Transferrin and transferrin receptor


Transferrin is a glycoprotein composed of 700 amino acids, with molecular weight of 79.6 kDa. Transferrin concentration in plasma is normally 2-4 g/L, and it is found in similar concentrations in extracellular fluids. Transferrin contains two binding sites for ferric ion (Fe3+), one in both of its subunits. Transferrin is mainly synthesized in the liver, but other tissues, including central nervous system (oligodendrocytes) and testes synthesize transferrin for local use. So called β2- or τ-transferrin variant is found in the cerebrospinal fluid.

Human body contains about 3.5-5 g iron, but only about 3-4 mg is circulating in plasma. Iron in the tissues must be protected from uncontrolled reactions with oxygen to prevent formation of reactive oxygen species (ROS). 60-70% of the body iron is bound in haemoglobin, 10% in myoglobin, and 20% in storage forms, mainly as ferritin. Essentially all circulating iron in plasma is bound to transferrin. Normally 1/3 of the capacity of circulating transferrin is used by ferric ions. Transferrin has very high affinity for ferric ion, but binding can only happen with a bridging anion, which in physiological conditions is carbonate. Ferric ion is released from the binding site when the carbonate anion is protonated.

Isotope studies have shown that >80% of transferrin-bound iron is delivered to bone marrow and incorporated into new erythrocytes. Reticuloendothelial cells in the liver collect iron mainly by phagocytosis of senescent erythrocytes, releasing it into hepatocytes and into circulation, bound to transferrin.

Transferrin has a role in the innate immune system called iron withholding: it creates an environment low in free iron, for example in mucosa, thus preventing bacterial growth. Only few bacteria (such as Lyme disease causing Borrelia burgdorferi) have evolved to survive without iron by using manganese instead.

Other metals

Transferrin can bind also other metal cations than Fe3+; stable complexes are formed with more than forty metallic cations (Chahine et al., 2012). Transferrin acquires rapidly the metal cations from low molecular weight chelators such as citrate. Transferrin has a physiological role in transport of Mn3+. In addition, it binds metal ions that are important in diagnostics and therapeutics, such as Ga3+, In3+, Ti4+, VO2+, Cr3+, Ru3+, and Bi3+. Gallium-transferrin complex can be internalized, while indium-bound transferrin is only bound to TfRs. The affinity of transferrin for Fe3+ is ∼400 times higher than for Ga3+, but exchange half-life is very slow.

Transferrin can also bind Al3+, and it is possible that it can be internalized in cells and incorporated in ferritin. However, transferrin-Al3+ complex does not seem to interact with transferrin receptor 1 (Hémadi et al., 2003).

Transferrin receptors

Transferrin receptors (TfR1 and TfR2) are transmembrane proteins with 66% homology. TfR1 has a high degree of homology with PSMA, too. TfR1 (TFRC, CD71) is a high affinity ubiquitously expressed receptor; TfR1s are abundant in hepatocytes, erythrocyte precursors especially in bone marrow, and other tissues, especially rapidly dividing cells, but not in mature erythrocytes. In the central nervous system TfRs are found in the grey matter, mainly at the luminal side of brain capillary endothelial cells, but very little on neurons or glial cells (Roelcke et al., 1996). TfR1 expression on cell surface is increased when intracellular iron concentration is low. TfR2 has lower affinity to diferric transferrin than TfR1, and it is only expressed in hepatocytes, enterocytes of the small intestine, and erythroid cells. TfR2 expression is independent on the intracellular iron concentration, but it is instead modulated by cell growth rate.

When transferrin receptor binds transferrin, the complex is internalized into endocytic vesicles. Receptor binds diferric transferrin with very high affinity, and affinity to monoferric transferrin and transferrin without iron (apotransferrin) is lower. With physiological concentrations the cellular transferrin receptors are saturated. Inside endosomes the lower pH promotes the protonation of the carbonate anion coordinating the position of the ferric ion, induces conformational change in transferrin, and additionally membrane bound oxidoreductase catalyses the reduction of Fe3+ to Fe2+. After Fe2+ (ferrous ion) is released, the transferrin receptor bound apotransferrin is recycled to the cell surface, and in the extracellular neutral pH apotransferrin is released from the complex. Ferrireductase family proteins (STEAP) reduce the ferrous ion back to ferric ion for further transport in the cytoplasm and into mitochondria.

Serum contains soluble transferrin receptor (sTfR), which is a truncated monomer form of the transmembrane receptors, formed by proteolytic cleavage. Increased levels of sTfRs are found in patients with increased erythropoiesis and iron deficiency.

Hemochromatosis is an inherited disorder causing iron overload. Normal HFE gene codes binds to transferrin receptor reducing its affinity to diferric transferrin, thus reducing cellular uptake of iron, but the mutated HFE gene produces protein that does not bind transferrin receptor (Chitambar & Wereley, 2003).

PET imaging

Tumour cells usually express high levels of TfRs because of high demand for iron. Transcription factors MYC and HIF-1α activate transferrin receptor transcription in many cancers. Labelled transferrin can be used for detecting MYC-positive cancer (Aggarwal et al., 2017). However, upregulated transferrin uptake is also seen in active inflammatory cells, and other rapidly dividing or metabolically active cells.

Transferrin can be labelled in vivo by administering 68Ga3+-citrate or 52Fe3+-citrate, and has been used in imaging of infection and inflammation and cancers. [68Ga]transferrin can also be prepared in vitro.

Transferrin does not bind 89Zr, but chelate desferrioxamine B (DFO) can be linked to transferrin, and the produced [89Zr]DFO-transferrin can provide good quality PET images at least in mouse models (Evans et al., 2013; Holland et al., 2014; Henry et al., 2018).

Transferrin has also been labelled with 18F, providing good in vitro uptake, but the in vivo imaging results have not been very promising (Aloj et al., 1996, 1997, and 1999).

In addition to transferrin receptors, cancer cells overexpress oxidoreductase STEAP3 within lysosomes to increase the cytosolic labile iron pool (LIP). Therapies could either exacerbate LIP-associated redox stress, or induce LIP starvation, in cancer cells. [18F]TRX, based on antimalarial drug artefenomel, can be used to assess LIP (Muir et al., 2019; Zhao et al., 2021).


Ferritin protein complexes function as an intracellular ferric ion carriers and storage. Its structure is highly conserved in animals, plants, and bacteria. Ferritin consists of a protein shell (apoferritin) of 24 subunits, and an iron core containing about 2500 Fe3+ ions. Apoferritin synthesis is increased when iron levels are high. Ferritin composition is slightly different (isoferritins) in different organs and depending on the demand for iron. A subtype of ferritin is also found in mitochondria. Ferritin tends to aggregate over time, and the aggregates are degraded by lysosomes into hemosiderin, which is an agglomerate of denatured protein, lipids, and iron oxide. Hemosiderin functions as a long-term iron storage, mainly in the liver, spleen, and bone marrow.

Cationized ferritin can be used as a contrast agent in MRI (CFE-MRI). In the kidneys, it binds to anionic sites of glomerular basement membranes, and can be used to measure the number and volume of glomeruli (Baldelomar et al., 2018).

Ferritin binds also Ga3+.


Transferrin protein superfamily includes lactoferrin (LTF) which too binds two ferric ions with high affinity, even at lower pH than transferrin. Like transferrin, also lactoferrin binds iron with CO32-/HCO3-. Lactoferrin has higher affinity for Ga3+ than transferrin (Harris, 1986). Lactoferrin is found in mucosal secretions, and neutrophil granules, especially in secondary peroxidase-negative granules of mature neutrophils.

Lactoferrin is bound by specific membrane receptors, belonging to several unrelated protein families, but it is not bound to transferrin receptors. Lactoferrin receptors are found on many cell types, including hepatocytes, T cells, platelets, and endothelial cells.

Lactoferrin shows anti-microbial activity via several mechanisms: it participates in iron withholding, it inactivates colonization factors of some bacteria, and it destabilizes the membranes of some Gram-negative bacteria by interacting with their outer membrane porins. Additionally, a peptide called lactoferricin can be detached from it, and it interacts with bacterial lipopolysaccharides (LPSs). On the other hand, some bacteria express lactoferrin binding receptors, which they use to deprive lactoferrin from its iron.


Melanotransferrin (MTF, tumour-bound antigen 97) belongs also to the transferrin glycoprotein family. It is widely expressed on the cell membranes of normal tissues, including liver, intestine, salivary glands, and sweat glands. Its expression on melanocytes has lead to its use in diagnosis of melanoma.

Targeted delivery using transferrin

Cellular uptake of drugs, therapeutical nanoparticles and siRNA molecules can be increased by attached targeting ligands. Transferrin is one of the possible targeting ligands (Qian et al., 2002; Daniels et al., 2012), since TfRs are expressed on almost all cell types, and especially in fast dividing cells like in tumours.

See also:


Crichton R: Iron Metabolism: From Molecular Mechanisms to Clinical Consequences. 4th edition. Wiley, 2016. doi: 10.1002/9781118925645.

Leitner DF, Connor JR. Functional roles of transferrin in the brain. Biochim Biophys Acta 2012; 1820: 393-402. doi: 10.1016/j.bbagen.2011.10.016.

Mayle KM, Le AM, Kamei DT. The intracellular trafficking pathway of transferrin. Biochim Biophys Acta 2012; 1820: 264-281. doi: 10.1016/j.bbagen.2011.09.009.

Messori L, Kratz F. Transferrin: from inorganic biochemistry to medicine. Metal-Based Drugs 1994; 1(2-3): 161-167. doi: 10.1155/MBD.1994.161.

Testa U: Proteins of Iron Metabolism. CRC Press, 2002.

Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat B, Tissot J-D. Physiology of iron metabolism. Transfus Med Hemother. 2014; 41(3): 213-221. doi: 10.1159/000362888.

Wick M, Pinggera W, Lehmann P: Clinical Aspects and Laboratory - Iron Metabolism, Anemias. 6th edition. Springer, 2011. doi: 10.1007/978-3-7091-0087-5.

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Updated at: 2021-01-18
Created at: 2017-03-30
Written by: Vesa Oikonen