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Transferrin receptor 2: a new molecule in iron metabolism

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Abstract

Transferrin receptor 1 (TfR1) which mediates uptake of transferrin-bound iron, is essential for life in mammals. Recently, a close homologue of human transferrin receptor 1 was cloned and called transferrin receptor 2 (TfR2). A similar molecule has been identified in the mouse. Human transferrin receptor 2 is 45% identical with transferrin receptor 1 in the extracellular domain, but contains no iron responsive element in its mRNA and is apparently not regulated by intracellular iron concentration nor by interaction with HFE. Transferrin receptor 2, like transferrin receptor 1, binds transferrin in a pH-dependent manner (but with 25 times lower affinity) and delivers iron to cells. However, transferrin receptor 2 distribution differs from transferrin receptor 1, increasing in differentiating hepatocytes and decreasing in differentiating erythroblasts. Expression of both receptors is cell cycle dependent. Mutations in the human transferrin receptor 2 gene cause iron overload disease, suggesting it has a role in iron homeostasis.

Introduction

Iron is an essential requirement for the synthesis of molecules that are needed for cellular processes such as proliferation, energy production and oxygen transport. Normally iron is transported in the plasma in a non-toxic form bound to the plasma protein transferrin, which delivers iron to almost all cells in the body by a transferrin receptor mediated process. Until recently, only one type of human transferrin receptor 1 (TfR1) had been identified. However, in 1999, Kawabata et al. [1] cloned a second human transferrin receptor 2 (TfR2) that was mapped to chromosome 7q22 and had significant sequence homology with TfR1, and also mediated the cellular uptake of transferrin-bound iron. In this review the structure, distribution and regulation of expression of TfR2 and its putative role in iron homeostasis will be addressed.

Section snippets

Structure

Two transcripts of human TfR2 gene have been identified, an alpha form (TfR2-α) which is 2.9 kb long and a beta form (TfR2-β) which is 2.5 kb in length. The TfR2-α form has 18 exons and encodes an 802 amino acid type II transmembrane protein that consists of cytoplasmic, transmembrane and a long extracellular domain containing the C-terminus. The extracellular domain has a high degree of homology (45% identity and 66% similarity) with TfR1 and contains two cysteine residues, suggesting the

Biological function

To determine if TfR2 is able to mediate the uptake of transferrin-bound iron Kawabata et al. [1] transfected CHO cells that do not express either TfR1 or TfR2, with TfR2 cDNA. An increase in biotin-labelled transferrin binding by cells transfected with TfR2 was detected by flow cytometry. The binding was specific for transferrin as it was displaced by an excess of unlabelled transferrin but not by lactoferrin [1]. The affinity of TfR2 for transferrin was 25–30-fold less than that of TfR1 [5],

Medical applications

Patients with mutations in TfR2 (termed HFE3) develop characteristics typical of the iron overload disease haemochromatosis [11]. The frequency of TfR2 mutations is low and they have been detected in several Italian families and not in other patients of Asian, American or European descent with non-HFE iron overload [12]. Four mutations in TfR2 have been identified. The first is a nonsense mutation Y250X in exon 6 [13] and the second mutation is E60X in exon 2 causing a premature stop codon at

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