Transferrin Receptors: Comparison
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Mohd Nazam Ansari.

 Transferrin is an iron-binding protein. It can be used as a ligand to deliver various proteins, genes, ions, and drugs to the target site via transferrin receptors for therapeutic or diagnostic purposes via transferrin receptors. 

  • transferrin receptor
  • Transferrin

1. Transferrin

Transferrin is a monomeric glycoprotein [8][1]. It is present in human serum at a concentration of 200–300 mg/dL [9][2] and has a half-life of about 8 days [10][3]. It is an iron-binding protein but can also bind to various other metals, e.g., zinc [11][4], aluminum [12][5], cadmium [13][6], and gallium [14][7]. In serum, it can exist in various forms such as non-iron-bound transferrin (apo-transferrin), bound to a single ferric ion, i.e., monoferric, or bound to two ferric ions, i.e., diferric transferrin (holo-transferrin) [9][2].
Transferrin has a polymeric chain and contains 19 disulfide bonds and three carbohydrate moieties; two are N-linked and one is O-linked. Transferrin molecules have two lobes, the N-lobe, which has 336 amino acids, and the C-lobe, which has 343 amino acids; the two lobes are connected by a short linkage sequence [15][8]. Thus, transferrin has a total of 679 amino acids, and its molecular weight is around 80 kDa [16][9]. Each lobe has an α-helix domain and a β-sheet domain. The four amino acids, i.e., one aspartic acid, two tyrosine, and one histidine, present in the N- and C-terminal lobes of transferrin, are the binding sites for Fe3+ and many other divalent and trivalent metal ions. Therefore, transferrin can be used as a delivery agent for various beneficial or harmful metal ions [17,18][10][11]. The iron ion is stabilized at the binding sites by two oxygen molecules donated by carbonate molecules [15][8].
The highest transferrin concentration is present in hepatocytes [9][2]. Other cells where it is found are sertoli [19][12], oligodendroglia [20][13], myocytes [15][8], pneumocytes [18][11], nephrons [21][14], parietal cells [22][15], immune cells [23][16], and cancer cell lines such as human breast and metastatic melanoma [24][17]; it is also found in bodily fluids such as plasma [9][2], lymph [23][16], amniotic fluid [25][18], cerebrospinal fluid [26][19], colostrum, and milk [21][14].
Transferrin + 2Fe3+ ⇌ Transferrin(Fe3+)2
Various polymorphic forms of transferrin have been detected in more than 30 species, with three major known isotypes: B, C, and D. The C-allele form is most common, particularly C1, whereas, in southwest Africa, the D allele predominates [15][8]. Egg white contains ovotransferrin [19][12], and milk, saliva, tears, white blood cells, and mucus contain lactoferrin [18][11]. The melanocyte surface contains melanotransferrin [27][20]. Transferrins are acidic, except for lactoferrin. Lactoferrin has an isoelectric point of 8.7. Diferric transferrin species have isoelectric points of 5.6–5.8 [18][11]. Transferrin controls iron homeostasis through sequestering, binding, transporting, storing, and utilizing iron [28][21]. In addition to iron absorption, lactoferrin has a role in inflammatory and immune responses [2][22]. Lactoferrin and ovotransferrin also have antimicrobial activity [9][2]. Transferrin plays an important function in the body because it helps in the growth, cytoprotection, and differentiation of proliferative, myotrophic, mitogenic, embryo-morphogenic, angiogenic, and neurotropic cells. Due to its iron-binding properties, transferrin is vital for growth, differentiation, and cytoprotection [15][8].

2. Transferrin Receptors

Transferrin receptors are membrane-bound glycoproteins responsible for cellular iron uptake [29][23]. Transferrin receptors are transmembrane homodimers with two identical subunits, each showing a molecular weight of approximately 85 kDa. Each polymeric unit has 760 amino-acid units [30][24]. Two disulfide bonds, one at cysteine 89 and another at cysteine 98, bind the two monomer units in the transferrin receptor, forming a homodimer [31][25]. Each subunit can be divided into three parts: the extracellular C-terminal with 670 amino acids, the intramembrane region with 28 amino acids, and intracellular N-terminal with 61 amino acids [29][23]. The extracellular domain contains two glycosylation sites; one is N-linked at three asparagine residues, and the other is O-linked at threonine. The normal functioning of transferrin receptors requires glycosylation [30][24]. The intracellular domain has a site for phosphorylation through activated protein kinase C [21][14]. Each transferrin receptor monomer has three lobes, giving the transferrin dimer a butterfly structure on the plasma membrane [18][11]. Binding sites are situated in the extracellular domain. Each subunit can bind one molecule of transferrin. The C-terminal domain of transferrin is essential for binding to the transferrin receptor [29][23]. Transferrin receptors are involved in the transportation and storage of iron [30][24]. As every cell has a requirement for iron, transferrin receptors are expressed in all cells except mature erythrocytes. Highly proliferative cells have a high requirement for iron; accordingly, transferrin receptor expression is also high. The cells with the highest densities of transferrin receptors are placental tissues, immature erythrocytes, and rapidly dividing cells [29][23]. Transferrin receptors are found in the gastrointestinal tract (duodenum, ileum, and colon cells), endocrine pancreatic cells, hepatocytes, and Kupfer cells [23][16]. Transferrin receptors can be identified in the anterior pituitary, thyroid cells, seminiferous tubules of the testis, kidney cells, and basal epidermis cells [21][14]. Transferrin receptors are localized in brain capillary endothelial cells. Cancer cells have elevated levels of transferrin receptors [18][11]. There are many studies reporting the presence of transferrin receptors in different cells. However, a limited number of studies have investigated the relative distribution of transferring receptors.

2.1. Transferrin Receptor 1 (TfR 1)

TfR 1 internalizes holo-transferrin via clathrin-mediated endocytosis [32][26]. At pH 7.4, the transferrin receptor is bound to holo-transferrin but not apo-transferrin [29][23]. In the endosomes, at an acidic pH, ferric ion becomes dissociated from holo-transferrin and the transferrin receptor complex [30][24]. Ferric ions are converted into ferrous ions by enzyme metalloreductase, and the divalent metal transporter (DMT1) transports them to the cytosol [9][2]. Recycling endosomes move the TfR 1–transferrin complex to the cell surface, where apo-transferrin becomes separated from the transferrin receptor, and apo-transferrin is released into the bloodstream [9,18][2][11]. The expression of TfR 1 is regulated by the concentration and time duration of the presence of iron [33][27]. When iron is present at high concentrations for a long time, it decreases the expression of TfR 1 and increases intracellular ferritin and vice versa [18][11]. The hypoxia response element (HRE) promotes TfR gene expression. In iron deficiency and hypoxia, hypoxia-inducible factor (HIF) expression increases, promoting HRE and TfR expression [9][2]. The 3′ untranslated site of mRNA has five hairpin-like structures called iron-responsive elements (IREs). Iron-regulatory proteins (IRPs) recognize these sites [32][26]. There are two types of IRPs: IRP 1 and IRP 2. In iron deprivation conditions, both can bind to IREs. IRP 1 has a dual role, playing a role in RNA binding and acting as an enzyme aconitase, depending on the iron status of the cell [9][2]. In iron deficiency, IRP 1 binds to IREs of ferritin, present on a 5′ untranslated site, and inhibits the translation of ferritin [21][14]. However, when IRP 1 binds to IREs of the transferrin receptor, it stabilizes the transferrin receptor’s transcription, upregulates TfR 1, and increases the cellular uptake of iron. In iron-rich conditions, IRP 1 binds to mRNA enzymatically, not at the hairpin loop, resulting in the degradation of TfR 1 mRNA. IRP 2 has an equal affinity to mRNA as IRP 1 and binds to all sites; however, it is not active enzymatically. Separate genes encode both proteins [9,18][2][11]. Nitric oxide and hydrogen peroxide levels also regulate IRPs in the cell [34][28]. When iron causes oxidative stress and generates nitric oxide and hydrogen peroxide, IRP 1 is activated by a post-translation mechanism [29][23]. IPR 2 is activated by de novo protein synthesis [18][11]. TfR expression is also regulated by cell proliferation. Markedly proliferating cells show a higher expression level of TfRs than nonproliferating cells [21][14].

2.2. Transferrin Receptor 2 (TfR 2)

TfR 2 has two isoforms: α and β [35][29]. TfR 2α is highly expressed in erythrocyte precursors and hepatocytes and has a molecular weight of 90 kDa [9][2]. In the cytoplasm, TfR 2α has a short tail of amino acids (1–80) involved in endocytosis, the transmembrane domain, spanning amino acids 81–104, and the extracellular domain of amino acids (105–801), which consists of the protease-associated domain, and can bind to two ferric ions [36][30]. Hepatic tetraspanin CD81 can interact with the TfR 2α receptor and cause its degradation [9][2]. TfR 2β receptors are present ubiquitously but at low concentrations, expressed mainly in the brain, heart, and spleen [37][31]. TfR 2β is a cytosolic protein with a molecular weight of 60 kDa [36][30]. Many therapeutic and diagnostic agents can bind to transferrin, and the complex thus formed can be targeted to transferrin receptors present at various sites. As transferrin receptors are highly expressed in cancer cells, they can be utilized as potential targets for the delivery of anticancer agents [18][11]. In order to target transferrin receptors present in cancer cells, various drugs, proteins, or genes are conjugated with transferrin or transferrin-mimicking peptides. This strategy helps increase selectivity and reduces the toxicity and resistance of anticancer drugs [38][32]. The viral vectors used for gene delivery can be cytopathic or immunogenic. However, nonviral vectors have low transfection efficiency. Nucleic acids conjugated with polycations and crosslinked with transferrin can be used for the delivery of therapeutic genes to cancer cells [18][11]. Lu et al. [39][33] proposed the cationic gene vector-mediated delivery of plasmid DNA for gene therapy of prostate cancer. The delivery of non-lipophilic drugs to the brain is limited due to the presence of tightly packed capillary endothelial cells. Transferrin receptors are highly expressed in the capillary endothelial cells of the blood–brain barrier. Therefore, drugs, proteins, and genes linked to transferrin or transferrin-mimicking peptides can be delivered to the brain using transferrin/transferrin receptors [40][34]. The abovementioned strategy is useful for the treatment of neurological diseases such as Parkinson’s disease, Alzheimer’s disease, stroke, psychiatric disorders, and brain tumors [41][35]. Targeted drug delivery is required to reduce treatment-related adverse drug reactions. Transferrin receptors are excellent for delivering therapeutic agents such as drugs, metals, and genes to the target site. This bibliometric analysis provides insights into how transferrin receptor-mediated drug delivery has evolved over the years and highlights the contributors to its evolution. Transferrin receptor-mediated targeted drug delivery is beneficial in cancer, gene therapy, and diseases or disorders related to the brain because transferrin receptors are present in high concentrations in cancer cells and in the blood–brain barrier.


  1. Steinlein, L.M.; Graf, T.N.; Ikeda, R.A. Production and Purification of N-Terminal Half-Transferrin in Pichia Pastoris. Protein Expr. Purif. 1995, 6, 619–624.
  2. Kawabata, H. Transferrin and Transferrin Receptors Update. Free Radic. Biol. Med. 2019, 133, 46–54.
  3. de Jong, G.; van Eijk, H.G. Microheterogeneity of Human Serum Transferrin: A Biological Phenomenon Studied by Isoelectric Focusing in Immobilized PH Gradients. Electrophoresis 1988, 9, 589–598.
  4. Evans, G.W. Transferrin Function in Zinc Absorption and Transport. Exp. Biol. Med. 1976, 151, 775–778.
  5. Cochran, M.; Coates, J.; Neoh, S. The Competitive Equilibrium between Aluminium and Ferric Ions for the Binding Sites of Transferrin. FEBS Lett. 1984, 176, 129–132.
  6. Harris, W.R.; Madsen, L.J. Equilibrium Studies on the Binding of Cadmium(II) to Human Serum Transferrin. Biochemistry 2002, 27, 284–288.
  7. Harris, W.R.; Pecoraro, V.L. Thermodynamic Binding Constants for Gallium Transferrin. Biochemistry 2002, 22, 292–299.
  8. Gomme, P.T.; Mccann, K.B.; Bertolini, J. Transferrin: Structure, Function and Potential Therapeutic Actions. Drug Discov. Today 2005, 10, 267–273.
  9. MacGillivray, R.T.A.; Mendez, E.; Shewale, J.G.; Sinha, S.K.; Lineback-Zins, J.; Brew, K. The Primary Structure of Human Serum Transferrin. The Structures of Seven Cyanogen Bromide Fragments and the Assembly of the Complete Structure. J. Biol. Chem. 1983, 258, 3543–3553.
  10. Bailey, S.; Evans, R.W.; Garratt, R.C.; Gorinskv, B.; Mydin, A.; Horsburg, C.; Jhoti, H.; Lindley, P.F.; Hasnain, S.; Sarra, R.; et al. Molecular Structure of Serum Transferrin at 3: 3-A Resolution. Biochemistry 1988, 27, 5804–5812.
  11. Li, H.; Qian, Z.M. Transferrin/Transferrin Receptor-Mediated Drug Delivery. Med. Res. Rev. 2002, 22, 225–250.
  12. de Jong, G.; van Dijk, J.P.; van Eijk, H.G. The Biology of Transferrin. Clin. Chim. Acta 1990, 190, 1–46.
  13. Silva, A.M.N.; Moniz, T.; de Castro, B.; Rangel, M. Human Transferrin: An Inorganic Biochemistry Perspective. Coord. Chem. Rev. 2021, 449, 214186.
  14. Macedo, M.F.; de Sousa, M. Transferrin and the Transferrin Receptor: Of Magic Bullets and Other Concerns. Inflamm. Allergy-Drug Targets 2008, 7, 41–52.
  15. Mason, D.Y.; Taylor, C.R. Distribution of Transferrin, Ferritin, and Lactoferrin in Human Tissues. J. Clin. Pathol. 1978, 31, 316–327.
  16. Huebers, H.A.; Finch, C.A. The Physiology of Transferrin and Transferrin Receptors. Physiol. Rev. 1987, 67, 520–582.
  17. Rossiello, R.; Carriero, M.V.; Giordano, G.G. Distribution of Ferritin, Transferrin and Lactoferrin in Breast Carcinoma Tissue. J. Clin. Pathol. 1984, 37, 51–55.
  18. Larsen, B.; Snyder, I.S.; Galask, R.P. Transferrin Concentration in Human Amniotic Fluid. Am. J. Obstet. Gynecol. 1973, 117, 952–954.
  19. Murakami, Y.; Saito, K.; Ito, H.; Hashimoto, Y. Transferrin Isoforms in Cerebrospinal Fluid and Their Relation to Neurological Diseases. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2019, 95, 198–210.
  20. Rahmanto, Y.S.; Bal, S.; Loh, K.H.; Yu, Y.; Richardson, D.R. Melanotransferrin: Search for a Function. Biochim. Biophys. Acta-Gen. Subj. 2012, 1820, 237–243.
  21. Yu, Y.; Jiang, L.; Wang, H.; Shen, Z.; Cheng, Q.; Zhang, P.; Wang, J.; Wu, Q.; Fang, X.; Duan, L.; et al. Hepatic Transferrin Plays a Role in Systemic Iron Homeostasis and Liver Ferroptosis. Blood 2020, 136, 726–739.
  22. Li, H.; Sun, H.; Qian, Z.M. The Role of the Transferrin–Transferrin-Receptor System in Drug Delivery and Targeting. Trends Pharmacol. Sci. 2002, 23, 206–209.
  23. Ponka, P.; Lok, C.N. The Transferrin Receptor : Role in Health and Disease. Int. J. Biochem. Cell Biol. 1999, 31, 1111–1137.
  24. Speeckaert, M.M.; Speeckaert, R.; Delanghe, J.R. Biological and Clinical Aspects of Soluble Transferrin Receptor. Crit. Rev. Clin. Lab. Sci. 2010, 47, 213–228.
  25. Skikne, B.S. Serum Transferrin Receptor. Am. J. Hematol. 2008, 83, 872–875.
  26. Gammella, E.; Buratti, P.; Cairo, G.; Recalcati, S. The Transferrin Receptor: The Cellular Iron Gate. Metallomics 2017, 9, 1367–1375.
  27. Aisen, P. Transferrin Receptor 1. Int. J. Biochem. Cell Biol. 2004, 36, 2137–2143.
  28. Pantopoulos, K. Iron Metabolismo and the IRE/IRP Regulation System. Ann. N. Y. Acad. Sci. 2004, 1012, 1–13.
  29. Kawabata, H.; Nakamaki, T.; Ikonomi, P.; Smith, R.D.; Germain, R.S.; Phillip Koeffler, H. Expression of Transferrin Receptor 2 in Normal and Neoplastic Hematopoietic Cells. Blood 2001, 98, 2714–2719.
  30. Roetto, A.; Mezzanotte, M.; Pellegrino, R.M. The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value. Pharmaceuticals 2018, 11, 115.
  31. Trinder, D.; Baker, E. Transferrin Receptor 2: A New Molecule in Iron Metabolism. Int. J. Biochem. Cell Biol. 2003, 35, 292–296.
  32. Verma, S.; Gustafsson, A. Investigating the Emerging COVID-19 Research Trends in the Field of Business and Management: A Bibliometric Analysis Approach. J. Bus. Res. 2020, 118, 253–261.
  33. Donthu, N.; Kumar, S.; Mukherjee, D.; Pandey, N.; Lim, W.M. How to Conduct a Bibliometric Analysis: An Overview and Guidelines. J. Bus. Res. 2021, 133, 285–296.
  34. Aparicio, G.; Iturralde, T.; Maseda, A. Conceptual Structure and Perspectives on Entrepreneurship Education Research: A Bibliometric Review. Eur. Res. Manag. Bus. Econ. 2019, 25, 105–113.
  35. Pinto, G.; Rastogi, S.; Kadam, S.; Sharma, A. Bibliometric Study on Dividend Policy. Qual. Res. Financ. Mark. 2020, 12, 72–95.
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