Transferrin

Transferrin
250px PDB rendering based on 1a8e.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1A8E, 1A8F, 1B3E, 1BP5, 1BTJ, 1D3K, 1D4N, 1DTG, 1FQE, 1FQF, 1JQF, 1N7W, 1N7X, 1N84, 1OQG, 1OQH, 1RYO, 1SUV, 2HAU, 2HAV, 2O7U, 2O84, 3FGS, 3QYT, 3S9L, 3S9M, 3S9N, 3SKP, 3V83, 3V89, 3V8X, 3VE1, 4H0W, 4X1B, 4X1D
Identifiers
Symbols	TF ; PRO1557; PRO2086; TFQTL1
External IDs	OMIM: 190000 MGI: 98821 HomoloGene: 68153 ChEMBL: 4865 GeneCards: TF Gene
Gene ontology Molecular function • protein binding • ferrous iron binding • ferric iron binding • ferric iron transmembrane transporter activity • transferrin receptor binding Cellular component • extracellular region • extracellular space • early endosome • late endosome • coated pit • basal plasma membrane • cell surface • endosome membrane • cytoplasmic membrane-bounded vesicle • apical plasma membrane • endocytic vesicle • extrinsic component of external side of plasma membrane • vesicle • secretory granule lumen • basal part of cell • perinuclear region of cytoplasm • recycling endosome • extracellular exosome • blood microparticle • HFE-transferrin receptor complex Biological process • retina homeostasis • platelet degranulation • cellular iron ion homeostasis • actin filament organization • activation of JUN kinase activity • blood coagulation • platelet activation • osteoclast differentiation • regulation of protein stability • transferrin transport • positive regulation of bone resorption • positive regulation of transcription, DNA-templated • positive regulation of receptor-mediated endocytosis • iron ion homeostasis • transmembrane transport • SMAD protein signal transduction • ERK1 and ERK2 cascade • cellular response to iron ion • ferrous iron import into cell • positive regulation of cell motility Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE TF 203400 s at tn.png
File: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: 133.75 – 133.78 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
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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

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 10²³ M⁻¹ at pH 7.4) 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⁺
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.

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

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. 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).

Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer. 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.

• PDB 1suv EBI.jpg

  Transferrin bound to its receptor.

• PDB 2nsu EBI.jpg

  Transferrin receptor complex.

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. The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.

Immune system

Transferrin 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.

Role in disease

An increased plasma transferrin level is often seen in patients suffering from iron deficiency anemia. 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.

Other effects

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 through laboratory testing.

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

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. 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

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

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.

See also

• Beta-2 transferrin
• Transferrin receptor
• Total iron-binding capacity
• Transferrin saturation
• Ferritin

External links

• Transferrin at the US National Library of Medicine Medical Subject Headings (MeSH)