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Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron (Fe) in biological fluids.[5] Human transferrin produced in the liver is encoded by the TF gene and as a 76-kDa glycoprotein.[6][7]

TF
Protein TF PDB 1a8e.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTF, PRO1557, PRO2086, TFQTL1, HEL-S-71p, transferrin
External IDsOMIM: 190000 MGI: 98821 HomoloGene: 68153 GeneCards: TF
Gene location (Human)
Chromosome 3 (human)
Chr.Chromosome 3 (human)[1]
Chromosome 3 (human)
Genomic location for TF
Genomic location for TF
Band3q22.1Start133,746,040 bp[1]
End133,796,641 bp[1]
RNA expression pattern
PBB GE TF 203400 s at fs.png

PBB GE TF 214063 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001063
NM_001354704
NM_001354703

NM_133977

RefSeq (protein)

NP_001054
NP_001341633
NP_001341632

NP_598738

Location (UCSC)Chr 3: 133.75 – 133.8 MbChr 9: 103.2 – 103.23 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Transferrin
Identifiers
SymbolTransferrin
PfamPF00405
InterProIPR001156
PROSITEPDOC00182
SCOPe1lcf / SUPFAM

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)[8] but decreases progressively with decreasing pH below neutrality. Transferrins are not limited to only binding to iron but also to different metal ions.[9] These glycoproteins are located in various bodily fluids of vertebrates.[10][11] Some invertebrates have proteins that act like transferrin found in the hemolymph.[10][12]

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

Transport mechanismEdit

When a transferrin protein loaded with iron encounters a transferrin receptor on the surface of a cell, e.g., erythroid precursors in the bone marrow, it binds to it and is transported into the cell in a vesicle by receptor-mediated endocytosis.[13] The pH of the vesicle is reduced by hydrogen ion pumps (H+
ATPases
) to about 5.5, causing transferrin to release its iron ions.[10] Iron release rate is dependent on several factors including pH levels, interactions between lobes, temperature, salt, and chelator.[13] The receptor with its ligand bound transferrin 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+
).[12]

The gene coding for transferrin in humans is located in chromosome band 3q21.[6]

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

StructureEdit

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.[14] The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.[11]

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−
3
).[14][12]

Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer.[15] 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 atoms 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.[14] Two main transferrin receptors found denoted as transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2). Although both being similar in structure, TfR1 can only bind specifically to human TF where TfR2 also has the capability to interact with bovine TF.[7]

Tissue distributionEdit

The liver is the main site of transferrin synthesis but other tissues and organs, including the brain, also produce transferrin. A major source of transferrin secretion in the brain is the choroid plexus in the ventricular system.[18] 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.[15] The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.[15]

Immune systemEdit

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.[19]

Role in diseaseEdit

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. 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[20] 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.

Transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.[15]

Transferrin and NanomedicineEdit

Many drugs are hindered when providing treatment across the blood-brain barrier yielding poor uptake into areas of the brain. Transferrin glycoproteins are able bypass the blood-brain barrier via receptor-mediated transport to transferrin receptors found in the brain capillary endothelial cells.[21] Due to this functionality, it is theorized that nanoparticles acting as drug carriers bound to transferrin glycoproteins can penetrate the blood-brain barrier allowing these substances to reach the diseased cells in the brain.[22] Advances with transferrin conjugated nanoparticles can lead to non-invasive drug distribution in the brain with potential therapeutic consequences of central nervous system (CNS) targeted diseases (e.g. Alzheimer's or Parkinson's disease).[23]

Other effectsEdit

Carbohydrate deficient transferrin increases in the blood with heavy ethanol consumption and can be monitored through laboratory testing.[24]

Transferrin is an acute phase protein and is therefore seen to decrease in inflammation, cancers, and certain diseases.[25]

PathologyEdit

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 rangesEdit

An example reference range for transferrin is 204–360 mg/dL.[26] 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.

InteractionsEdit

Transferrin has been shown to interact with insulin-like growth factor 2[27] and IGFBP3.[28] Transcriptional regulation of transferrin is upregulated by retinoic acid.[29]

Related proteinsEdit

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.[30]

See alsoEdit

ReferencesEdit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000091513 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032554 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Crichton RR, Charloteaux-Wauters M (May 1987). "Iron transport and storage". European Journal of Biochemistry. 164 (3): 485–506. doi:10.1111/j.1432-1033.1987.tb11155.x. PMID 3032619.
  6. ^ a b Yang F, Lum JB, McGill JR, Moore CM, Naylor SL, van Bragt PH, et al. (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. Bibcode:1984PNAS...81.2752Y. doi:10.1073/pnas.81.9.2752. PMC 345148. PMID 6585826.
  7. ^ a b Kawabata H (March 2019). "Transferrin and transferrin receptors update". Free Radical Biology & Medicine. 133: 46–54. doi:10.1016/j.freeradbiomed.2018.06.037. PMID 29969719.
  8. ^ Aisen P, Leibman A, Zweier J (March 1978). "Stoichiometric and site characteristics of the binding of iron to human transferrin". The Journal of Biological Chemistry. 253 (6): 1930–7. PMID 204636.
  9. ^ Nicotra S, Sorio D, Filippi G, De Gioia L, Paterlini V, De Palo EF, et al. (November 2017). "Terbium chelation, a specific fluorescent tagging of human transferrin. Optimization of conditions in view of its application to the HPLC analysis of carbohydrate-deficient transferrin (CDT)". Analytical and Bioanalytical Chemistry. 409 (28): 6605–6612. doi:10.1007/s00216-017-0616-z. PMID 28971232.
  10. ^ a b c MacGillivray RT, Moore SA, Chen J, Anderson BF, Baker H, Luo Y, et al. (June 1998). "Two high-resolution crystal structures of the recombinant N-lobe of human transferrin reveal a structural change implicated in iron release". Biochemistry. 37 (22): 7919–28. doi:10.1021/bi980355j. PMID 9609685.
  11. ^ a b Dewan JC, Mikami B, Hirose M, Sacchettini JC (November 1993). "Structural evidence for a pH-sensitive dilysine trigger in the hen ovotransferrin N-lobe: implications for transferrin iron release". Biochemistry. 32 (45): 11963–8. doi:10.1021/bi00096a004. PMID 8218271.
  12. ^ a b c Baker EN, Lindley PF (August 1992). "New perspectives on the structure and function of transferrins". Journal of Inorganic Biochemistry. 47 (3–4): 147–60. doi:10.1016/0162-0134(92)84061-q. PMID 1431877.
  13. ^ a b Halbrooks PJ, He QY, Briggs SK, Everse SJ, Smith VC, MacGillivray RT, Mason AB (April 2003). "Investigation of the mechanism of iron release from the C-lobe of human serum transferrin: mutational analysis of the role of a pH sensitive triad". Biochemistry. 42 (13): 3701–7. doi:10.1021/bi027071q. PMID 12667060.
  14. ^ a b c "Transferrin Structure". St. Edward's University. 2005-07-18. Archived from the original on 2012-12-11. Retrieved 2009-04-24.
  15. ^ a b c d Macedo MF, de Sousa M (March 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.
  16. ^ 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.
  17. ^ 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. Bibcode:2007PNAS..104.6585H. doi:10.1073/pnas.0701574104. PMC 1871829. PMID 17420467.
  18. ^ Moos T (November 2002). "Brain iron homeostasis". Danish Medical Bulletin. 49 (4): 279–301. PMID 12553165.
  19. ^ 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.
  20. ^ Miller JL (July 2013). "Iron deficiency anemia: a common and curable disease". Cold Spring Harbor Perspectives in Medicine. 3 (7): a011866. doi:10.1101/cshperspect.a011866. PMC 3685880. PMID 23613366.
  21. ^ Ghadiri M, Vasheghani-Farahani E, Atyabi F, Kobarfard F, Mohamadyar-Toupkanlou F, Hosseinkhani H (October 2017). "Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier". Journal of Biomedical Materials Research. Part A. 105 (10): 2851–2864. doi:10.1002/jbm.a.36145. PMID 28639394.
  22. ^ Gaspar R (February 2013). "Nanoparticles: Pushed off target with proteins". Nature Nanotechnology. 8 (2): 79–80. Bibcode:2013NatNa...8...79G. doi:10.1038/nnano.2013.11. PMID 23380930.
  23. ^ Li S, Peng Z, Dallman J, Baker J, Othman AM, Blackwelder PL, Leblanc RM (September 2016). "Crossing the blood-brain-barrier with transferrin conjugated carbon dots: A zebrafish model study". Colloids and Surfaces. B, Biointerfaces. 145: 251–256. doi:10.1016/j.colsurfb.2016.05.007. PMID 27187189.
  24. ^ Sharpe PC (November 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.
  25. ^ Jain S, Gautam V, Naseem S (January 2011). "Acute-phase proteins: As diagnostic tool". Journal of Pharmacy & Bioallied Sciences. 3 (1): 118–27. doi:10.4103/0975-7406.76489. PMC 3053509. PMID 21430962.
  26. ^ "Normal Reference Range Table". Interactive Case Study Companion to Pathlogical Basis of Disease. The University of Texas Southwestern Medical Center at Dallas. Archived from the original on 2011-12-25. Retrieved 2008-10-25.
    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.
  27. ^ Storch S, Kübler B, Höning S, Ackmann M, Zapf J, Blum W, Braulke T (December 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.
  28. ^ Weinzimer SA, Gibson TB, Collett-Solberg PF, Khare A, Liu B, Cohen P (April 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.
  29. ^ Hsu SL, Lin YF, Chou CK (April 1992). "Transcriptional regulation of transferrin and albumin genes by retinoic acid in human hepatoma cell line Hep3B". The Biochemical Journal. 283 ( Pt 2) (2): 611–5. doi:10.1042/bj2830611. PMC 1131079. PMID 1315521.
  30. ^ Chung MC (October 1984). "Structure and function of transferrin". Biochemical Education. 12 (4): 146–154. doi:10.1016/0307-4412(84)90118-3.

Further readingEdit

External linksEdit