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Stoichiometries of transferrin receptors 1 and 2 in human liver.

ABSTRACT: Mutations in either the hereditary hemochromatosis protein, HFE, or transferrin receptor 2, TfR2, result in a similarly severe form of the most common type of iron overload disease called hereditary hemochromatosis. Models of the interactions between HFE, TfR1, and TfR2 imply that these proteins are present in different molar concentrations in the liver, where they control expression of the iron regulatory hormone, hepcidin, in response to body iron loading. The aim of this study was to determine in vivo levels of mRNA by quantitative RT-PCR and concentrations of these proteins by quantitative immunoblotting in human liver tissues. The level of TfR2 mRNA was 21- and 63-fold higher than that of TfR1 and HFE, respectively. Molar concentration of TfR2 protein was the highest and determined to be 1.95 nmol/g protein in whole cell lysates and 10.89 nmol/g protein in microsomal membranes. Molar concentration of TfR1 protein was 4.5- and 6.1-fold lower than that of TfR2 in whole cell lysates and membranes, respectively. The level of HFE protein was below 0.53 nmol/g of total protein. HFE is thus present in substoichiometric concentrations with respect to both TfR1 and TfR2 in human liver tissue. This finding supports a model, in which availability of HFE is limiting for formation of complexes with TfR1 or TfR2.

SUBMITTER: Chloupkova M

PROVIDER: S-EPMC2818201 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Stoichiometries of transferrin receptors 1 and 2 in human liver.

Chloupková Maja M Zhang An-Sheng AS Enns Caroline A CA

Blood cells, molecules & diseases 20091012 1

Mutations in either the hereditary hemochromatosis protein, HFE, or transferrin receptor 2, TfR2, result in a similarly severe form of the most common type of iron overload disease called hereditary hemochromatosis. Models of the interactions between HFE, TfR1, and TfR2 imply that these proteins are present in different molar concentrations in the liver, where they control expression of the iron regulatory hormone, hepcidin, in response to body iron loading. The aim of this study was to determin ...[more]

PMID: 19819738

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Project description:Three types of asialo-transferrin were obtained from immunologically pure human transferrin by chromatography on DEAE-cellulose, followed by desialylation and affinity chromatography on a column of the immobilized asialo-glycoprotein-binding hepatic lectin from rabbit liver. Of the asialo-transferrins, type 1 was derived from the principal DEAE-cellulose chromatographic component of transferrin, i.e. the one that contains two biantennary glycans. The two other asialo-transferrins (types 2 and 3) were derived from a minor DEAE-chromatographic transferrin component, which is assumed to possess one biantennary and one triantennary glycan. The three asialo-transferrin types were indistinguishable by electrophoretic mobility, but they were readily distinguished on the basis of their binding strengths to the hepatic lectin in intact rats. Glycan structures responsible for the difference in binding strengths between asialo-transferrin types 2 and 3 are not known. Metabolic studies in rats showed that none of the individual asialo-transferrin types was capable of generating a signal for endocytosis at low doses (<1mug/100g body wt.) and, consequently, most of the injected protein was recoverable with the plasma and the liver 35min after injection. However, endocytosis and catabolism of each asialo-transferrin type was readily induced by injecting a larger dose (50-250mug/100g body wt.) of unlabelled asialo-transferrin of the same type or of a different type a short interval after the labelled dose. These findings support the view that the dose-dependent uptake of human asialo-transferrin by the hepatocyte, as established in an earlier study with asialo-transferrin made from whole transferrin [Regoeczi, Taylor, Hatton, Wong & Koj (1978) Biochem. J.174, 171-178], also holds for these asialo-transferrin subfractions. Furthermore, the present studies indicate that asialo-transferrins of different carbohydrate compositions are capable of synergistically promoting endocytosis of each other.

Dataset Information

Stoichiometries of transferrin receptors 1 and 2 in human liver.

Publications

Stoichiometries of transferrin receptors 1 and 2 in human liver.

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