Transferrin glycoproteins bind iron very tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of the total body iron, it is the most important iron pool, with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80 KDa and contains two specific high-affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (1023 M−1 at pH 7.4) but decreases progressively with decreasing pH below neutrality.
When not bound to iron, it is known as "apotransferrin" (see also apoprotein).
When a transferrin protein loaded with iron encounters a transferrin receptor on the surface of a cell (e.g., to erythroid precursors in the bone marrow), it binds to it and, as a consequence, is transported into the cell in a vesicle by receptor-mediated endocytosis. The pH of the vesicle is reduced by hydrogen ion pumps (H+ ATPases) to about 5.5, causing transferrin to release its iron ions. The receptor (with its ligand, transferrin, bound) is then transported through the endocytic cycle back to the cell surface, ready for another round of iron uptake. Each transferrin molecule has the ability to carry two iron ions in the ferric form (Fe3+ ).
In humans, transferrin consists of a polypeptide chain containing 679 amino acids. The protein is composed of alpha helices and beta sheets to form two domains. The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.
Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer. In humans, each monomer consists of 760 amino acids. It enables ligand bonding to the transferrin, as each monomer can bind to one or two molecules of iron. Each monomer consists of three domains: the protease, the helical, and the apical domains. The shape of transferrin receptor resembles a butterfly-like complex, due to the three clearly shaped domains.
The liver is the main site of transferrin synthesis, but other tissues and organs, such as the brain, also produce it. The main role of transferrin is to deliver iron from absorption centers in the duodenum and white blood cell macrophages to all tissues. Transferrin plays a key role where erythropoiesis and active cell division occur. The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.
Transferrin is also associated with the innate immune system. It is found in the mucosa and binds iron, thus creating an environment low in free iron that impedes bacterial survival in a process called iron withholding. The level of transferrin decreases in inflammation.
Role in disease
An increased plasma transferrin level is often seen in patients suffering from iron deficiency anemia. A decreased plasma transferrin can occur in iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia; a condition characterized by anemia and hemosiderosis in the heart and liver that leads to many complications, including heart failure.
Most recently, transferrin and its receptor have been shown to diminish tumour cells by using the receptor to attract antibodies.
The metal-binding properties of transferrin have a great influence on the biochemistry of plutonium in humans.
^Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY (1999). "Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort". J. Clin. Lab. Anal.13 (6): 273–9. doi:10.1002/(SICI)1098-2825(1999)13:6<273::AID-JCLA4>3.0.CO;2-X. PMID10633294.
^"Normal Reference Range Table". Interactive Case Study Companion to Pathlogical Basis of Disease. The University of Texas Southwestern Medical Center at Dallas. Retrieved 2008-10-25. Kumar V, Hagler HK (1999). Interactive Case Study Companion to Robbins Pathologic Basis of Disease (6th Edition (CD-ROM for Windows & Macintosh, Individual) ed.). W B Saunders Co. ISBN0-7216-8462-9.
^Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T (December 2001). "Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3". FEBS Lett.509 (3): 395–8. doi:10.1016/S0014-5793(01)03204-5. PMID11749962.
^Weinzimer SA, Gibson TB, Collett-Solberg PF, Khare A, Liu B, Cohen P (April 2001). "Transferrin is an insulin-like growth factor-binding protein-3 binding protein". J. Clin. Endocrinol. Metab.86 (4): 1806–13. doi:10.1210/jc.86.4.1806. PMID11297622.