Cobalt and the Iron Acquisition Pathway: Competition towards Interaction with Receptor 1

Chikh, Zohra; Hémadi, Miryana; Miquel, Geneviève; Ha-Duong, Nguyêt-Thanh; Chahine, Jean‐Michel El Hage

doi:10.1016/j.jmb.2008.05.045

Cited by 28 publications

(49 citation statements)

References 42 publications

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“…Indeed, Li et al (30) report IRP1 activation and reduction in ferritin protein, with Co(II) and Mn(II) treatment in A549 cells. In addition, the Co 2 Tf transport experiments suggest that transferrin can donate cobalt to the hepatoma cells, although less efficiently than it does iron, supporting the concept that cobalt and iron are both taken up by the hepatoma cells via TFRs (7). Similar work performed with Mn 2 Tf indicates that uptake by developing erythrocytes also involves TFR-mediated endocytosis, although the efficiency of uptake and the affinity of the receptors for Mn 2 Tf was lower than for Fe 2 Tf (11).…”

Section: Discussionmentioning

confidence: 69%

The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells

Herbison

Thorstensen

Chua

et al. 2009

American Journal of Physiology-Cell Physiology

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Herbison CE, Thorstensen K, Chua AC, Graham RM, Leedman P, Olynyk JK, Trinder D. The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells. Am J Physiol Cell Physiol 297: C1567-C1575, 2009. First published October 14, 2009; doi:10.1152/ajpcell.00649.2008.-Transferrin receptor (TFR) 1 and 2 are expressed in the liver; TFR1 levels are regulated by cellular iron levels while TFR2 levels are regulated by transferrin saturation. The aims of this study were to 1) determine the relative importance of TFR1 and TFR2 in transferrin-bound iron (TBI) uptake by HuH7 human hepatoma cells and 2) characterize the role of metal-transferrin complexes in the regulation of these receptors. TFR expression was altered by 1) incubation with metal-transferrin (Tf) complexes, 2) TFR1 and TFR2 small interfering RNA knockdown, and 3) transfection with a human TFR2 plasmid. TBI uptake was measured using 59 Fe-125 I-labeled Tf and mRNA and protein expression by real-time PCR and Western blot analysis, respectively. Fe2Tf, Co2Tf, and Mn2Tf increased TFR2 protein expression, indicating that the upregulation was not specifically regulated by iron-transferrin but also other metal-transferrins. In addition, Co2Tf and Mn2Tf upregulated TFR1, reduced ferritin, and increased hypoxia-inducible factor-1␣ protein expression, suggesting that TFR1 upregulation was due to a combination of iron deficiency and chemical hypoxia. TBI uptake correlated with changes in TFR1 but not TFR2 expression. TFR1 knockdown reduced iron uptake by 80% while TFR2 knockdown did not affect uptake. At 5 M transferrin, iron uptake was not affected by combined TFR1 and TFR2 knockdown. Transfection with a hTFR2 plasmid increased TFR2 protein expression, causing a 15-20% increase in iron uptake and ferritin levels. This shows for the first time that TFR-mediated TBI uptake is mediated primarily via TFR1 but not TFR2 and that a high-capacity TFR-independent pathway exists in hepatoma cells. cobalt; small interfering RNA; chemical hypoxia; metal-transferrin; manganese TRANSFERRIN RECEPTOR 2 (TFR2) is a membrane protein homologous to the well-characterized TFR1. TFR1 has a high affinity for diferric transferrin (Fe 2 Tf) and delivers iron to cells via receptor-mediated endocytosis (15). Chinese hamster ovary (CHO) cells overexpressing human (h)TFR2 but lacking endogenous TFR1 also exhibit increased iron uptake and transferrin binding along with internalization and recycling of transferrin, suggesting a similar role for TFR2 (16,25,26,42).However, there are a number of differences between TFR1 and TFR2. TFR2 has a 30-fold lower affinity for Fe 2 Tf than TFR1 (25, 44) and, while TFR1 is ubiquitously expressed, TFR2 is predominantly expressed in the liver, suggesting a tissuespecific function. TFR2 protein levels show a dose-dependent response to transferrin saturation, with increasing concentrations of Fe 2 Tf increase receptor levels by stabilizing TFR2 protein (21, 35). The expression of TFR2 is also regulated by the hemochromatosis protein (...

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Section: Discussionmentioning

confidence: 69%

The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells

Herbison

Thorstensen

Chua

et al. 2009

American Journal of Physiology-Cell Physiology

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“…The apoTfTfR complex returns to the cell surface, and the apoTf is dissociated from the complex, allowing the recycling of both the proteins [20]. It should also be noted that gallium-, bismuth-, and cobalt-loaded Tf interact with TfR at pH 7.4 [21][22][23]. However, no interaction was observed between aluminum-loaded Tf (Al 2 Tf) and TfR [24].…”

Section: Introductionmentioning

confidence: 99%

Absence of Binding Between the Human Transferrin Receptor and the Transferrin Complex of Biological Toxic Trace Element, Aluminum, Because of an Incomplete Open/Closed Form of the Complex

Sakajiri

Yamamura

Kikuchi

et al. 2009

Biol Trace Elem Res

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Human transferrin (Tf) very tightly binds two ferric ions to deliver iron to cells. Fe(III)(2)Tf (Fe(2)Tf) binds to the Tf receptor (TfR) at pH 7.4; however, iron-free Tf (apoTf) does not. Iron uptake is facilitated by endocytosis of the Fe(2)Tf-TfR complex. Tf can also bind aluminum ions, which cause toxic effects and are associated with many diseases. Since Al(III)(2)Tf (Al(2)Tf) does not bind to TfR, the uptake of aluminum by the cells does not occur through a TfR-mediated pathway. We have studied the absence of binding between Al(2)Tf and TfR by investigating the physicochemical characteristics of apoTf, Al(2)Tf, Fe(2)Tf, and TfR. The hydrodynamic radius of 38.8 A for Al(2)Tf obtained by dynamic light scattering was between that of 42.6 A for apoTf and 37.2 A for Fe(2)Tf. The zeta potential of -11.3 mV for Al(2)Tf measured by capillary electrophoresis was close to -11.2 mV for apoTf as compared to -11.9 mV for Fe(2)Tf, indicating that the Al(2)Tf surface had a relatively scarce negative charge as the apoTf surface had. These results demonstrated that the structure of Al(2)Tf was a trade-off between the closed and open forms of Fe(2)Tf and apoTf, respectively. Consequently, it is suggested that Al(2)Tf cannot form specific ionic interresidual interactions, such as those formed by Fe(2)Tf, to bind to TfR, resulting in impossible complex formation between Al(2)Tf and TfR.

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“…The TM 2 s were synthesized, purified and then characterized spectrophotometrically [25][26][27][28][29], and by electrophoresis [30]. R was extracted from human placenta and purified on an Affigel column doped with holotransferrin [31].…”

Section: Introductionmentioning

confidence: 99%

Kinetics and thermodynamics of metal-loaded transferrins: transferrin receptor 1 interactions

Ha-Duong

Hémadi

Chikh

et al. 2008

Biochemical Society Transactions

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Transferrin receptor 1 (R) and human serum transferrin (T) are the two main actors in iron acquisition by the cell. R binds TFe(2) (iron-loaded transferrin), which allows its internalization in the cytoplasm by endocytosis. T also forms complexes with metals other than iron. In order to follow the iron-acquisition pathway, these metals should obey at least two essential rules: (i) formation of a strong complex with T; and (ii) interaction of this complex with R. In the present paper, we propose a general mechanism for the interaction of five metal-loaded Ts [Fe(III), Al(III), Bi(III), Ga(III) and Co(III)] with R and we discuss their potential incorporation by the iron-acquisition pathway. With iron- and cobalt-loaded Ts, the interaction of R takes place in two steps: the first is detected by the T-jump technique and occurs in the 100 micros range, whereas the second is slow and occurs in the hour range. Bi(III)- and Ga(III)-loaded Ts interact with R in a single fast kinetic step, which occurs in the 100-500 micros range. No interaction is detected between R and aluminium-saturated T. The fast steps are ascribed to the interaction of the C-lobe of metal-loaded T with the helical domain of R: dissociation constant, K'(1), of 0.50+/-0.07, 0.82+/-0.25, 4+/-0.4 and 1.10+/-0.12 microM for Fe(III), Co(III), Bi(III) and Ga(III) respectively. The second slow steps are ascribed to changes in the conformation of the protein-protein adducts which increase the stability to achieve, at thermodynamic equilibrium, an overall dissociation constant, K(1), of 2.3 and 25 nM for Fe(III) and Co(III) respectively. This last step occurs over several hours, whereas endocytosis takes place in several minutes. This implies that metal-loaded Ts are internalized with only the C-lobe interacting with R. This suggests that, despite a lower affinity for R when compared with TFe(2), some metal-loaded Ts can compete kinetically with TFe(2) for the interaction with R and thus follow the iron-acquisition pathway.

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Cobalt and the Iron Acquisition Pathway: Competition towards Interaction with Receptor 1

Cited by 28 publications

References 42 publications

The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells

The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells

Absence of Binding Between the Human Transferrin Receptor and the Transferrin Complex of Biological Toxic Trace Element, Aluminum, Because of an Incomplete Open/Closed Form of the Complex

Kinetics and thermodynamics of metal-loaded transferrins: transferrin receptor 1 interactions

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