Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites

West, Anthony P.; Giannetti, Anthony M.; Herr, Andrew B.; Bennett, M. J.; Nangiana, Jasvinder; Pierce, James; Weiner, Leslie P.; Snow, Peter M.; Björkman, Pamela J.

doi:10.1006/jmbi.2001.5048

Cited by 120 publications

(110 citation statements)

References 41 publications

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“…The residues mutated in cia hp327 and cia hs019 are both located in the Tfr1a regions of the helical domain involved in Tf binding (Buchegger et al, 1996;Cheng et al, 2004;Lawrence et al, 1999). Mutagenesis studies have further localized the Tf/Tfr binding interface to include a conserved RGD sequence, and mutation of the glycine in particular severely abrogates Tf binding (Dubljevic et al, 1999;Giannetti et al, 2003;Liu et al, 2003;West et al, 2001). As the cia hs019 mutation occurs at this particular glycine, we predict it may directly eliminate Tf binding, although this tripeptide in Tfr1a is replaced by QGS residues.…”

Section: Zebrafish Tfr1a Is the Gene Defective In Ciamentioning

confidence: 91%

Thechiantizebrafish mutant provides a model for erythroid-specific disruption oftransferrin receptor 1

et al. 2004

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Iron is a crucial metal for normal development, being required for the production of heme, which is incorporated into cytochromes and hemoglobin. The zebrafish chianti (cia) mutant manifests a hypochromic,microcytic anemia after the onset of embryonic circulation, indicative of a perturbation in red blood cell hemoglobin production. We show that cia encodes tfr1a, which is specifically expressed in the developing blood and requisite only for iron uptake in erythroid precursors. In the process of isolating zebrafish tfr1, we discovered two tfr1-like genes (tfr1a and tfr1b) and a single tfr2 ortholog. Abrogation of tfr1b function using antisense morpholinos revealed that this paralog was dispensable for hemoglobin production in red cells. tfr1b morphants exhibited growth retardation and brain necrosis, similar to the central nervous system defects observed in the Tfr1 null mouse, indicating that tfr1b is probably used by non-erythroid tissues for iron acquisition. Overexpression of mouse Tfr1, mouse Tfr2, and zebrafish tfr1b partially rescued hypochromia in cia embryos, establishing that each of these transferrin receptors are capable of supporting iron uptake for hemoglobin production in vivo. Taken together, these data show that zebrafish tfr1a and tfr1b share biochemical function but have restricted domains of tissue expression, and establish a genetic model to study the specific function of Tfr1 in erythroid cells.

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Section: Zebrafish Tfr1a Is the Gene Defective In Ciamentioning

confidence: 91%

Thechiantizebrafish mutant provides a model for erythroid-specific disruption oftransferrin receptor 1

et al. 2004

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“…Although loss of multiple members of the iron-sensing mechanism, including HFE (34), the classic hereditary hemochromatosis gene, and TFR2 (transferrin receptor 2) (35), a homolog of the iron uptake receptor TFR1, is known to diminish hepcidin expression, leading to excess iron absorption, how they interact with the BMP/ SMAD signaling complex is uncertain. HFE binds to transferrin receptor 1 (TFR1), sharing a binding site on the receptor with TF (36). One model asserts that increasing transferrin saturation displaces HFE from TFR1, leading to increased hepcidin expression (37).…”

Section: Regulation Of Hepcidin Through the Bone Morphogenetic Proteimentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

139

105

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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“…Recently, it has been shown, in mammalian cell culture, that TfR2 competes with TfR1 to bind HFE, 50 an atypical MHC class I protein (reviewed in Pietrangelo 51 ), and that holotransferrin competes with HFE to bind TfR1. 52 Genomic analysis has failed to identify a close ortholog for human HFE in the zebrafish 53 or in the other fish species for which sequence data are available (P.F. and Y.G., unpublished data, April 14, 2008).…”

Section: Transferrin-a and Tfr2 Are Required For Hepcidin Expression mentioning

confidence: 99%

Transferrin-a modulates hepcidin expression in zebrafish embryos

Fraenkel

Gibert

Holzheimer

et al. 2009

Blood

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The iron regulatory hormone hepcidin is transcriptionally up-regulated in response to iron loading, but the mechanisms by which iron levels are sensed are not well understood. Large-scale genetic screens in the zebrafish have resulted in the identification of hypochromic anemia mutants with a range of mutations affecting conserved pathways in iron metabolism and heme synthesis. We hypothesized that transferrin plays a critical role both in iron transport and in regulating hepcidin expression in zebrafish embryos. Here we report the identification and characterization of the zebrafish hypochromic anemia mutant, gavi, which exhibits transferrin deficiency due to mutations in transferrin-a. Morpholino knockdown of transferrin-a in wild-type embryos reproduced the anemia phenotype and decreased somite and terminal gut iron staining, while coinjection of transferrin-a cRNA partially restored these defects. Embryos with transferrin-a or transferrin receptor 2 (TfR2) deficiency exhibited low levels of hepcidin expression, however anemia, in the absence of a defect in the transferrin pathway, failed to impair hepcidin expression. These data indicate that transferrin-a transports iron and that hepcidin expression is regulated by a transferrin-a-dependent pathway in the zebrafish embryo. IntroductionTransferrin, a serum protein with 2 iron binding sites, is the major carrier of ferric iron in human plasma and is required to deliver iron to developing erythroid and other cells. Iron-bound holotransferrin binds transferrin receptor 1 (TfR1) on the surface of the cell, resulting in endocytosis of an endosome containing both transferrin and TfR1 (reviewed in Aisen 1 ). After acidification of the endosome, ferrous iron exits the endosome via the divalent metal transporter (DMT1). 2,3 Transferrin receptor 2 (TfR2), a homolog of TfR1, with restricted expression to hepatocytes and erythroid cells, 4 binds transferrin at lower affinity than TfR1 5,6 and is involved in the regulation of iron homeostasis.As humans have no active means of iron excretion, maintaining iron homeostasis requires adjustment of iron absorption to reflect the body's iron stores. Hepcidin is a peptide hormone, primarily expressed in the liver, 7 which modulates iron absorption and iron delivery to erythrocytes by binding the iron transporter ferroportin (fpn), resulting in internalization and degradation of fpn. 8 In mammalian models, hepcidin is transcriptionally up-regulated in response to inflammation 9,10 or iron overload 11 and down-regulated in response to anemia, iron deficiency, or hypoxia. 9 Although mutations in HFE, 12 transferrin receptor 2 (TFR2), 13 hepcidin (HAMP), 14 or hemojuvelin (HJV or HFE2) 15 have each been associated with hemochromatosis and impaired hepcidin expression, 16 the mechanisms by which iron overload is sensed and hepcidin is regulated are not completely understood.The zebrafish, Danio rerio, provides an excellent system for the identification and analysis of genes involved in iron metabolism and erythroid development. La...

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Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites

Cited by 120 publications

References 41 publications

Thechiantizebrafish mutant provides a model for erythroid-specific disruption oftransferrin receptor 1

Thechiantizebrafish mutant provides a model for erythroid-specific disruption oftransferrin receptor 1

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Transferrin-a modulates hepcidin expression in zebrafish embryos

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