The International Journal of Biochemistry & Cell Biology
Molecules in focusTransferrin receptor 1
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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