Chemistry:Transferrin

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Transferrin
Identifiers
SymbolTransferrin
PfamPF00405
InterProIPR001156
PROSITEPDOC00182
SCOP21lcf / SCOPe / SUPFAM

Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma.[1] They are produced in the liver and contain binding sites for two Fe3+ ions.[2] Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.[3][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. Transferrins are not limited to only binding to iron but also to different metal ions.[6] These glycoproteins are located in various bodily fluids of vertebrates.[7][8] Some invertebrates have proteins that act like transferrin found in the hemolymph.[7][9]

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

Occurrence and function

Transferrins are glycoproteins that are often found in biological fluids of vertebrates. 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.[10] The pH of the vesicle is reduced by hydrogen ion pumps (H+ ATPases) to about 5.5, causing transferrin to release its iron ions.[7] Iron release rate is dependent on several factors including pH levels, interactions between lobes, temperature, salt, and chelator.[10] 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+).[9]

Humans and other mammals

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.[11] 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.[12] The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.[12]

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

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

Other species

Drosophila melanogaster has three transferrin genes and is highly divergent from all other model clades, Ciona intestinalis one, Danio rerio has three highly divergent from each other, as do Takifugu rubripes and Xenopus tropicalis and Gallus gallus, while Monodelphis domestica has two divergent orthologs, and Mus musculus has two relatively close and one more distant ortholog. Relatedness and orthology/paralogy data are also available for Dictyostelium discoideum, Arabidopsis thaliana, and Pseudomonas aeruginosa.[13]

Structure

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.[8]

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][9]

Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer.[12] 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 in humans denoted as transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2). Although both are similar in structure, TfR1 can only bind specifically to human TF where TfR2 also has the capability to interact with bovine TF.[4]

  • Transferrin bound to its receptor.[15]

  • Transferrin receptor complex.[16]

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.[17]

Role in disease

An increased plasma transferrin level is often seen in patients with 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[18]

A decreased plasma transferrin level 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 as well as to H63D syndrome.

Studies reveal that a transferrin saturation (serum iron concentration ÷ total iron binding capacity) over 60 percent in men and over 50 percent in women identified the presence of an abnormality in iron metabolism (Hereditary hemochromatosis, heterozygotes and homozygotes) with approximately 95 percent accuracy. This finding helps in the early diagnosis of Hereditary hemochromatosis, especially while serum ferritin still remains low. The retained iron in Hereditary hemochromatosis is primarily deposited in parenchymal cells, with reticuloendothelial cell accumulation occurring very late in the disease. This is in contrast to transfusional iron overload in which iron deposition occurs first in the reticuloendothelial cells and then in parenchymal cells. This explains why ferritin levels remain relative low in Hereditary hemochromatosis, while transferrin saturation is high.[19][20]

Transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.[12]

Transferrin and nanomedicine

Many drugs are hindered when providing treatment when crossing the blood-brain barrier yielding poor uptake into areas of the brain. Transferrin glycoproteins are able to bypass the blood-brain barrier via receptor-mediated transport for specific 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 effects

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 seen to decrease in inflammation, cancers, and certain diseases (in contrast to other acute phase proteins, e.g., C-reactive protein, which increase in case of acute inflammation).[25]

Pathology

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.[26] Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test[citation needed].

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.

Interactions

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 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.[30]

See also

References

  1. ↑ "Iron transport and storage". European Journal of Biochemistry 164 (3): 485–506. May 1987. doi:10.1111/j.1432-1033.1987.tb11155.x. PMID 3032619. 
  2. ↑ "The crystal and molecular structures of diferric porcine and rabbit serum transferrins at resolutions of 2.15 and 2.60 A, respectively". Acta Crystallographica. Section D, Biological Crystallography 58 (Pt 1): 70–80. January 2002. doi:10.1107/s0907444901017309. PMID 11752780. Bibcode: 2002AcCrD..58...70H. 
  3. ↑ 3.0 3.1 "Human transferrin: cDNA characterization and chromosomal localization". Proceedings of the National Academy of Sciences of the United States of America 81 (9): 2752–6. May 1984. doi:10.1073/pnas.81.9.2752. PMID 6585826. Bibcode: 1984PNAS...81.2752Y. 
  4. ↑ 4.0 4.1 "Transferrin and transferrin receptors update". Free Radical Biology & Medicine 133: 46–54. March 2019. doi:10.1016/j.freeradbiomed.2018.06.037. PMID 29969719. 
  5. ↑ "Stoichiometric and site characteristics of the binding of iron to human transferrin". The Journal of Biological Chemistry 253 (6): 1930–7. March 1978. doi:10.1016/S0021-9258(19)62337-9. PMID 204636. 
  6. ↑ "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. November 2017. doi:10.1007/s00216-017-0616-z. PMID 28971232. 
  7. ↑ 7.0 7.1 7.2 "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. June 1998. doi:10.1021/bi980355j. PMID 9609685. 
  8. ↑ 8.0 8.1 "Structural evidence for a pH-sensitive dilysine trigger in the hen ovotransferrin N-lobe: implications for transferrin iron release". Biochemistry 32 (45): 11963–8. November 1993. doi:10.1021/bi00096a004. PMID 8218271. 
  9. ↑ 9.0 9.1 9.2 "New perspectives on the structure and function of transferrins". Journal of Inorganic Biochemistry 47 (3–4): 147–60. August 1992. doi:10.1016/0162-0134(92)84061-q. PMID 1431877. 
  10. ↑ 10.0 10.1 "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. April 2003. doi:10.1021/bi027071q. PMID 12667060. 
  11. ↑ "Brain iron homeostasis". Danish Medical Bulletin 49 (4): 279–301. November 2002. PMID 12553165. 
  12. ↑ 12.0 12.1 12.2 12.3 "Transferrin and the transferrin receptor: of magic bullets and other concerns". Inflammation & Allergy - Drug Targets 7 (1): 41–52. March 2008. doi:10.2174/187152808784165162. PMID 18473900. 
  13. ↑ "Functional and evolutionary implications of gene orthology". Nature Reviews. Genetics (Nature Portfolio) 14 (5): 360–6. May 2013. doi:10.1038/nrg3456. PMID 23552219. 
  14. ↑ 14.0 14.1 14.2 "Transferrin Structure". St. Edward's University. 2005-07-18. http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Projects04/Transferrin/structure.htm. 
  15. ↑ PDB: 1suv​; "Structure of the human transferrin receptor-transferrin complex". Cell 116 (4): 565–76. Feb 2004. doi:10.1016/S0092-8674(04)00130-8. PMID 14980223. 
  16. ↑ PDB: 2nsu​; "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. Apr 2007. doi:10.1073/pnas.0701574104. PMID 17420467. Bibcode: 2007PNAS..104.6585H. 
  17. ↑ "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. 1999. doi:10.1002/(SICI)1098-2825(1999)13:6<273::AID-JCLA4>3.0.CO;2-X. PMID 10633294. 
  18. ↑ "Iron deficiency anemia: a common and curable disease". Cold Spring Harbor Perspectives in Medicine 3 (7): a011866. July 2013. doi:10.1101/cshperspect.a011866. PMID 23613366. 
  19. ↑ "Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases". Hepatology (Baltimore, Md.) 54 (1): 328–43. July 2011. doi:10.1002/hep.24330. PMID 21452290. 
  20. ↑ "Hemochromatosis". guidelinecentral.com. http://eguideline.guidelinecentral.com/i/98549-aasld-hemochromatosis/2. 
  21. ↑ "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. October 2017. doi:10.1002/jbm.a.36145. PMID 28639394. 
  22. ↑ "Nanoparticles: Pushed off target with proteins". Nature Nanotechnology 8 (2): 79–80. February 2013. doi:10.1038/nnano.2013.11. PMID 23380930. Bibcode: 2013NatNa...8...79G. 
  23. ↑ "Crossing the blood-brain-barrier with transferrin conjugated carbon dots: A zebrafish model study". Colloids and Surfaces. B, Biointerfaces 145: 251–256. September 2016. doi:10.1016/j.colsurfb.2016.05.007. PMID 27187189. 
  24. ↑ "Biochemical detection and monitoring of alcohol abuse and abstinence". Annals of Clinical Biochemistry 38 (Pt 6): 652–64. November 2001. doi:10.1258/0004563011901064. PMID 11732647. 
  25. ↑ "Acute-phase proteins: As diagnostic tool". Journal of Pharmacy & Bioallied Sciences 3 (1): 118–27. January 2011. doi:10.4103/0975-7406.76489. PMID 21430962. 
  26. ↑ "Normal Reference Range Table". Interactive Case Study Companion to Pathological Basis of Disease. The University of Texas Southwestern Medical Center at Dallas. http://pathcuric1.swmed.edu/PathDemo/nrrt.htm. 
    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. ↑ "Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3". FEBS Letters 509 (3): 395–8. December 2001. doi:10.1016/S0014-5793(01)03204-5. PMID 11749962. 
  28. ↑ "Transferrin is an insulin-like growth factor-binding protein-3 binding protein". The Journal of Clinical Endocrinology and Metabolism 86 (4): 1806–13. April 2001. doi:10.1210/jcem.86.4.7380. PMID 11297622. 
  29. ↑ "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. April 1992. doi:10.1042/bj2830611. PMID 1315521. 
  30. ↑ "Structure and function of transferrin". Biochemical Education 12 (4): 146–154. October 1984. doi:10.1016/0307-4412(84)90118-3. 

Further reading

External links



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