor 1 was established as a gatekeeper for regulating iron uptake by most cells, and the transferrin-to-cell endocytic pathway characterized in detail. HFE, the protein incriminated in the pathogenesis of hereditary hemochromatosis, a disorder of progressive and toxic iron overload, competes with transferrin for binding to receptor, thereby impeding the uptake of iron from transferrin. Mutation of HFE destroys this competition, thus facilitating access of transferrin and its iron to cells. Availability of the crystal structure of transferrin receptor 1, along with those of transferrin and HFE, opened research on molecular mapping of the transferrin-HFE- transferrin receptor interfaces by correlated synchrotron-generated hydroxyl radical footprinting and cryo-electron microscopy. The emerging challenge is to relate structure to the functional effects of receptor binding on the iron-binding and iron-releasing properties of transferrin within the iron-dependent cell.

Section snippets

Historical perspective and general features of receptor-mediated iron uptake from transferrin

The original characterization and naming of transferrin (Tf) as the serum protein with two specific Fe³⁺-binding sites (Holmberg & Laurell, 1947, Laurell & Ingelman, 1947) led to the demonstration that Tf serves as iron source for hemoglobin synthesis (Jandl, Inman, Simmons, & Allen, 1959). The latter was accompanied by the recognition that cellular uptake of Tf-borne iron requires interaction of the protein with a specific Tf receptor now known as TfR1 (Jandl et al., 1959). (A recently

Structure of TfR1

Mammalian TfR1 is a homodimer of disulfide-bonded 760-residue subunits (Hu & Aisen, 1978; McClelland et al., 1984, Seligman et al., 1979). From the primary sequence three regions can be identified within each subunit of the protein: a globular extracellular portion (residues 90–760) where Tf binds, a hydrophobic intramembranous region (residues 62–89) and the remaining 61 residues lying within the cytoplasm. Cryo-electron microscopic image reconstruction of phospholipid-reconstituted TfR1

Structural considerations

Hereditary hemochromatosis, one of the commonest genetic aberrations of man, is characterized by accumulation of iron to toxic, even lethal, levels in virtually all tissues. The disease is caused by a mutation in a gene, HFE, encoding a protein similar to class I molecules of the major histocompatibility complex (Feder et al., 1996). The mutation, Cys260Tyr in the mature protein, disrupts the formation of a disulfide bond required for non-covalent association of the protein with

Problem and prospects

The convergence of new technologies on revealing structures of Tf–TfR1 complexes justifies optimism of continued success. A persistent challenge is in relating structural information to the functional effects of TfR1 on the iron-binding and iron-releasing activities of Tf. Given the pace of recent progress, culmination of ongoing research in a detailed understanding of structure and its effect on function may be confidently anticipated.

Acknowledgements

Preparation of this manuscript was supported in part by Grant 1 PO1 DK55495 from the National Institutes of Health, U.S. Public Health Service.

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Molecules in focusTransferrin receptor 1

Abstract

Section snippets

Historical perspective and general features of receptor-mediated iron uptake from transferrin

Structure of TfR1

Structural considerations

Problem and prospects

Acknowledgements

Journal of Biological Chemistry

Structure

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Cell

Journal of Molecular Biology

Cell

Journal of Biological Chemistry

Cell

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

Receptor-modulated iron release from transferrin: Differential effects on N- and C-terminal sites

Biochemistry

Receptor-induced switch in site–site cooperativity during iron release by transferrin

Biochemistry

A new role for the transferrin receptor in the release of iron from transferrin

Biochemistry

Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor

Nature

Molecules in focus
Transferrin receptor 1