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Function

Transferrin (or siderophilin) is a beta-globulin protein of 76 kDa molecular weight, synthesized by the liver [1]. Human transferrin is encoded by the TF gene [2]. It consists of a single polypeptide chain carrying two iron uptake sites, at the rate of 2 iron atoms per transfer molecule. The transferrin function is the transport of iron from the intestine to hepatic reserves and reticulocytes. The affinity of transferrin for Fe(III) is extremely high (association constant is 1020 M−1 at pH 7.4) but decreases progressively with decreasing pH [3]. So transferrins are iron-binding blood plasma glycoproteins that control the level of free iron (Fe) in biological fluids in link with the pH [4]. When not bound to iron, transferrin is known as "apotransferrin".


Structure

Human serum transferrin is a monomeric glycoprotein of about 80 kDa[5]. It is composed of 679 amino acids distributed in two homologous sequences: the N-terminal sequence (amino acids 1 to 336) and the C-terminal sequence (amino acids 337 to 679). Each sequence represents a globular lobe which contains two domains. The cleft between the two domains is the iron-binding site, so transferrin can bind two iron molecules [6].

The status of one lobe (bound with a Fe3+ ion or not) can influence the binding or release of iron from the other lobe [7]. Moreover, it seems that the the N-terminal site is preferentially occupied than the C-terminal one in human serum. However, in all the cases, the binding of one Fe3+ ion is only possible if one carbonate or bicarbonate ion is already bound to the iron-binding site. Then, 3 protons are released, so the equations of the reaction between Fe3+ ions and transferrin are: first Fe3+ ion binding: Fe3+ + H6Tf + HCO3- --> [Fe-H3Tf-HCO3]- + 3H+ second Fe3+ ion binding: Fe3+ + [Fe-H3Tf-HCO3]- + HCO3- --> [Fe2-Tf-(HCO3)2]2- + 3H+

The three protons released come from the two tyrosines of the binding site and from one water molecule previously bound to the Fe3+ ion.

If there is no carbonate or bicarbonate ion, other anions such as oxalate, pyruvate, thioglycolate, nitrilotriacetate, glycine or phenylalanine could replace them. These anions possess a carboxyl group and a second electron-withdrawing functional group (typically another carboxyl, an amino, or a sulphydryl group), within 0.63 nm of the first carboxyl group, and can adopt a 'carbonate-like' configuration.

The N and C-terminal sequences have 40 % identity, that is why an ancestral gene duplication is proposed (3). However, the two lobes are a bit different in terms of structure, stability and ease of iron release. Globally, the iron-binding sites are located less than 1.7 nm below the surface of the protein. In the N-terminal sequence, the binding site is located near a disulfure bound between Cys-117 and Cys- 194. It is composed of two tyrosines and two histidines which bind to the ferric ion whereas an arginine binds to the carbonate ion. The organisation of the amino acids in the C-terminal sequence is similar [8].

The binding cleft is hydrophilic, containing many polar side chains and water molecules (about 10 to 20), as appropriate for binding an ionic species. Second, there are two antiparallel-strands at the back of the binding cleft that connect the two domains. These contain a hinge that enables one domain to move relative to the other, opening or closing the cleft [9]


Different types of carbohydrate are linked to the transferrin protain (it represents about 11,8% og the weight of the protein). The biological functions of these heterosaccharide chains have not been clearly established. They probably play a role in enhancing the solubility of the protein by virtue of their hydrophilic groups and increased charges [10].


Disease

Transferrin can be implicated in diseases, directly or not, such as congenital atransferrinemia (also called familial hypotransferrinemia) or Hemochromatosis type 3.

Atransferrinemia: Atransferrinemia is a rare hereditary metabolic disorder which have a frequency of 1/1 000 000. It is an autosomal recessive disease caused by a mutation of the TF gene.

This disease caused by a deficiency of transferrin, causes a lack of iron in the medullary precursors of red blood cells, an accumulation of iron in the peripheric tissue in the liver, heart, pancreas, thyroid, kidney and bone joints and a diminution of red blood cell synthesis. It can cause death by heart failure or infection (pneumonia).

Atransferrinemia has a lot of different symptom which are mainly: growth retardation, infections prevalence, anaemia, heart failure, hepatics insufficiency, arthropathy and hypothyroidy. Moreover, other symptoms can be detected with an adult. Indeed, it can cause chronic alcoholism, neurosis, and GRACILE syndrome.

Some diagnostic methods must confirm the disease, it can be a prenatal diagnostic which is a research of mutation for the parents, or molecular genetic testing to detect the mutation of TF, or a dosage of transferrin to detect anaemia (if there are less of 35mg/dL, the patient is sick).

A mutation of TF gene which codes for the transferrin causes this disease. This mutation could be between substitution mutation 77 to 477 positions. This mutation have to consequence to respectively replace aspartic acid asparagine and arginine by proline.

Today, Atransferrinemia is incurable but treatments exist, permitting to live with the deases. A monthly injection of plasma or apotransferrin can decrease the overage of irons with a substitution of TF. Those injections are for lifetime.


Hemochromatosis type 3:

Hemochromatosis type 3 is another rare disease caused by failure of the transferrin receptor 2. A mutation on the chromosome 7 cause a lack of receptor and an accumulation of iron on liver and heart. Dosage of transferrin detects it; a saturation is consequence of hemochromatosis type 3.


Interactions

Interaction with insulin-like growth factor: In the circulation, most of the insulin-like growth factors (IGFs) are bound to a ternary 150 kDa complex with IGF-binding protein (IGFBP)-3 and the acid labile subunit. Transferrin (Tf) is a component of a major IGF-binding fraction separated from human plasma and Tf binds to IGFs specifically. The data suggest that Tf may play an important role in regulating IGF/IGFBP-3 functions,[11].


References

  1. ↑ Aisen, P., Leibman, A., & Zweier, J. L. (1978). Stoichiometric and site characteristics of the binding of iron to human transferrin. Journal of Biological Chemistry, 253(6), 1930-1937.
  2. ↑ Yang, F., Lum, J. B., McGill, J. R., Moore, C. M., Naylor, S. L., Van Bragt, P. H., ... & Bowman, B. H. (1984). Human transferrin: cDNA characterization and chromosomal localization. Proceedings of the National Academy of Sciences, 81(9), 2752-2756.
  3. ↑ Aisen, P., Leibman, A., & Zweier, J. L. (1978). Stoichiometric and site characteristics of the binding of iron to human transferrin. Journal of Biological Chemistry, 253(6), 1930-1937.
  4. ↑ : CRICHTON, R. R., & CHARLOTEAUX‐WAUTERS, M. (1987). Iron transport and storage. European Journal of Biochemistry, 164(3), 485-506.
  5. ↑ Chung MC-M. Structure and function of transferrin. Biochem Educ. 1984 Oct 1;12(4):146–54.
  6. ↑ Maria de Sousa MFM. Transferrin and the Transferrin Receptor: Of Magic Bullets and Other Concerns. Inflamm Allergy. 2008;7:41–52.
  7. ↑ Dealing with iron: Common structural principles in proteins that transport iron and heme. Heather M. Baker
  8. ↑ Chung MC-M. Structure and function of transferrin. Biochem Educ. 1984 Oct 1;12(4):146–54.
  9. ↑ Baker, H. M., Anderson, B. F., & Baker, E. N. (2003). Dealing with iron: common structural principles in proteins that transport iron and heme. Proceedings of the National Academy of Sciences, 100(7), 3579-3583.
  10. ↑ Chung, M. C. M. (1984). Stucture and function of transferrin. Biochemical Education, 12(4), 146-154.
  11. ↑ Storch, S., Kübler, B., Höning, S., Ackmann, M., Zapf, J., Blum, W., & Braulke, T. (2001). Transferrin binds insulin‐like growth factors and affects binding properties of insulin‐like growth factor binding protein‐3. FEBS letters, 509(3), 395-398

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Nikita Pallaoro

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