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281  structures 121  species 12  interactions 916  sequences 19  architectures

Family: Transferrin (PF00405)

Summary: Transferrin

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This is the Wikipedia entry entitled "Transferrin". More...

Transferrin Edit Wikipedia article

Protein TF PDB 1a8e.png
Available structures
PDB Ortholog search: PDBe RCSB
Aliases TF, PRO1557, PRO2086, TFQTL1, HEL-S-71p, transferrin
External IDs OMIM: 190000 MGI: 98821 HomoloGene: 68153 GeneCards: 7018
RNA expression pattern
PBB GE TF 203400 s at tn.png

PBB GE TF 214063 s at tn.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 3: 133.75 – 133.78 Mb Chr 9: 103.2 – 103.23 Mb
PubMed search [1] [2]
View/Edit Human View/Edit Mouse
Symbol Transferrin
Pfam PF00405
InterPro IPR001156
SCOP 1lcf
OPM superfamily 161
OPM protein 1lfc

Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids.[3] Human transferrin is encoded by the TF gene.[4]

Transferrin glycoproteins bind iron tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of total body iron, it forms the most vital iron pool with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80 KDa and contains two specific high-affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (association constant is 1020 M−1 at pH 7.4)[5] but decreases progressively with decreasing pH below neutrality.

When not bound to iron, transferrin is known as "apotransferrin" (see also apoprotein).

Transport mechanism

When a transferrin protein loaded with iron encounters a transferrin receptor on the surface of a cell (e.g., to erythroid precursors in the bone marrow), it binds to it and, as a consequence, is transported into the cell in a vesicle by receptor-mediated endocytosis. The pH of the vesicle is reduced by hydrogen ion pumps (H+
) to about 5.5, causing transferrin to release its iron ions. The receptor (with its ligand, transferrin, bound) is then transported through the endocytic cycle back to the cell surface, ready for another round of iron uptake. Each transferrin molecule has the ability to carry two iron ions in the ferric form (Fe3+

The gene coding for transferrin in humans is located in chromosome band 3q21.[4]

Medical professionals may check serum transferrin level in iron deficiency and in iron overload disorders such as hemochromatosis.


In humans, transferrin consists of a polypeptide chain containing 679 amino acids and two carbohydrate chains. The protein is composed of alpha helices and beta sheets that form two domains.[6] The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.

The amino acids which bind the iron ion to the transferrin are identical for both lobes; two tyrosines, one histidine, and one aspartic acid. For the iron ion to bind, an anion is required, preferably carbonate (CO2−

Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer.[7] In humans, each monomer consists of 760 amino acids. It enables ligand bonding to the transferrin, as each monomer can bind to one or two molecules of iron. Each monomer consists of three domains: the protease, the helical, and the apical domains. The shape of a transferrin receptor resembles a butterfly based on the intersection of three clearly shaped domains.[6]

Tissue distribution

The liver is the main site of transferrin synthesis but other tissues and organs, including the brain, also produce transferrin. The main role of transferrin is to deliver iron from absorption centers in the duodenum and white blood cell macrophages to all tissues. Transferrin plays a key role in areas where erythropoiesis and active cell division occur.[7] The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.[7]

Immune system

Transferrin is also associated with the innate immune system. It is found in the mucosa and binds iron, thus creating an environment low in free iron that impedes bacterial survival in a process called iron withholding. The level of transferrin decreases in inflammation.[10]

Role in disease

An increased plasma transferrin level is often seen in patients suffering from iron deficiency anemia, during pregnancy, and with the use of oral contraceptives, reflecting an increase in transferrin protein expression. As follows, when plasma transferrin levels rise, there is a reciprocal decrease in percent transferrin iron saturation, and a corresponding increase in total iron binding capacity in iron deficient states[11] A decreased plasma transferrin can occur in iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia, a condition characterized by anemia and hemosiderosis in the heart and liver that leads to heart failure and many other complications.

Most recently, transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.[7]

Other effects

Carbohydrate deficient transferrin increases in the blood with heavy ethanol consumption and can be monitored through laboratory testing.[12]

Transferrin is an acute phase protein and is therefore seen to decrease in inflammation, cancers and certain diseases.[13]


Atransferrinemia is associated with a deficiency in transferrin.

In nephrotic syndrome, urinary loss of transferrin, along with other serum proteins such as thyroxine-binding globulin, gammaglobulin, and anti-thrombin III, can manifest as iron-resistant microcytic anemia.

Reference ranges

An example reference range for transferrin is 204–360 mg/dL.[14] Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test.

Reference ranges for blood tests, comparing blood content of transferrin and other iron-related compounds (shown in brown and orange) with other constituents

A high transferrin level may indicate an iron deficiency anemia. Levels of serum iron and total iron binding capacity (TIBC) are used in conjunction with transferrin to specify any abnormality. See interpretation of TIBC. Low transferrin likely indicates malnutrition.


Transferrin has been shown to interact with insulin-like growth factor 2[15] and IGFBP3.[16] Transcriptional regulation of transferrin is upregulated by retinoic acid.[17]

Related proteins

Members of the family include blood serotransferrin (or siderophilin, usually simply called transferrin); lactotransferrin (lactoferrin); milk transferrin; egg white ovotransferrin (conalbumin); and membrane-associated melanotransferrin.[18]

See also


  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Crichton RR, Charloteaux-Wauters M (May 1987). "Iron transport and storage". European Journal of Biochemistry / FEBS. 164 (3): 485–506. doi:10.1111/j.1432-1033.1987.tb11155.x. PMID 3032619. 
  4. ^ a b Yang F, Lum JB, McGill JR, Moore CM, Naylor SL, van Bragt PH, Baldwin WD, Bowman BH (May 1984). "Human transferrin: cDNA characterization and chromosomal localization". Proceedings of the National Academy of Sciences of the United States of America. 81 (9): 2752–6. doi:10.1073/pnas.81.9.2752. PMC 345148free to read. PMID 6585826. 
  5. ^ Aisen P, Leibman A, Zweier J (Mar 1978). "Stoichiometric and site characteristics of the binding of iron to human transferrin" (PDF). The Journal of Biological Chemistry. 253 (6): 1930–7. PMID 204636. 
  6. ^ a b c "Transferrin Structure". St. Edward's University. 2005-07-18. Retrieved 2009-04-24. 
  7. ^ a b c d Macedo MF, de Sousa M (Mar 2008). "Transferrin and the transferrin receptor: of magic bullets and other concerns". Inflammation & Allergy Drug Targets. 7 (1): 41–52. doi:10.2174/187152808784165162. PMID 18473900. 
  8. ^ PDB: 1suv​; Cheng Y, Zak O, Aisen P, Harrison SC, Walz T (Feb 2004). "Structure of the human transferrin receptor-transferrin complex". Cell. 116 (4): 565–76. doi:10.1016/S0092-8674(04)00130-8. PMID 14980223. 
  9. ^ PDB: 2nsu​; Hafenstein S, Palermo LM, Kostyuchenko VA, Xiao C, Morais MC, Nelson CD, Bowman VD, Battisti AJ, Chipman PR, Parrish CR, Rossmann MG (Apr 2007). "Asymmetric binding of transferrin receptor to parvovirus capsids". Proceedings of the National Academy of Sciences of the United States of America. 104 (16): 6585–9. doi:10.1073/pnas.0701574104. PMC 1871829free to read. PMID 17420467. 
  10. ^ Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY (1999). "Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort". Journal of Clinical Laboratory Analysis. 13 (6): 273–9. doi:10.1002/(SICI)1098-2825(1999)13:6<273::AID-JCLA4>3.0.CO;2-X. PMID 10633294. 
  11. ^ Miller JL. Iron Deficiency Anemia: A Common and Curable Disease. Cold Spring Harbor perspectives in medicine. 2013;3(7):10.1101/cshperspect.a011866 a011866. doi:10.1101/cshperspect.a011866.
  12. ^ Sharpe PC (Nov 2001). "Biochemical detection and monitoring of alcohol abuse and abstinence". Annals of Clinical Biochemistry. 38 (Pt 6): 652–64. doi:10.1258/0004563011901064. PMID 11732647. 
  13. ^ Jain S, Gautam V, Naseem S (Jan 2011). "Acute-phase proteins: As diagnostic tool". Journal of Pharmacy & Bioallied Sciences. 3 (1): 118–27. doi:10.4103/0975-7406.76489. PMC 3053509free to read. PMID 21430962. 
  14. ^ "Normal Reference Range Table". Interactive Case Study Companion to Pathlogical Basis of Disease. The University of Texas Southwestern Medical Center at Dallas. Retrieved 2008-10-25. [dead link]
    Kumar V, Hagler HK (1999). Interactive Case Study Companion to Robbins Pathologic Basis of Disease (6th Edition (CD-ROM for Windows & Macintosh, Individual) ed.). W B Saunders Co. ISBN 0-7216-8462-9. 
  15. ^ Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T (Dec 2001). "Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3". FEBS Letters. 509 (3): 395–8. doi:10.1016/S0014-5793(01)03204-5. PMID 11749962. 
  16. ^ Weinzimer SA, Gibson TB, Collett-Solberg PF, Khare A, Liu B, Cohen P (Apr 2001). "Transferrin is an insulin-like growth factor-binding protein-3 binding protein". The Journal of Clinical Endocrinology and Metabolism. 86 (4): 1806–13. doi:10.1210/jcem.86.4.7380. PMID 11297622. 
  17. ^ Hsu SL, Lin YF, Chou CK (Apr 1992). "Transcriptional regulation of transferrin and albumin genes by retinoic acid in human hepatoma cell line Hep3B". The Biochemical Journal. 283 (2): 611–5. doi:10.1042/bj2830611. PMC 1131079free to read. PMID 1315521. 
  18. ^ M Ching-Ming Chung (October 1984). "Structure and function of transferrin". Biochemical Education. 12 (4): 146–154. doi:10.1016/0307-4412(84)90118-3. 

Further reading

External links

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Transferrin Provide feedback

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001156

Transferrins are eukaryotic iron-binding glycoproteins that control the level of free iron in biological fluids [PUBMED:3032619]. Evidence suggests that members of the TF family arose from the duplication and fusion of two homologous domains, with each duplicated domain binding one iron atom. Members of the family include blood serotransferrin (siderophilin); milk lactotransferrin (lactoferrin); egg white ovotransferrin (conalbumin); and membrane-associated melanotransferrin. Family members that do not bind iron have also been discovered, including inhibitor of carbonic anhydrase (ICA), which strongly binds to and inhibits certain isoforms of carbonic anhydrase [PUBMED:20572014].

This entry represents the transferrin-like domain, which can be further divided into two subdomains that form a cleft inside of which the iron atom is bound in iron-transporting transferrin [PUBMED:2585506]. The iron-coordinating residues consist of an aspartic acid, two tyrosines and a histidine, as well as an arginine that coordinates a requisite anion. In addition to iron and anion liganding residues, the transferrin-like domain contains conserved cysteine residues involved in disulphide bond formation.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan PBP (CL0177), which has the following description:

Periplasmic binding proteins (PBPs) consist of two large lobes that close around the bound ligand. This architecture is reiterated in transcriptional regulators, such as the lac repressors. In the process of evolution, genes encoding the PBPs have fused with genes for integral membrane proteins. Thus, diverse mammalian receptors contain extracellular ligand binding domains that are homologous to the PBPs; these include glutamate/glycine-gated ion channels such as the NMDA receptor, G protein-coupled receptors, including metabotropic glutamate, GABA-B, calcium sensing, and pheromone receptors, and atrial natriuretic peptide-guanylate cyclase receptors [2].

The clan contains the following 25 members:

DctP DUF3834 HisG Lig_chan-Glu_bd Lipoprotein_8 Lipoprotein_9 LysR_substrate Mycoplasma_p37 NMT1 NMT1_2 NMT1_3 OpuAC PBP_like PBP_like_2 Phosphonate-bd SBP_bac_1 SBP_bac_11 SBP_bac_3 SBP_bac_5 SBP_bac_6 SBP_bac_8 TctC Transferrin VitK2_biosynth YhfZ_C


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Curation and family details

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Seed source: Prosite
Previous IDs: transferrin;
Type: Domain
Author: Finn RD
Number in seed: 8
Number in full: 916
Average length of the domain: 288.10 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 84.18 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.3 20.3
Trusted cut-off 20.3 20.4
Noise cut-off 19.6 20.1
Model length: 329
Family (HMM) version: 15
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 12 interactions for this family. More...

Transferrin TFR_dimer Porin_1 TonB_dep_Rec Lipoprotein_5 Lipoprotein_5 Porin_1 MHC_II_alpha MHC_II_beta Plug Lectin_legB Peptidase_S8


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Transferrin domain has been found. There are 281 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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