Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • George Papanikolaou
  • Konstantinos Gkouvatsos
  • Kostas Pantopoulos
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101940


Historical Background

Transferrin is a secreted glycoprotein that transports ferric iron (Fe3+) from extracellular fluids to tissues. It was first documented as “iron-binding component” of human blood plasma back in 1946. The “iron-binding component” was subsequently purified, biochemically characterized, and named transferrin. A similar protein from egg white (ovotransferrin) was previously reported to inhibit bacterial and yeast growth via its iron-binding capacity. A historical account of the early discovery and characterization of transferrin can be found in an excellent review article (Morgan 1981). Functional studies demonstrated that plasma transferrin delivers iron to developing erythroid cells upon binding to cell surface transferrin receptors. The mechanism involves internalization of iron-loaded transferrin within the recipient cell, release of iron following acidification of the endosome, and recycling of iron-free transferrin (Klausner et al. 1983). Other historical milestones were the determination of the primary structure of human transferrin (MacGillivray et al. 1983), the cloning and genomic mapping of the human transferrin gene TF (Yang et al. 1984), and the acquisition of high-resolution crystallographic data of transferrin alone (Bailey et al. 1988) or in complex with its receptor (Cheng et al. 2004).

Structure and Biochemical Properties

Human transferrin consists of 679 amino acids and has a molecular weight of ∼79 kD (Gomme et al. 2005). The polypeptide undergoes N-glycosylation (at N413 and N611) and O-glycosylation (at S32). Transferrin molecules are typically divided into homologous N- and C-terminal lobes, which fold into several α-helices around a central β-sheet backbone, and are connected by an unstructured peptide spacer (Fig. 1a). The structure is stabilized by several intrachain disulfide bridges. Each lobe contains two subdomains (N1, N2 and C1, C2) forming a hydrophilic iron-binding cleft. This includes highly conserved amino acid residues (an aspartic acid, two tyrosines, and a histidine) that interact with Fe3+ at four of its coordination sites; the remaining two are occupied by a bidentate carbonate in a distorted octahedral arrangement. Carbonate stabilizes the Fe3+-transferrin complex but also confers specificity for iron and against other metals (Harris 2012). Surrounding amino acids may contribute to further stabilization of the iron-binding site by forming hydrogen bonds (for instance, N-terminal K206 and K296).
Transferrin, Fig. 1

The three-dimensional structure of transferrin. (a) Crystal structure of human holo-transferrin at 2.1 Å resolution obtained by X-ray diffraction (PDB ID: 3 V83). The red spheres embedded in each lobe represent Fe3+ ions. (b) Structure of the human transferrin/TfR1 complex at 7.5 Å resolution obtained by cryo-electron microscopy (PDB ID: 1SUV). The helical ectodomain of the TfR1 homodimer is shown in purple and blue. Each monomer interacts with the C-lobe of one transferrin molecule (depicted in gray and orange, respectively). The N-lobes of the transferrin molecules (brown and green, respectively) are sandwiched between the helical ectodomain of TfR1 and the plasma membrane (not shown)

The iron-binding affinity of transferrin is extremely high at pH 7.4 (KD = 1020 M−1) but drops dramatically at acidic pH 5.6, resulting in release of iron. This is associated with protonation and removal of carbonate from the Fe3+-transferrin complex, followed by a conformational change in the transferrin polypeptide. The structural alteration is caused by disruption of hydrogen bonds stabilizing the iron-binding site and rotation of the subdomains of each lobe around a few connecting hinge residues by approximately 60°. The rate of iron release from transferrin can be affected by binding of anions (such as carbonate or others) to allosteric sites, which remain poorly characterized (Harris 2012). The pH dependence of the iron-transferrin interaction has important implications on the mechanism for iron delivery to cells (see below). Transferrin can also bind to other metals (Ti4+, VO2+, V4+, Cr3+, Ru3+, Ga3+, and Bi3+), which may have toxicological implications, but can also be employed for therapeutic purposes (Vincent and Love 2012).

Function and Evolution

Transferrin evolved to capture, solubilize, and transport Fe3+ to cells and tissues. Almost all cells and organisms utilize iron as cofactor for fundamental biochemical activities and require iron for growth. Nevertheless, even though iron is highly abundant, its bioavailability is limited due to spontaneous aerobic oxidation of Fe2+ to virtually insoluble Fe3+ (Kfree Fe3+ = 10−17 M at physiological pH). Transferrin solubilizes Fe3+ and maintains it in a redox-inert state. While the redox reactivity of iron is crucial for many of its biological functions, it also renders it to a potential biohazard. Iron’s toxicity is based on its capacity to catalyze generation of noxious hydroxyl radicals (OH.) via Fenton/Haber-Weiss chemistry. Transferrin detoxifies circulating iron and prevents the generation of oxidative stress in the plasma and other extracellular fluids, which can damage cellular membranes and proteins. Transferrin also promotes cell growth and inhibits apoptosis, primarily via its iron-transport function but also independently of it (Morgan 1981). Importantly, transferrin-bound iron is inaccessible to most bacteria during infection. Thus, transferrin also exhibits bactericidal activity and mediates innate immune responses by depriving pathogens from an essential nutrient (Barber and Elde 2014).

Members of the transferrin superfamily are evolutionary conserved in metazoans including halotolerant algae, insects, crustaceans, hemichordates, urochordates, sea urchins, reptiles, fish, birds, and mammals (Lambert 2012). The extended (30%) sequence identity between the C- and N-lobes of mammalian transferrins indicates evolution via duplication of an ancestral gene encoding a monolobal transferrin. This view is further supported by the existence of monolobal transferrin homologs in marine invertebrates, which very likely represent preduplication forms. The duplication of the lobes may have served to prevent urinary excretion of transferrin from the kidneys. Atypical transferrins possessing long insertions within the lobes, membrane anchors or even three lobes have also been reported, mostly in invertebrates. Some atypical transferrins operate as iron carriers but others appear to have iron-independent functions, which remain unexplored.

The closest homologs of mammalian transferrin are ovotransferrin and lactoferrin. Ovotransferrin is found in egg white and plasma of birds and reptiles and exhibits important iron transporting, growth promoting, bacteriostatic, antifungal, and antiviral activities. Lactoferrin shares a similar structure with transferrin and ovotransferrin and binds iron with similar affinity to these proteins but in a broader pH range. Lactoferrin is present in milk, colostrum, and other mucosal secretions such as tears, saliva, nasal mucus, sputum, semen, vaginal fluids, etc. In addition, it is abundant in secondary granules of neutrophils, which indicates an immune function. In fact, lactoferrin is a multifunctional protein that protects against bacterial, fungal, viral, and parasitic infections but also exhibits immunomodulatory and anti-inflammatory properties, as well as enzymatic and gene regulatory activities. Melanotransferrin is a more distant family member that was discovered as a tumor antigen. It binds iron only in the N-terminal lobe. Melanotransferrin is expressed in melanoma cells and attaches to their plasma membrane via a glycosyl-phosphatidylinositol anchor, but its molecular and physiological function remains elusive.


The human TF gene is localized on chromosome 3q21 (Yang et al. 1984). Circulating transferrin is derived from the liver and is synthesized in hepatocytes (Zakin 1992; Gkouvatsos et al. 2012). Transferrin is also expressed in other tissues, but at much lower levels. The major sites of extrahepatic transferrin production are the brain (oligodendrocytes and astrocytes) and testis (Sertoli cells), which are separated from circulation by blood-brain and blood-testis barriers, respectively. Transferrin is also expressed in ovaries, spleen, kidney, and the mammary gland.

Tissue specificity of transferrin expression is mediated by differential recruitment of transcription factors to promoter regions. Transcription of the TF gene in hepatocytes is induced by the binding of HNF-4 (hepatocyte nuclear factor 4) and C/EBP (CCAAT enhancer-binding protein) to proximal (−125/+1 bases) promoter regions. CHOP (nuclear protein C/EBP homologous protein 10, or GADD153) antagonizes C/EBP binding and thereby inhibits TF transcription. Distal promoter regions contain either positive and negative (−620/−125 bases) or just negative (−1000/−620 bases) cis-acting elements. An enhancer region (−4.0/−3.6 kilobases) stimulates TF transcription via HNF-3α and other factors only in hepatocytes but not in Sertoli cells, which express tenfold lower levels of transferrin mRNA. TF transcription in neuronal cells and oligodendrocytes is induced by C/EBP and CRI-BP (central region I binding protein) and suppressed by COUP-TF (chicken ovalbumin upstream promoter transcription factor).

The expression of transferrin is upregulated by iron deficiency, estrogens, or hypoxia and downregulated by iron or inflammation (Bartnikas 2012; Gkouvatsos et al. 2012). Decreased levels of transferrin also occur under conditions of chronic liver diseases, malnutrition, protein-losing diseases, or the nephrotic syndrome. Iron deficiency stimulates transferrin synthesis in the liver but not in other tissues. Conversely, iron was found to suppress transferrin in the human HepG2 and murine BWT G2 hepatoma cell lines. Conditions of estrogen excess (pregnancy, use of oral contraceptives, or estrogen therapy) are associated with increased circulating transferrin levels, very likely due to transcriptional induction. Systemic inflammation triggers a decrease in circulating transferrin levels; thus, transferrin is considered as a negative acute phase protein. Consistently, the inflammatory cytokines IL-6, IL-1β, and TNFα decrease transferrin synthesis in primary human hepatocytes. Nonetheless, IL-6 was reported to increase transferrin synthesis in HepG2 and BWT G2 cells, suggesting that cell transformation may affect transferrin regulation by inflammatory stimuli. Notably, exposure of HepG2 cells to hypoxia recapitulated inflammatory regulation of several acute phase proteins but led to induction (rather suppression) of transferrin expression. This is caused by transcriptional activation of the TF gene upon binding of HIF-1 (hypoxia-inducible factor-1) to hypoxia response elements (HREs) in its enhancer region.

The Transferrin Cycle

Transferrin delivers iron to cells upon binding to transferrin receptor 1 (TfR1), a transmembrane homodimeric glycoprotein. TfR1 is almost ubiquitously expressed and is crucial for iron acquisition by erythroid cells and other cell types (Gkouvatsos et al. 2012). TfR2, a close homologue of TfR1, is specifically expressed in hepatocytes and erythroid cells, where it appears to coordinately regulate systemic iron homeostasis and erythropoiesis, respectively (Pantopoulos 2015).

TfR1 binds one molecule of diferric (holo-)transferrin at each of its subunits with a stoichiometry of 1:2:1 and equilibrium dissociation constant KD = 1 × 108M−1 at neutral pH. The affinities of TfR1 to monoferric and iron-free (apo-)transferrin are 30- and 500-fold lower, respectively. Cryo-electron studies provided a model for the structural arrangement of the transferrin/TfR1 complex (Cheng et al. 2004). Thus, the C-terminal lobe of transferrin interacts with the helical ectodomain of TfR1, while the N-terminal lobe is sandwiched between the TfR1 ectodomain and the plasma membrane (Fig. 1a). TfR1 is also known to interact with the hemochromatosis protein HFE (Bennett et al. 2000), which competes the binding of transferrin and mitigates cellular iron uptake.

The binding of holo-transferrin to TfR1 triggers endocytosis of the complex via clathrin-coated pits (Fig. 2). Acidification of the endosome by a proton pump ATPase to pH 5.5 (Klausner et al. 1983) results in rearrangement of the C-terminal lobe of transferrin to a more open conformation (Cheng et al. 2004). This allows release of Fe3+, while apo-transferrin remains bound to TfR1. Liberated Fe3+ undergoes reduction by the ferric reductase STEAP3 (six-transmembrane epithelial antigen of the prostate 3). The resulting Fe2+ is exported across the endosomal membrane to the cytosol via DMT1 (divalent metal transporter 1). In erythroid cells, which consume more than two thirds of body iron for heme biosynthesis, Fe2+ appears to be directly delivered to mitochondria without accessing the cytosol. The apo-transferrin/TfR1 complex returns to the cell membrane, through a process involving the trafficking protein Sec15l1, and apo-transferrin is recycled back to the bloodstream with the aid of Snx3 (sorting nexin 3). Apo-transferrin is available to bind Fe3+ and engage into another cycle of iron delivery. Considering that the half-life of human transferrin is approximately 8 days, and the transferrin cycle is completed within 5–20 min, each transferrin molecule is poised to accomplish hundreds of iron delivery cycles.
Transferrin, Fig. 2

The transferrin cycle. Holo-transferrin binds to TfR1 on the plasma membrane and the complex undergoes endocytosis via clathrin-coated pits. Acidification of the endosome by a proton pump results in the release of Fe3+. Following reduction by STEAP3, Fe2+ is transported across the endosomal membrane to the cytosol via DMT1. The apo-transferrin/TfR1 complex is recycled to the cell surface. Finally, apo-transferrin is released to plasma, where it can capture Fe3+ and engage into another cycle

Transferrin and Iron Physiology

The iron content of the adult human body is approximately 3–5 g, corresponding to ∼55 mg/kg for males and ∼44 mg/g for females, respectively (Gkouvatsos et al. 2012). Most of body iron (>70%) is utilized in hemoglobin of red blood cells and excess is stored in liver hepatocytes (∼20%). A significant fraction of body iron is transiently distributed in tissue macrophages (∼5%), which eliminate senescent red blood cells and recycle their iron content for erythropoiesis. A smaller fraction is used in myoglobin of muscles (∼2.5%), while all other cell types have much lower iron needs (Fig. 3).
Transferrin, Fig. 3

Distribution of iron in the adult human body. Iron bound to transferrin represents a small but highly dynamic pool. Transferrin delivers iron to cells in the bone marrow, skeletal muscles, liver, and other tissues (blue arrows). It is replenished by iron released to the circulation from tissue macrophages, intestinal enterocytes, or liver hepatocytes (red arrows); the thick red arrow denotes that macrophages release much higher amounts of iron

Transferrin-bound circulating iron represents a tiny (∼0.1%) yet highly dynamic fraction of body. Considering that daily erythropoiesis requires 20–30 mg of iron, the transferrin iron pool turns over >10 times per day to supply sufficient amounts of iron to developing erythroid cells in the bone marrow. An iron atom entering the plasma transferrin pool remains in circulation only 90 min before being taken up by cells. More than 80% of transferrin-bound iron is delivered to bone marrow erythroblasts and the rest to nonerythroid cells. Circulating apo-transferrin is mostly replenished by iron recycled from tissue macrophages during erythrophagocytosis. The contribution of intestinal enterocytes to circulating transferrin pool is minimal, considering that adults do not absorb more 1–2 mg of iron per day from dietary sources. Hepatocytes may contribute iron from stores for erythropoiesis, especially under conditions of iron deficiency. It should be noted that iron is exported from cells in form of Fe2+ and undergoes oxidation to Fe3+ by soluble or membrane-bound ferroxidases (ceruloplasmin or hephaestin, respectively) before binding to transferrin.

Under physiological conditions, plasma transferrin concentration ranges between 200 and 400 mg/dl (2.5–5 μM/L) and is not severely influenced by age and sex. Nevertheless, approximately 30% of transferrin is saturated with iron and only 10% is in the diferric form. The presence of excessive apo-transferrin serves to buffer plasma iron levels and prevent accumulation of redox-active unshielded iron. Low transferrin saturation (<15%) indicates iron deficiency and high (>45%) iron overload. In disorders of iron overload (hemochromatosis), the buffering capacity of transferrin is exhausted and this results in emergence of nontransferrin bound iron (NTBI), which is deposited within tissue parenchymal cells and leads to tissue damage.

Hereditary hemochromatosis is caused by mutations in genes that prevent iron regulation of hepcidin, a liver-derived peptide hormone (Ganz 2013). Hepcidin physiologically restricts iron flux to the bloodstream by inactivating the iron exporter ferroportin in target cells (macrophages, enterocytes, and hepatocytes). The most common form of hereditary hemochromatosis (>95% of cases in the Caucasian population) is associated to mutations in HFE, an atypical major histocompatibility complex class 1 molecule. The clinical penetrance of this disease depends on several genetic and environmental factors. Interestingly, genome-wide association studies identified the TF gene as a modifier of the iron overload phenotype in HFE hemochromatosis (de Tayrac et al. 2015).

Under physiological conditions, transferrin plays an important role in coordinating iron supply with hepatic hepcidin expression and erythropoiesis. Thus, increased transferrin saturation stimulates hepcidin expression in hepatocytes, possibly via stabilization of TfR2 by holo-transferrin. TfR2 stabilization in hepatocytes leads to hypoferremia via hepcidin induction, while TfR2 stabilization in erythroid progenitor cells restricts sensitivity to signaling by erythropoietin. Conversely, in iron-deficient states, destabilized TfR2 prevents iron signaling to hepcidin and increases iron supply to the bone marrow, which becomes more sensitive to erythropoietin (Pantopoulos 2015).

As mentioned earlier, transferrin also contributes to the innate immunity system by sequestering iron from microbial pathogens. The biological importance of this mechanism is demonstrated by the susceptibility of hemochromatosis patients to infections. Moreover, several transferrin polymorphisms are evolutionary explained as adaptations to counteract bacterial iron piracy (Barber and Elde 2014).

Congenital Atransferrinemia/Hypotransferrinemia

Congenital atransferrinemia (OMIM#209300) is a very rare, early onset autosomal recessive disease characterized by very low to undetectable levels of serum transferrin (Hayashi et al. 1993). Transferrin insufficiency is associated with impaired erythropoiesis, microcytic hypochromic anemia, growth retardation, and iron overload affecting parenchymal tissues predominately the liver, heart, and pancreas. The first described patient (in 1961) was a 7-year-old child with traces of circulating serum transferrin and generalized iron overload that led to death due to congestive heart failure. The disease is also referred to as familial hypotransferrinemia, because the complete absence of functional transferrin is lethal. Levels of transferrin >20 mg/dl appear to be adequate for an apparently healthy phenotype.

To date, only 14 cases of congenital atransferrinemia have been reported worldwide. Most patients were compound heterozygotes harboring missense mutations, while others had nonsense mutations due to nucleotide deletions or duplications. Some patients succumbed to recurrent infections. No other associated congenital anomalies or syndromes accompany this disorder. Tranferrin saturation is high due to the low levels of circulating transferrin resulting in increased levels of NTBI. Hepcidin was found suppressed in hypotransferrinemic patients, explaining the increased iron absorption despite iron overload. Treatment with blood transfusions or iron preparations is ineffective and exacerbates iron overload. The standard of care involves supplementation with apo-transferrin (or plasma as a source of apo-transferrin), sometimes combined with iron chelation therapy. This regimen restores hemoglobin and hepcidin levels, decreases NTBI, and prolongs survival.

The hypotransferrinemic mouse (hpx), an animal model of congenital atransferrinemia, originated through routine breeding of the BALB/cJ strain. Hpx mice have very low levels of circulating transferrin (<1% of normal) due to a point mutation in a splice donor site of the transferrin gene. They die before weaning, unless they are treated with apo-transferrin or blood transfusions. Rescued animals are anemic and manifest suppression of hepcidin and severe iron overload (liver iron burden >100-fold higher compared to wild-type mice). In addition, adult hpx mice exhibit decreased white matter content in the brain and altered neuronal morphology in the brain and spinal cord.

Transferrin-Immune Complex Disease

Transferrin-immune complex disease (TICD) is an acquired disorder caused by the presence of IgM or IgG antitransferrin antibodies in the serum (Forni et al. 2013). Patients with antitransferrin antibodies have occasionally been described in the literature. TICD is characterized by hypersideremia and hypertransferrinemia, with varying degrees of transferrin saturation and ferritin levels. Iron overload is not a universal feature in TICD and its occurrence depends on the variable affinity and functional properties of the monoclonal antitransferrin antibodies, as well as the duration of the disease. In one reported case, hepatic iron overload was associated with hepcidin suppression due to iron-restricted erythropoiesis. Clinical suspicion of TICD should be raised in patients with marked hypersideremia, hypertransferrinemia, and monoclonal gammopathy of underdetermined significance (MGUS). Partial remission after the initiation of immunosuppressive therapy has been reported in some cases. Patients should be monitored for indices of both iron metabolism and MGUS.

Diagnostic and Potential Therapeutic Applications of Transferrin

Measurements of transferrin and transferrin saturation are routinely used to evaluate iron stores. Carbohydrate-deficient transferrin serves as a biomarker for detecting chronic alcohol abuse. Despite numerous caveats and limitations in terms of sensitivity and specificity, assessment of transferrin glycosylation is widely utilized in forensic medicine. The most common analytical techniques are high-performance liquid chromatography or capillary zone electrophoresis. Isoelectric focusing of serum transferrin is used as the initial step in the laboratory diagnosis of congenital disorders of glycosylation.

Patients with congenital atransferrinemia are managed by apo-transferrin supplementation. Further potential therapeutic applications of transferrin are currently under investigation. Apo-transferrin efficiently reduced free iron levels and renal injury in a mouse model of ischemia-reperfusion injury. In addition, it ameliorated anemia and increased serum hepcidin concentrations in a mouse model of thalassemia. Administration of apo-transferrin to mice prior to radiotherapy showed protective effects to bone marrow cells. Moreover, apo-transferrin prevented growth of Staphylococcus epidermidis in infected stem cell transplant patients. Finally, the transferrin-TfR1 system has been explored for targeted drug delivery applications involving transferrin conjugates with metal ions, drugs, proteins, or genes (Gomme et al. 2005).


Transferrin is an important molecule of iron metabolism. It serves as the plasma iron carrier and is essential for delivering iron via TfR1 to developing erythroid cells, the major iron consumers in the body. Importantly, transferrin keeps iron in a redox inactive form and prevents it from being toxic. The crucial role of transferrin as an iron detoxifier is illustrated in hereditary hemochromatosis, atransferrinemia, and other disorders of iron overload, where unrestricted dietary iron absorption and saturation of transferrin’s iron-binding capacity lead to accumulation of toxic NTBI. Transferrin also exerts a crucial innate immune function by depriving invading microorganisms from iron. This brings it at the forefront of the battle for iron between the host and microorganisms. More recently, transferrin was documented to act as an indirect regulator of iron homeostasis and erythropoiesis via TfR2. Finally, transferrin is widely used for diagnostic purposes and can also be potentially utilized for therapeutic applications.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • George Papanikolaou
    • 1
  • Konstantinos Gkouvatsos
    • 2
  • Kostas Pantopoulos
    • 3
  1. 1.Department of Nutrition and Dietetics, School of Health Science and EducationHarokopion UniversityAthensGreece
  2. 2.Hôpitaux universitaires de GenèveGenèveSwitzerland
  3. 3.Lady Davis Institute for Medical Research and Department of MedicineMcGill UniversityMontrealCanada