Serum transferrin receptor

RNA secondary structure plays a role in the regulation of iron metabolism in eukaryotes. Iron is an essential nutrient, required for the synthesis of hemoglobin, cytochromes, and many other proteins. However, excess iron can be quite harmful because, untamed by a suitable protein environment, iron can initiate a range of free-radical reactions that damage proteins, lipids, and nucleic acids. Animals have evolved sophisticated systems for the accumulation of iron in times of scarcity and for the safe storage of excess iron for later use. Key proteins include transferrin, a transport protein that carries iron in the serum, transferrin receptor, a membrane protein that binds iron-loaded transferrin and initiates its entry into cells, and ferritin, an impressively efficient iron-storage protein found primarily in the liver and kidneys. Twenty-four ferritin polypeptides form a nearly spherical shell that encloses as many as 2400 iron atoms, a ratio of one iron atom per amino acid (Figure 31.37). 

Worwood M (2002) Serum transferrin receptor assays and their application. Annals of Clinical Biochemistry 39 221-230. 

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

Figure 2.8. Scheme of a chimeric peptide with examples for each of the distinct domains. 0X26, anti-rat transferrin receptor monoclonal antibody (mAh) 84-15, anti-human insulin receptor mAh cHSA, cationized human serum albumin VIP, vasoactive intestinal polypeptide DALDA, dermorphin analogue NGF, nerve growth factor BDNF, brain-derived neurotrophic factor PNA, peptide nucleic acid (3-gal, (3-galactosidase. 

Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells. Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin. 

It appears that both halves of the transferrin molecule contain a recognition site for the receptor, and that both are necessary for binding. Thus, the two halves of ovotransferrin are much less effective than the whole molecule in binding to the receptor and donating iron into the chick embryo red blood cell.1143 One fragment of serum transferrin is ineffective.1124... 

There is further evidence that V(V) may be converted to V02+ in serum, which then binds to the iron transport protein transferrin. This hypothesis is supported by the observation of Hopkins that vanadium, a few hours after injection, becomes associated with transferring. Sabbioni and Marafante176 have also observed a small amount of vanadium bound to serum transferrin. However, in their experiments, and those of Hopkins, no precautions appear to have been taken to protect the vanadium from oxidation during the protein separation steps. Under these conditions, most VOz+ associated with transferrin may be lost from the protein. The possibility that vanadate(V) binds to transferrin has not been investigated. If, in fact, most of the vanadium is bound to transferrin after a few hours, this could explain the failure of red cells to acquire much of the metal. These cells have relatively few receptor sites for the protein. 

These observations come together with the evolutionary comparisons, which show that the N-lobe is highly conserved, through all species, whereas the C-lobe has become diversified. In serum transferrins, ovotransferrins, and lactoferrins it releases iron less readily than the N-lobe, because of its lesser flexibility, whereas in melanotransfer-rin and hornworm transferrin it no longer binds iron at all. Perhaps C-site binding has only remained where a receptor mechanism exists to extract iron from this site ... 

As noted above, iron-loaded serum transferrin has the role of transporting Fe(III) to cells requiring it. Once it reaches a target cell, it binds to the transferrin receptor (TfR) on the cell outer surface. TfR is a disulfide-linked dimer that binds two transferrin molecules. At neutral pH, apo transferrin does not bind to the transferrin receptor. Once formed, the transferrin receptor complex becomes detached from the cell membrane and enters the cell enclosed in a clathrin-coated vesicle. Uncoating of the vesicle generates an endosome in which the pH is lowered to 5.5, promoting release of iron. At this pH, the transferrin remains bound to its receptor, and... 

Kohgo, Y, Nishisato, X, Kondo, H., Tsushima, N., Niitsu, Y. and Urushizaki, I. (1986) Circulating transferrin receptor in human serum. Br. J. Haematol. 64, 277-281. 

There is a small amount of ferritin in the blood in balance with the iron stores. Iron is stored as ferritin (which sequesters iron in a nontoxic but readily mobilised form) and its aggregate, haemosiderin, in the cells of the liver, bone marrow and spleen. A measure of the state of iron stores is provided by the amount of ferritin in the serum (normally 20-300 mmol/1) and by the relationship of serum iron concentration (normally 10-30 mmol/1 reduced in iron deficiency) to the binding capacity of transferrin (normally 45-70 mmol/1 increased in iron deficiency). Ferritin is an acute-phase reactant and may be an inaccurate measure of iron stores in inflammatory states, e.g. rheumatoid arthritis. Recently developed techniques to measure the plasma level of soluble transferrin receptor (which is increased in iron deficiency but not by infection or inflammation) may help differentiate the anaenria of iron deficiency from that of chronic disease. 

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