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250  structures 229  species 2  interactions 1389  sequences 15  architectures

Family: Transferrin (PF00405)

Summary: Transferrin

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Transferrin Edit Wikipedia article

Transferrin

PDB rendering based on 1a8e.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TF; PRO1557; PRO2086; TFQTL1
External IDs OMIM190000 MGI98821 HomoloGene68153 ChEMBL: 4865 GeneCards: TF Gene
RNA expression pattern
PBB GE TF 203400 s at tn.png
PBB GE TF 214063 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7018 22041
Ensembl ENSG00000091513 ENSMUSG00000032554
UniProt P02787 Q921I1
RefSeq (mRNA) NM_001063 NM_133977
RefSeq (protein) NP_001054 NP_598738
Location (UCSC) Chr 3:
133.46 – 133.5 Mb
Chr 9:
103.2 – 103.23 Mb
PubMed search [1] [2]
Transferrin
Identifiers
Symbol Transferrin
Pfam PF00405
InterPro IPR001156
PROSITE PDOC00182
SCOP 1lcf
SUPERFAMILY 1lcf
OPM superfamily 161
OPM protein 1lfc

Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids.[1] Human transferrin is encoded by the TF gene.[2]

Transferrin glycoproteins bind iron very tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of the total body iron, it is the most important 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 (1023 M−1 at pH 7.4)[3] but decreases progressively with decreasing pH below neutrality.

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

Transport mechanism[edit]

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+
ATPases
) 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.[2]

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

Structure[edit]

In humans, transferrin consists of a polypeptide chain containing 679 amino acids. The protein is composed of alpha helices and beta sheets to form two domains.[4] 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−
3
).[4]

Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer.[5] 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 transferrin receptor resembles a butterfly-like complex, due to the three clearly shaped domains.[4]

Tissue distribution[edit]

The liver is the main site of transferrin synthesis, but other tissues and organs, such as the brain, also produce it. 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 where erythropoiesis and active cell division occur.[5] The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.[5]

Immune system[edit]

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.[8]

Role in disease[edit]

An increased plasma transferrin level is often seen in patients suffering from iron deficiency anemia.[5] 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 many complications, including heart failure.

Most recently, transferrin and its receptor have been shown to diminish tumour cells by using the receptor to attract antibodies.[5]

Other effects[edit]

The metal-binding properties of transferrin have a great influence on the biochemistry of plutonium in humans.

Carbohydrate deficient transferrin increases in the blood with heavy ethanol consumption and can be monitored via laboratory testing.[9]

Pathology[edit]

A deficiency is associated with atransferrinemia.

Reference ranges[edit]

An example reference range for transferrin is 204–360 mg/dL.[10] 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.

Interactions[edit]

Transferrin has been shown to interact with insulin-like growth factor 2[11] and IGFBP3.[12] Transcriptional regulation of transferrin is upregulated by retinoic acid.[13]

Related proteins[edit]

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.[14]

See also[edit]

References[edit]

  1. ^ Crichton RR, Charloteaux-Wauters M (1987). "Iron transport and storage". Eur. J. Biochem. 164 (3): 485–506. doi:10.1111/j.1432-1033.1987.tb11155.x. PMID 3032619. 
  2. ^ 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 345148. PMID 6585826. 
  3. ^ Aisen P, Leibman A, Zweier J (March 1978). "Stoichiometric and site characteristics of the binding of iron to human transferrin". J. Biol. Chem. 253 (6): 1930–7. PMID 204636. 
  4. ^ a b c "Transferrin Structure". St. Edward's University. 2005-07-18. Retrieved 2009-04-24. 
  5. ^ a b c d e 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. 
  6. ^ PDB 1suv; Cheng Y, Zak O, Aisen P, Harrison SC, Walz T (February 2004). "Structure of the human transferrin receptor-transferrin complex". Cell 116 (4): 565–76. doi:10.1016/S0092-8674(04)00130-8. PMID 14980223. 
  7. ^ PDB 2nsu; Hafenstein S, Palermo LM, Kostyuchenko VA, Xiao C, Morais MC, Nelson CD, Bowman VD, Battisti AJ, Chipman PR, Parrish CR, Rossmann MG (April 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 1871829. PMID 17420467. 
  8. ^ 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". J. Clin. Lab. Anal. 13 (6): 273–9. doi:10.1002/(SICI)1098-2825(1999)13:6<273::AID-JCLA4>3.0.CO;2-X. PMID 10633294. 
  9. ^ Sharpe PC (November 2001). "Biochemical detection and monitoring of alcohol abuse and abstinence". Ann. Clin. Biochem. 38 (Pt 6): 652–64. doi:10.1258/0004563011901064. PMID 11732647. 
  10. ^ "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. 
    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. 
  11. ^ 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 Lett. 509 (3): 395–8. doi:10.1016/S0014-5793(01)03204-5. PMID 11749962. 
  12. ^ 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". J. Clin. Endocrinol. Metab. 86 (4): 1806–13. doi:10.1210/jc.86.4.1806. PMID 11297622. 
  13. ^ Hsu SL, Lin YF, Chou CK (April 1992). "Transcriptional regulation of transferrin and albumin genes by retinoic acid in human hepatoma cell line Hep3B". Biochem. J. 283 (2): 611–5. PMC 1131079. PMID 1315521. 
  14. ^ 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[edit]

External links[edit]

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Transferrin Provide feedback

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Internal database links

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]. The proteins have arisen by duplication of a domain, 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.

Additional members of this family include inhibitor of carbonic anhydrase (ICA; mammals), major yolk protein (sea urchins), saxiphilin (frog), pacifastin (crayfish), and TTF-1 (algae). Most family members contain two transferrin-like domains of around 340 amino acids, the result of an ancient duplication event [PUBMED:15621505]. Each of the duplicated domains 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.

Human lactoferrin is a serine peptidase belonging to MEROPS peptidase family S60, clan SR. It is found at high concentrations in all human secretions, where it plays a major role in mucosal defence. Lactoferrin cleaves IgA1 protease at an arginine-rich region defined by amino acids RRSRRSVR and digests Hap at a similar arginine-rich sequence (VRSRRAAR). Ser259 and Lys73 form a catalytic dyad, reminiscent of a number of bacterial serine proteases.

Gene Ontology

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Domain organisation

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(10)
Full
(1389)
Representative proteomes NCBI
(1509)
Meta
(132)
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(88)
RP35
(121)
RP55
(296)
RP75
(465)
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  Seed
(10)
Full
(1389)
Representative proteomes NCBI
(1509)
Meta
(132)
RP15
(88)
RP35
(121)
RP55
(296)
RP75
(465)
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  Seed
(10)
Full
(1389)
Representative proteomes NCBI
(1509)
Meta
(132)
RP15
(88)
RP35
(121)
RP55
(296)
RP75
(465)
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Seed source: Prosite
Previous IDs: transferrin;
Type: Domain
Author: Finn RD
Number in seed: 10
Number in full: 1389
Average length of the domain: 257.20 aa
Average identity of full alignment: 32 %
Average coverage of the sequence by the domain: 86.39 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.3 20.3
Trusted cut-off 20.3 20.3
Noise cut-off 19.7 20.2
Model length: 330
Family (HMM) version: 12
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Interactions

There are 2 interactions for this family. More...

Transferrin TFR_dimer

Structures

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 250 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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