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PubMed1991

Microtubule-disrupting drugs blocked delivery of endocytosed transferrin to the cytocenter, but did not affect return of transferrin to plasma membrane.

The fluorescence of FL cells after endocytosis of rhodamine-labeled transferrin initially appeared as a dispersed punctate pattern over the whole cell and then accumulated in the cytocenter on further incubation. In nocodazole-treated cells, the punctate fluorescence appeared along the cell edges, and stayed there on further incubation but did not accumulate in the cytocenter. The localization of transferrin was examined at the electron microscopic level with horseradish peroxidase (HRP)-labeled transferrin. Nocodazole did not affect endosome formation but affected the distribution of the endosomes. Several types of endosomes (tubular, small spherical, and microvesicular endosomes) were observed in nocodazole-treated cells, as in control cells. The endosomes were in the Golgi area of the cytocenter and also in peripheral cytoplasm in control cells. In contrast, the endosomes were only in the periplasm, along the cell edges, in nocodazole-treated cells. The uptake and release of HRP-transferrin and the release of ferric ion into the cytoplasm in nocodazole-treated cells followed in the same time-course as those in control cells. The release of transferrin was the exponential with a half-time of 12 min. The activation energy of a rate-limiting step in the recycling was 5.5 kcal.mol-1 at around 37 degrees C and increased to 29 kcal.mol-1 below 25 degrees C. These results indicated that microtubule-dependent endosome transport was faster than the overall recycling process and was independent of the return event of transferrin to the plasma membrane.

Animals↗
PubMed1975

In vivo evidence for the functional heterogeneity of transferrin-bound iron. III. Studies of transferrin at high and low iron saturation.

The functional heterogeneity of the transferrin iron pool of rats was studied by means of selective radioiron labeling of transferrin at high and low iron saturations. A sample of iron-poor plasma transferrin brought to 90 per cent iron saturation by the addition of 59Fe-nitrilotriacetate was mixed with a similarly labeled plasma sample of 55Fe-transferrin at 10 per cent iron saturation. The mixture was injected intravenously into groups of normal rats which were killed after 30 minutes, 3, and 24 hours for measurement of the distribution of the 59Fe and 55Fe in various tissues. 59Fe from diferric transferrin disappeared more rapidly from plasma and was preferentially removed by red blood cells, bone marrow, liver, and spleen. This phenomenon was most apparent at 30 minutes and 3 hours with little difference in the distribution of 59Fe and 55Fe at 24 hours. These studies add further support for the Fletcher-Huehns hypothesis of the functional heterogeneity of the transferrin iron pool in the rat.

Animals↗
PubMed1990

Isolation and molecular cloning of transferrin from the tobacco hornworm, Manduca sexta. Sequence similarity to the vertebrate transferrins.

An iron-binding glycoprotein of Mr = 77,000 has been isolated from hemolymph of the adult sphinx moth Manduca sexta. Since this protein binds ferric ion both in vivo and in vitro and has a secondary structure similar to that of human serum transferrin and human lactoferrin as judged by CD spectra, we decided to clone its cDNA in order to determine its relationship to the vertebrate transferrins. Antiserum generated against this protein was used to screen a larval fat body cDNA library. A 2.0 kilobase clone was isolated that selects an mRNA which, when translated in vitro, produces an immunoprecipitable 77-kDa protein. When the library was rescreened using the 2.0-kilobase clone as a probe, three full-length clones were isolated, and the complete nucleotide sequence of one 2,183-base pair insert was determined. The deduced protein sequence contains an 18-amino acid signal sequence and a mature protein sequence of 663 amino acids with a calculated Mr of 73,436. The sequence was used to search the National Biomedical Research Foundation (NBRF) protein database, revealing significant similarity to the vertebrate transferrins, a family of 80-kDa glycoproteins which transport and sequester iron in the blood and other body fluids. A multiple sequence alignament shows the greatest areas of similarity to be around the two iron binding sites, although the insect protein seems to contain only one such functional site. Moreover, 23 of the 24 cysteine residues in the insect protein occupy identical positions as compared with the other transferrins, indicating a similar overall tertiary structure. Comparison of the two halves of the insect sequence indicates that the protein may have arisen as a result of gene duplication. The similarity of the M. sexta sequence to the vertebrate transferrins may provide important clues to transferrin evolution.

Amino Acid Sequence↗
PubMed1977

In vivo evidence for the functional heterogeneity of transferrin-bound iron. IV. Selective uptake by erythroid precursors of radioiron from portal vein plasma transferrin during intestinal iron absorption.

In addition to the previously demonstrated selective tissue uptake of iron from the two binding sites of transferrin, the Fletcher-Huehns hypothesis predicts that iron absorbed by the intestine is delivered selectively to the erythroblast-oriented iron-binding site of transferrin in portal plasma. We have tested this prediction in rats by measuring in vitro the rate and amount of radioiron taken up by reticulocytes and bone marrow erythroblasts from selectively labeled portal plasma and randomly labeled peripheral plasma. Portal plasma transferrin was significantly more effective than peripheral plasma in delivering radioiron to both reticulocytes and marrow erythroblasts; on a per-cell basis the erythroblasts took up about five times more radioiron. Iron-deficient reticulocytes were more avid but less discriminating than iron-replete reticulocytes in uptake of iron from the two plasma sources. When injected into normal test rats in vivo, radioiron from portal plasma was preferentially removed by red cell precursors and preferentially incorporated into heme extracted from marrow and spleen. These results support the concept of selective release of iron to erythroblast-oriented binding sites of portal plasma transferrin by intestinal cells during absorption. Combined with previously demonstrated selective tissue uptake of iron from transferrin, these experiments offer strong support for the active role of transferrin in the internal iron exchange of the rat.

Anemia↗
PubMed1998

A human transferrin-binding protein of Staphylococcus aureus is immunogenic in vivo and has an epitope in common with human transferrin receptor.

To understand human immune responses against the human transferrin-binding protein of Staphylococcus aureus (SA-tbp), we examined cell wall proteins from S. aureus ATCC 6538 using human convalescent sera, and a monoclonal antibody specific for human transferrin receptor (McAb-HTR). The SA-tbp, detected by immunoblot assay, was iron-repressible, reacted with the convalescent sera, and cross-reacted with McAb-HTR. Immunoelectron microscopy probed with McAb-HTR showed a reaction zone around the test strain from the deferrated BHI. After being preincubated with an S. aureus-bacteremic serum, the electroblot of the SA-tbp still reacted with McAb-HTR, but not with human transferrin-horseradish peroxidase conjugate. We conclude, there are at least two kinds of epitopes in the SA-tbp; one able to bind to human transferrin is immunogenic in humans, but the other sharing epitopes common with human transferrin receptor is not immunogenic in humans.

Antibodies, Bacterial↗
PubMed1992

Entry of iron into cells: a new role for the transferrin receptor in modulating iron release from transferrin.

The versatile chemistry of iron and the noxious reactions this essential metal may promote have compelled iron-dependent organisms to form specific iron-binding proteins to maintain iron in soluble, nontoxic, and accessible form for cellular needs. A variety of pathways can be traversed by iron to gain access to cells, some available to all cells, others restricted to specialized cells. Of these pathways, the most important and widely functioning is uptake of iron from transferrin in a receptor-mediated process. By regulating expression of the transferrin receptor, iron-dependent cells, including neurons, can be assured an adequate supply of the essential metal while guarding against toxic excess. However, the transferrin receptor functions not only in capturing iron-bearing transferrin, but also in restraining release of iron from transferrin at the cell surface, where iron-catalyzed lipid peroxidation is a threat, while facilitating iron release in acidified endosomes to ensure safe and efficient delivery to the cell.

Animals↗
PubMed1997

Increased N-glycosylation and reduced transferrin-binding capacity of transferrin receptor isolated from placentae of diabetic women.

Infants of diabetic mothers are frequently born iron deficient because their fetal iron demand exceeds placental iron transport capacity. Although transferrin receptor (TfR) expression is increased, binding to diferric transferrin is decreased proportionately to the severity of maternal disease. It is hypothesized that TfR isolated from diabetic placentae has altered N-glycosylation since proper glycosylation of N-linked oligosaccharides is important for normal TfR binding kinetics to diferric transferrin. TfR was obtained from syncytiotrophoblastic membranes of six diabetic and six non-diabetic human placentae. Competitive binding to 125I-transferrin demonstrated a higher Kd in the diabetic TfR (P = 0.04), directly correlated to cord serum C-peptide concentration (r = 0.81, P < 0.001). The molecular weight of the monomeric form of TfR prior to treatment with glycopeptidase F (PNG-F) was greater in the diabetic group (P < 0.001) was directly related to the Kd (r = 0.77, P = 0.002). Treatment with PNG-F eliminated the molecular weight difference between the two groups. Increased glycosylation of the N-linked oligosaccharides of TfR isolated from diabetic placentae may alter the three-dimensional structure or charge of the receptor, thus reducing its binding affinity for transferrin.

Binding, Competitive↗
PubMed1989

Evaluation of protein-N-(2-hydroxypropyl)methacrylamide copolymer conjugates as targetable drug carriers. 1. Binding, pinocytic uptake and intracellular distribution of transferrin and anti-transferrin receptor antibody conjugates.

The transferrin receptor of human skin fibroblasts was studied as an in vitro model target antigen receptor for interaction with protein-polymer conjugates having potential for targeted drug delivery. Pinocytic uptake of 125I-labelled N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugated to monoclonal antibody B3/25 (specific for the transferrin receptor) or transferrin was up to 9-fold greater than uptake of the parent HPMA copolymer. The ability of these conjugates to bind specifically was confirmed by Scatchard analysis. Pinocytic internalisation was dependent on the molecular mass of the conjugate. Intracellular routing following internalisation was evaluated using density-gradient centrifugation. Unmodified HPMA copolymer was transferred via the endosomal compartment into secondary lysosomes, where, being resistant to degradation, it accumulated. Although the majority of endocytosed transferrin is recycled via the endosome, it was shown that any transferrin reaching the lysosomes was rapidly degraded and low-molecular-weight degradation products were released. Monoclonal antibody B3/25 showed a subcellular distribution consistent with prolongation on the cell surface, followed by internalisation and subcellular trafficking, via endosomes, into the lysosomal compartment, with subsequent degradation. Conjugation of protein to HPMA copolymer increased lysosomal accumulation of polymer up to 9-fold, with no detectable degradation of conjugate. The data presented here have implications regarding clinical potential of protein-HPMA copolymer conjugates designed for lysosomotropic drug delivery.

Acrylamides↗
PubMedDate not supplied

Uptake and processing of 125I-labelled transferrin and 59Fe-labelled transferrin by isolated human trophoblast cells.

Trophoblast cells isolated from term human placenta and maintained as an adherent culture express surface receptors for transferrin as indicated by quantitative binding studies using 125I-labelled transferrin. The Kd was 5.3 x 10(-9) M. About 36 per cent of the total cell receptor population was found at the cell surface, the remainder being intracellular. Both 125I-labelled and 59Fe-labelled transferrin were internalized by receptor-mediated endocytosis with similar rates. Pulse-chase experiments showed that 125I-labelled transferrin was recycled and released back to the medium, whereas 59Fe accumulated intracellularly and was released slowly. Polyacrylamide gel electrophoresis followed by autoradiography revealed that 59Fe was accumulated by cells largely in the form of ferritin. A small intracellular pool of low molecular weight 59Fe was also detected. In the presence of monensin, the transfer of 59Fe to ferritin was greatly reduced. The nature and amount of 59Fe released from cells could be modulated by the incubation conditions. In the absence of chelating agents and iron salts, released 59Fe was found to be associated with a low molecular weight fraction as well as with transferrin and ferritin. The low molecular weight 59Fe readily formed a complex with added chelators such as apotransferrin, DTPA or desferrioxamine. The release of 59Fe could be increased by repeatedly changing the medium during the course of the incubation. 59Fe release from trophoblast cells exceeded the release of lactate dehydrogenase and also exceeded the release of 59Fe from 3T3 fibroblasts, suggesting a cell-specific process.

Cell Survival↗
PubMed2003

Iron release from transferrin, its C-lobe, and their complexes with transferrin receptor: presence of N-lobe accelerates release from C-lobe at endosomal pH.

Human transferrin, like other members of the transferrin class of iron-binding proteins, is a bilobal structure, the product of duplication and fusion of an ancestral gene during the course of biochemical evolution. Although the two lobes exhibit 45% sequence identity and identical ligand structures of their iron-binding sites (one in each lobe), they differ in their iron-binding properties and their responsiveness to complex formation with the transferrin receptor. A variety of interlobe interactions modulating these iron-binding functions has been described. We have now studied the kinetics of iron release to pyrophosphate from the isolated recombinant C-lobe and from that lobe in the intact protein, each free and bound to receptor. The striking finding is that the rates of iron release at the pH of the endosome to which transferrin is internalized by the iron-dependent cell are similar in the free proteins but 18 times faster from full-length monoferric transferrin selectively loaded with iron in the C-lobe than from isolated C-lobe when each is complexed to the receptor. The possibility that the faster release in the receptor complex of the full-length protein at endosomal pH contributes to the evolutionary advantage of the bilobal structure is considered.

Endosomes↗
PubMed1991

Role of transferrin, transferrin receptors, and iron in macrophage listericidal activity.

It is not yet known what properties distinguish macrophages which can kill facultative intracellular bacteria, such as Listeria monocytogenes, from those which cannot. Listeria is an organism which requires iron for growth, yet macrophage listericidal mechanisms are also likely to be iron dependent. We show here that resident peritoneal macrophages and thioglycollate-elicited macrophages cannot kill listeria, but proteose peptone-elicited and FCS-elicited macrophages can. All these cell populations phagocytose listeria. Transferrin receptor expression is low on resident cells, intermediate on peptone- and FCS-elicited cells, and high on thioglycollate-elicited cells. Transferrin transports iron into cells via the transferrin receptor: thus, iron content of resident cells is low, of peptone- and FCS-elicited cells is intermediate, and of thioglycollate-elicited cells is high. Moreover, antibody to transferrin, which prevents it binding its receptor, inhibits listericidal macrophages from killing this bacterium. Finally, nonlistericidal cells with high transferrin receptor expression and high intracellular iron become listericidal if they are incubated with apotransferrin, an iron-free ligand which prevents iron uptake by cells. These data suggest that macrophages must have enough available intracellular iron to support listericidal mechanisms, but too much iron favors growth of the bacterium, which no longer can be killed by the macrophage.

Animals↗
PubMed1997

Immunohistochemical demonstration of transferrin and transferrin receptor in mammalian integument.

The present study demonstrates the distribution of transferrin and the transferrin receptor in the integument of eleven wild mammalian species using immunohistochemical methods. Both substances were regularly found in or near the peripheral cells of the sebaceous glands, especially of dense-haired animals. The transferrin receptor was also detectable in the epidermis, the secretory portion of tubular apocrine glands, and the outer epithelium of primary hair follicles. Transferrin as well as the transferrin receptor reacted strongly in macrophages of the papillary dermis only in the common seal. The results obtained are discussed with regard to possible biological functions in the skin of the substances demonstrated.

Animals↗
PubMed2000

Iron, ferritin, transferrin, and transferrin receptor in the adult rat retina.

PURPOSE: The retina and other tissues need iron to survive. However, the normal iron metabolism in rodent retinas had not been characterized. This study was intended to investigate iron and iron homeostasis protein (ferritin, transferrin [Tf] and transferrin receptor [Tf-R]) distribution in 20- to 55-day-old rat retinas. METHODS: Iron was revealed on retinal sections directly by proton-induced x-ray emission (PIXE) and indirectly by electron microscopy (EM). Ferritin, Tf, and Tf-R proteins were localized by immunohistochemistry. Transferrin expression was localized by in situ hybridization (ISH). Transferrin and ferritin proteins and mRNA were analyzed by Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: Iron is widely and unevenly distributed throughout the adult rat retina. The highest concentration was observed by PIXE in the choroid and the retinal pigmented epithelial cell (RPE) layer, and in inner segments of photoreceptors (IS). Outer segments of photoreceptors (OS) also contain iron. EM studies suggested the presence of iron inclusions inside the photoreceptor discs. Choroid, RPE, and IS showed a strong immunoreactivity for ferritin. Transferrin accumulated mainly in the IS and OS areas and in RPE cells but can also be detected slightly in retinal capillaries. Western blot analysis for Tf and ferritin confirmed their presence in the adult neural retina. By RT-PCR, H- and L-chains of ferritin and Tf mRNAs were expressed in neural retina, but the main sites of Tf synthesis observed by ISH were the RPE and choroid cell layers. Tf-R immunoreactivity was detected in the ganglion cell layer, inner nuclear layer, outer plexiform layer, IS, RPE, and choroid. These results were similar for all stages studied. CONCLUSIONS: For the first time, the present study characterized both iron and iron homeostasis proteins in rodent retinas. In the outer retina, iron and ferritin shared the same distribution patterns. In contrast, Tf, mainly synthesized by RPE cells and detected in OS and IS areas, probably helps to transport iron to photoreceptors through their Tf-R. This is a likely pathway for filling iron needs in the outer retina.

Animals↗
PubMed1989

Comparison of iron-59, indium-111, and gallium-69 transferrin as a macromolecular tracer of vascular permeability and the transferrin receptor.

Tracer amounts of [59Fe++]citrate, [111In+++]chloride, and [68Ga+++]chloride were complexed with autologous plasma transferrin. Each of these complexes were co-administered with [125I]albumin by i.v. injection and their biodistribution was studied in Wistar rats. The plasma clearance of 59Fe and [125I]albumin was monoexponential with half-times of 49-70 and 277 min, respectively. The plasma clearance of 68Ga and 111In was biexponential with second component half-times of 157 and 232 min, respectively. Indium-111 tissue distribution was similar to that of [125I]albumin in heart, lung, muscle, brain and Walker-256 allograft. Iron-59 distribution spaces were generally the highest of the metal complexes in all tissues except muscle, where the 68Ga space was highest. The effects of transferrin-specific receptor-mediated endocytosis can be avoided in many organs and Walker-256 allografts by using the indium-transferrin complex, and the radiolabeled complex may be a convenient macromolecular tracer to estimate vascular permeability and vessel pore size in tumor and systemic tissue. In contrast, the iron-transferrin complex may be useful for measuring and imaging transferrin-specific receptors in brain and tumor tissue.

Animals↗
PubMed1987

Rabbit reticulocyte coated vesicles carrying the transferrin-transferrin receptor complex: I. Purification and partial characterization.

Coated vesicles bearing the transferrin-transferrin receptor complex were isolated from rabbit reticulocytes by freeze-thaw cell lysis, followed by differential centrifugation with pelleting of vesicles at 100,000 g. Electronmicroscopy demonstrated the vesicles to have the characteristic morphology of coated vesicles, including the appearance of triskelions. The protein composition of the vesicles as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis included transferrin, transferrin receptor, and proteins of apparent mol wt of approximately 180,000, 140,000, 100,000, and 47,000 daltons. The 180,000 and 100,000 mol wt proteins were identified as clathrin and coated vesicle assembly factor proteins, respectively, by Western blot analyses. The vesicles had a Mg2+-dependent ATPase with a specific activity of approximately 8.5 nmoles ATP converted/min/mg vesicle protein. The vesicles could acidify the intravesicular space, as evidenced by the stimulation of the Mg2+-ATPase by the protonophore FCCP. Reticulocytes appear to be an excellent source of coated vesicles and as such should provide a model for studying the endocytosis of transferrin and the steps of iron uptake that proceed in these vesicles.

Acid-Base Equilibrium↗
PubMed1998

Biochemical evidence for a conserved interaction between bacterial transferrin binding protein A and transferrin binding protein B.

As an adaptation to the iron-restricted environment of the host, some bacterial pathogens possess iron acquisition pathways mediated by surface receptors that specifically bind transferrin from the host. The receptor is composed of two receptor proteins, TbpA and TbpB, which are both capable of binding to transferrin. Previous studies have demonstrated that affinity isolation of TbpB from Neisseria meningitidis or Haemophilus influenzae with immobilized human transferrin required the homologous TbpA, implicating a TbpA-TbpB interaction. In this study, we demonstrated that TbpA from either species can facilitate isolation of either TbpB, indicating that the TbpA-TbpB interaction is conserved within these species. Extension of these studies to veterinary pathogens in which a TbpA-Tf complex is used to affinity isolate heterologous TbpBs, demonstrated an interaction between the receptor proteins from N. meningitidis and Actinobacillus pleuropneumoniae. Further delineation of the TbpA-TbpB-transferrin interaction with recombinant chimeric N. meningitidis/A. pleuropneumoniae TbpBs has identified a region encoded by the first 1/4 of the tbpB gene which is involved in Tf binding.

Actinobacillus pleuropneumoniae↗
PubMed1995

Metal-induced conformational heterogeneity of transferrins: a spectroscopic study of indium(III) and other metal(III)-substituted transferrins.

The conformation in solution of three different metal(III)-transferrins, namely aluminum(III), gallium(III) and indium(III) transferrin, was investigated by absorption, CD, 1H NMR and 13C NMR spectroscopies. The formation of the respective metal-transferrin complexes and the characteristic 2:1 metal-to-protein binding stoichiometry were unambiguously demonstrated, in all cases, through UV difference studies. The 13C NMR spectra of these metallotransferrins in the carbonyl region are very similar to one another pointing out that the arrangement of the synergistic anion in the binding site must be essentially the same. However, the CD spectra in the near UV (aromatic region) reveal the occurrence of significant differences between indium transferrin, on one side, and the other two derivatives, on the other. Also, the 1H NMR spectra exhibit a number of different features suggesting the occurrence of metal-induced conformational heterogeneity around the metal sites. Such metal-induced conformational heterogeneity probably affects the transferrin-receptor recognition process, resulting in a different metabolic fate of these metals in the organisms.

Carbon Isotopes↗
PubMed1984

Expression of the transferrin gene during development of non-hepatic tissues: high level of transferrin mRNA in fetal muscle and adult brain.

Using a cloned rat transferrin cDNA probe, we looked for transferrin mRNA in the various rat tissues during development. In all the cases the mRNA detected seemed to be the same and to be product of a single gene. The transferrin gene is early expressed at a high level during liver differentiation. In the muscle and other non-hepatic and non-nervous tissues, the gene expression is maximal just before birth (19-20th day of gestational age), then markedly decreases during the postnatal development, the mRNA level being very low in the adult tissues. In brain, by contrast, transferrin mRNA level is very low before birth, then gradually increases during the postnatal development and reaches a plateau in the adult. Maximal mRNA concentration in fetal muscle (2 days before birth) and adult brain is about 1:7 to 1:10 of that obtained in adult liver. These results are analyzed in the light of the evidence that transferrin is not only an iron-binding protein, but also a factor involved in cell proliferation and differentiation, and particularly in nerve control of muscle differentiation.

Aging↗