# Transferrin
**Transferrin** is a blood plasma glycoprotein that binds ferric iron (Fe³⁺) tightly but reversibly and delivers it to cells through receptor-mediated endocytosis. Human serum transferrin (hTF) circulates at a natural abundance of about 35 μM, and its iron-bearing form binds the transferrin receptor (TFR1) on the surface of iron-requiring cells with nanomolar affinity.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/)
| Key fact | Detail |
|---|---|
| Molecular form | Monomeric glycoprotein of 80 kDa with two homologous lobes (N- and C-) joined by a short peptide; the carbohydrate moiety sits on the C-lobe[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) |
| Iron binding | Binds up to two Fe³⁺ atoms with high affinity, one per lobe; a carbonate anion must be present to attract and stabilize the iron in each site[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) |
| Serum abundance | About 35 μM in blood[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/) |
| Receptor affinity | At pH 7.4, diferric hTF binds TFR1 with Kd ~4 nM; the monoferric forms bind at Kd ~36 nM (N-lobe iron) and ~32 nM (C-lobe iron)[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) |
| Lobe asymmetry | At pH 7.4 the C-lobe binds iron with an affinity constant about 6 times stronger than the N-lobe[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/) |
| Iron release trigger | Endosomal acidification to about pH 5.6 lowers iron affinity and, with the receptor, stimulates iron release[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) |
| Clinical use | Serum transferrin, total iron-binding capacity, and transferrin saturation are standard markers of iron status; a transferrin saturation below 15% indicates iron deficiency in clinical studies[4](https://iris.who.int/bitstream/handle/10665/75368/9789241596107_eng.pdf?sequence=1) |
## Structure
Transferrin is a single polypeptide of 80 kDa folded into two homologous lobes, N and C, connected by a short peptide. Each lobe divides into two subdomains (N1/N2 and C1/C2) that form clefts where iron binds; the subdomains act as flexible joints, closing when iron is bound and opening to release it.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) The iron in each cleft is coordinated by one aspartic acid, two tyrosine residues, one histidine, and one arginine, with a carbonate anion serving as an additional ligand that stabilizes the bound Fe³⁺.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/)
The primary sequence, determined by MacGillivray and colleagues in the Brew laboratory by producing overlapping peptides and confirmed a year later by cDNA sequencing, resolved earlier disputes over the protein's mass and composition and showed that all 38 cysteine residues form disulfide bonds.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/) Iron-saturated transferrin is considerably more resistant to heat, chemicals, and proteolysis than the iron-free (apo) form.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/)
## Function
Transferrin's central role is iron transport. Free Fe³⁺ is insoluble at neutral pH, so binding to transferrin keeps iron soluble in plasma; the protein also prevents the formation of reactive oxygen species, chelates free toxic iron, and contributes to innate immunity by sequestering iron away from bacteria.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) It carries iron between sites of absorption, utilization, and storage, and the liver increases transferrin production when iron levels fall, raising the blood's iron-binding capacity.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/)
Transferrin belongs to a small protein family whose founding members, serum transferrin, lactoferrin, and ovotransferrin, have served as model systems for developing many experimental techniques in protein chemistry.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/)
## The transferrin cycle
Uptake of iron proceeds through a seven-step cycle, and because it has been so thoroughly studied, this pathway is now the textbook illustration of clathrin-dependent receptor-mediated endocytosis and is frequently used as a positive control when studying other trafficking systems.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) • [5](https://www.nature.com/articles/s12276-025-01436-x)
1. **Binding.** At serum pH (~7.4), iron-bearing transferrin binds TFR1, a type 2 transmembrane glycoprotein homodimer of 97 kDa on the surface of iron-requiring cells; two holo-transferrin molecules bind one dimeric receptor.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) • [5](https://www.nature.com/articles/s12276-025-01436-x)
2. **Endocytosis.** The complex is internalized through clathrin-coated pits.[5](https://www.nature.com/articles/s12276-025-01436-x)
3. **Acidification and dissociation.** ATP-dependent proton pumps lower the endosomal pH to about 5.6, reducing the iron-transferrin affinity and stimulating receptor-assisted iron release.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/)
4. **Reduction.** Released Fe³⁺ is reduced to Fe²⁺ within the endosome; in erythroid cells the metalloreductase STEAP3 performs this step, with Dcytb and STEAP2 proposed in other contexts.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) • [5](https://www.nature.com/articles/s12276-025-01436-x)
5. **Translocation.** Fe²⁺ crosses the endosomal membrane through DMT1 or ZIP14.[5](https://www.nature.com/articles/s12276-025-01436-x)
6. **Mobilization.** Iron enters mitochondria or the cell's labile iron pool for metabolic use.[5](https://www.nature.com/articles/s12276-025-01436-x)
7. **Recycling.** Apotransferrin remains bound to TFR1 at endosomal pH, so the complex returns to the cell surface instead of being degraded in lysosomes; at neutral pH apotransferrin is released into the serum, free to bind more iron.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) • [5](https://www.nature.com/articles/s12276-025-01436-x)
The pH dependence of the cycle is its key mechanism: high-affinity binding at pH 7.4 captures iron-loaded transferrin, while the acidic endosome releases the iron yet stabilizes the apotransferrin-receptor pair for the return trip.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3837343/) The Morgan and Appleton study of 1969, which described this internalization, provided the first example of plasma protein internalization essential for the protein's function, a result described as a paradigm shift for cell biology.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/)
## Clinical significance
Transferrin is a standard laboratory marker of iron status. [Total iron-binding capacity](https://www.edgepedia.org/total-iron-binding-capacity) measures the blood's capacity to bind iron with transferrin; in iron deficiency the liver raises transferrin production, producing high transferrin levels with low transferrin saturation, a key sign of iron deficiency anemia.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/) The World Health Organization reports that clinical studies identify a transferrin saturation below 15% as indicating iron deficiency.[4](https://iris.who.int/bitstream/handle/10665/75368/9789241596107_eng.pdf?sequence=1) Guidelines continue to recommend serum transferrin and ferritin for evaluating iron-related disorders, although a critical review found the accuracy of transferrin and transferrin saturation in diagnosing iron deficiency too low to recommend them definitively on their own.[7](https://www.sciencedirect.com/science/article/abs/pii/S0009898112001933) Transferrin levels also fall during inflammation, so it serves as a marker for inflammatory states.[3](https://www.ncbi.nlm.nih.gov/books/NBK532928/)
## Transferrin receptor as a drug target
Because TFR1-mediated uptake is the primary route by which iron crosses the blood-brain barrier, the receptor has become a vehicle for brain drug delivery: a 2025 study in Science used the transferrin receptor on brain endothelial cells to transport a therapeutic antibody targeting amyloid-beta into the mouse brain, with improved brain distribution and safety compared with the unshuttled antibody.[8](https://www.nature.com/articles/d41573-025-00140-9) Elevated TFR1 expression in malignant cells has also made the receptor a target for antibody-mediated cancer therapy; a mouse/human chimeric IgG3 specific for human TFR1 shows antitumor activity against certain malignant B cells in vitro through receptor degradation and iron deprivation.[5](https://www.nature.com/articles/s12276-025-01436-x)
## References
1. [A brief history of human serum transferrin, Biochimica et Biophysica Acta (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC3258305/)
2. [Transferrin-Mediated Cellular Iron Delivery, Biochimica et Biophysica Acta (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC4479283/)
3. [Biochemistry, Transferrin, StatPearls, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK532928/)
4. [Assessing the iron status of populations, WHO](https://iris.who.int/bitstream/handle/10665/75368/9789241596107_eng.pdf?sequence=1)
5. [Transferrin receptors, Experimental & Molecular Medicine (2025)](https://www.nature.com/articles/s12276-025-01436-x)
6. [Pharmacology of Iron Transport, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3837343/)
7. [Diagnostic value of transferrin, Clinica Chimica Acta](https://www.sciencedirect.com/science/article/abs/pii/S0009898112001933)
8. [Transport vehicle delivers antibodies to the brain, Nature Reviews Drug Discovery (2025)](https://www.nature.com/articles/d41573-025-00140-9)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Elemental and cofactor metabolism › Iron metabolism › Transferrin and iron transport proteins*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license