Transferrin receptor-2 (TFR2) is a type II transmembrane glycoprotein with significant sequence similarity to the orthologous TFR1. TFR2 is able to bind diferric-transferrin in a pH-dependent manner with an affinity approximately 25-fold lower than TFR1. TFR2 encodes an 801 amino acid protein that consists of a short cytoplasmic domain, a transmembrane domain and a long extracellular domain containing the C-terminus. The C-terminal ectodomain has a protease-associated domain, a peptidase M28-like domain and a dimerization domain with two RGD motifs that are important for protein-protein interactions and transferrin binding. In Fe homeostasis, TFR2 appears to have regulatory rather than transport functions, as TFR2 mutations in humans and TFR2 inactivation in mice result in Fe overload and low hepcidin. TFR2 is mainly expressed in the liver where it is essential for hepcidin control. Its expression is up-regulated during hepatic development but is not modulated by Fe.
|Basic Information of TFR2|
|Protein Name||Transferrin receptor protein 2|
|Organism||Homo sapiens (Human)|
Fe is an essential nutrient required for a variety of biochemical processes such as proliferation, energy production and oxygen transport. To maintain intracellular Fe levels, cells possess tight regulation mechanisms for Fe absorption and metabolism. In vertebrates, Transferrin (Tf) is the major Fe transport protein in the blood that delivers Fe to cells by binding to the TFR2. Human TFR2 is mainly expressed in hepatocytes and erythrocyte precursors. Hepatic TFR2 participates to Fe sensing and is involved in hepcidin activation, although the specific mechanism remains unclear. TFR2 forms a complex with the hemochromatosis protein HFE and acts as a component of the Fe-sensing mechanism in hepatocytes. Mutations in the TFR2 gene cause type 3 hemochromatosis. Mutations result in loss of function, and types of mutations include frameshift, premature cessation, small deletions and missense mutations, which primarily affect the C-terminus of the protein, especially the peptidase-like and dimerization domains. In addition, TFR2 forms a complex with the erythropoietin receptor and regulates erythropoiesis in erythroid cells. TFR2 promotes the transport of Fe from lysosomes to mitochondria in erythroblasts and dopaminergic neurons. Thus, TFR2 is essential to control erythrocyte production in Fe deficiency.
Fig.1 The cartoon on the left human represents TFR dimers (blue and purple monomers) with apical, helix and protease-like domains labeled A, H and P, respectively. The cartoon on the right depicts the proportion of the receptor surface region occupied by two TF molecules (red and faint red). (Maier, 2016)
This review updates and summarizes the knowledge of mammalian transferrin and its receptors.
This study finds that Tfr2 is a key regulator of brain iron homeostasis and suggests the role of Tfr2α in the regulation of anxiety circuits by analyzing Tfr2-KO mice.
This study confirmes that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia.
This review indicates that membrane transferrin receptor-2, a sensor of circulating iron, is released from the cell membrane in iron deficiency.
This article highlights the differences in Tf interactions with the two TfRs (TfR1 and TfR2).
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