Transferrin
Encyclopedia
Transferrins are iron-binding blood plasma
glycoprotein
s that control the level of free iron
in biological fluids. In humans, it is encoded by the TF gene
.
Transferrin is a glycoprotein
that binds 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 2 specific high-affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (1023 M−1 at pH 7.4) but decreases progressively with decreasing pH below neutrality.
When not bound to iron, it is known as "apo-transferrin" (see also apoprotein
).
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 ( ATPases
), 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 .
The gene
coding for transferrin in humans is located in chromosome
band 3q21. Research on kingsnake
s by Dessauer and Zwiefel in 1981 revealed that the inheritance of transferrin is a codominant trait.
Medical professionals may check serum transferrin level in iron deficiency
, hemochromatosis, and other iron overload disorder
s.
and beta sheet
s to form two domains
(the first situated in the N-terminus and the second in the C-terminus). 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
. In order for the iron ion to bind an anion is required, preferably carbonate
. Recent advances in transferrin research have led to animal free and recombinant transferrin (see Optiferrin) that avoids the concern using of blood plasma derived transferrin.
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 domain, the helical domain, and apical domain. The shape of transferrin receptor resembles a butterfly-like complex, due to the three clearly shaped domains.
is the main source of manufacturing transferrin, but other sources such as the brain also produce this molecule . The main role of transferrin is to deliver iron from absorption centres in the duodenum
and white blood cell macrophages to all tissues. Predominantly, transferrin plays a key role where erythropoiesis and active cell division occur. In order for iron ion to be introduced into the cell a carrier protein
is used, known as a transferrin receptor. The receptor helps maintain iron homeostasis
in the cells by controlling iron concentrations.
Transferrin imbalance can have serious health effects for those with low or high serum transferrin levels. A patient with an increased serum transferrin level often suffers from iron deficiency anemia
. A patient with decreased plasma transferrin can suffer from 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.
in humans.
Transferrin has a bacteriocidal effect on bacteria, in that it makes unavailable to the bacteria.
Carbohydrate deficient transferrin
increases in the blood with heavy ethanol
consumption and can be monitored via laboratory testing.
A high transferrin level may indicate 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.
with Insulin-like growth factor 2
and IGFBP3
.
Transcriptional regulation of transferrin is upregulated by retinoic acid.
(conalbumin); and membrane-associated melanotransferrin.
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s that control the level of free iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
in biological fluids. In humans, it is encoded by the TF gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Transferrin is a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
that binds 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
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
and contains 2 specific high-affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (1023 M−1 at pH 7.4) but decreases progressively with decreasing pH below neutrality.
When not bound to iron, it is known as "apo-transferrin" (see also apoprotein
Apoprotein
Apoprotein can refer to:*Apoenzyme, the protein part of an enzyme without its characteristic prosthetic group.*Apolipoprotein, a lipid-binding protein that is a constituent of the plasma lipoprotein....
).
Transport mechanism
When a transferrin protein loaded with iron encounters a transferrin receptorTransferrin receptor
Transferrin receptor is a carrier protein for transferrin. It is needed for the import of iron into the cell and is regulated in response to intracellular iron concentration...
on the surface of a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
(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
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
by receptor-mediated endocytosis
Receptor-mediated endocytosis
Receptor-mediated endocytosis , also called clathrin-dependent endocytosis, is a process by which cells internalize molecules by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized.-Process:After the binding of a...
. The pH of the vesicle is reduced by hydrogen ion pumps ( ATPases
V-ATPase
Vacuolar-type H+-ATPase is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. V-ATPases acidify a wide array of intracellular organelles and pump protons across the plasma membranes of numerous cell types...
), causing transferrin to release its iron ions. The receptor (with its ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
, transferrin, bound) is then transported through the endocytic cycle
Endocytic cycle
Most animal cells take up portions of their surface plasma membranes in a process called endocytosis. The main route of endocytosis is the coated pit, which buds into a cell to form a cytoplasmic vesicle — a clathrin-coated vesicle. The membrane so internalised is processed in a series of...
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
Ferric
Ferric refers to iron-containing materials or compounds. In chemistry the term is reserved for iron with an oxidation number of +3, also denoted iron or Fe3+. On the other hand, ferrous refers to iron with oxidation number of +2, denoted iron or Fe2+...
form .
The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
coding for transferrin in humans is located in chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
band 3q21. Research on kingsnake
Kingsnake
Kingsnakes are a type of colubrid snake that are members of the Lampropeltis genus, which also includes the milk snake along with another four species and 45 sub-species....
s by Dessauer and Zwiefel in 1981 revealed that the inheritance of transferrin is a codominant trait.
Medical professionals may check serum transferrin level in iron deficiency
Iron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
, hemochromatosis, and other iron overload disorder
Iron overload disorder
In medicine, iron overload indicates accumulation of iron in the body from any cause. The most important causes are hereditary hemochromatosis , a genetic disease, and transfusional iron overload, which can result from repeated blood transfusion....
s.
Structure
In humans, transferrin consists of a polypeptide chain containing 679 amino acids. It is a complex composed of alpha helicesAlpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
s to form two domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
(the first situated in the N-terminus and the second in the C-terminus). 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
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
to the transferrin are identical for both lobes; two tyrosines, one histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
, and one aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
. In order for the iron ion to bind an anion is required, preferably carbonate
Carbonate
In chemistry, a carbonate is a salt of carbonic acid, characterized by the presence of the carbonate ion, . The name may also mean an ester of carbonic acid, an organic compound containing the carbonate group C2....
. Recent advances in transferrin research have led to animal free and recombinant transferrin (see Optiferrin) that avoids the concern using of blood plasma derived transferrin.
Transferrin also has a transferrin iron-bound receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
; it is a disulfide-linked homodimer. In humans, each monomer consists of 760 amino acids. It enables ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
bonding to the transferrin, as each monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
can bind to one or two molecules of iron. Each monomer consists of three domains: the protease domain, the helical domain, and apical domain. The shape of transferrin receptor resembles a butterfly-like complex, due to the three clearly shaped domains.
Tissue distribution
The liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
is the main source of manufacturing transferrin, but other sources such as the brain also produce this molecule . The main role of transferrin is to deliver iron from absorption centres in the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and white blood cell macrophages to all tissues. Predominantly, transferrin plays a key role where erythropoiesis and active cell division occur. In order for iron ion to be introduced into the cell a carrier protein
Carrier protein
Carrier proteins are proteins involved in the movement of ions, small molecules, or macromolecules, such as another protein, across a biological membrane. Carrier proteins are integral membrane proteins; that is they exist within and span the membrane across which they transport substances. The...
is used, known as a transferrin receptor. The receptor helps maintain iron homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
in the cells by controlling iron concentrations.
Immune system
Transferrin is also associated with the innate immune system. Transferrin is found in the mucosa and binds iron, thus creating an environment low in free iron that impedes bacteria survival in a process called iron withholding. The level of transferrin decreases in inflammation.Transferrin imbalance can have serious health effects for those with low or high serum transferrin levels. A patient with an increased serum transferrin level often suffers from iron deficiency anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. A patient with decreased plasma transferrin can suffer from iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia
Atransferrinemia
Atransferrinemia, also called familial hypotransferrinemia, is an autosomal recessive metabolic disorder in which there is an absence of transferrin, a plasma protein that transports iron through the blood....
; a condition characterized by anemia and hemosiderosis
Hemosiderosis
Idiopathic pulmonary haemosiderosis is a lung disease of unknown cause that is characterized by alveolar capillary bleeding and accumulation of haemosiderin in the lungs...
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.
Other effects
The metal binding properties of transferrin have a great influence on the biochemistry of plutoniumPlutonium
Plutonium is a transuranic radioactive chemical element with the chemical symbol Pu and atomic number 94. It is an actinide metal of silvery-gray appearance that tarnishes when exposed to air, forming a dull coating when oxidized. The element normally exhibits six allotropes and four oxidation...
in humans.
Transferrin has a bacteriocidal effect on bacteria, in that it makes unavailable to the bacteria.
Carbohydrate deficient transferrin
Carbohydrate deficient transferrin
Carbohydrate-deficient transferrin is a laboratory test used to help detect heavy ethanol consumption.Carbohydrate-deficient transferrin is elevated in the blood of heavy alcoholism but raised levels can also be found in a number of medical conditions.Transferrin is a plasma protein that carries...
increases in the blood with heavy ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
consumption and can be monitored via laboratory testing.
Reference ranges
Normal reference ranges for transferrin are 204–360 mg/dL.A high transferrin level may indicate iron deficiency anemia
Iron deficiency anemia
Iron-deficiency anemia is a common anemia that occurs when iron loss occurs, and/or the dietary intake or absorption of iron is insufficient...
. Levels of serum iron
Serum iron
Serum iron is a medical laboratory test that measures the amount of circulating iron that is bound to transferrin. Clinicians order this laboratory test when they are concerned about iron deficiency, which can cause anemia and other problems....
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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Insulin-like growth factor 2
Insulin-like growth factor 2
Insulin-like growth factor 2 is one of three protein hormones that share structural similarity to insulin.-Gene structure:In humans, the IGF2 gene is located on chromosome 11p15.5, a region which contains numerous imprinted genes. In mice this homologous region is found at distal chromosome 7...
and IGFBP3
IGFBP3
Insulin-like growth factor-binding protein 3, also known as IGFBP3, is a protein that, in humans, is encoded by the IGFBP3 gene.- Function :...
.
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 ovotransferrinOvotransferrin
Ovotransferrin is a glycoprotein of egg white albumen. Transferrins are iron binding proteins and acute phase reactants of animal serum. The sequence of ovotransferrin is similar to that observed for serum transferrin in many species. However, structurally this protein differs from its serum...
(conalbumin); and membrane-associated melanotransferrin.
See also
- Beta-2 transferrinBeta-2 transferrinBeta-2 transferrin is a carbohydrate-free isoform of transferrin, which is almost only found in the cerebrospinal fluid. It is not found in blood, mucus or tears, thus making it a specific marker of cerebrospinal fluid, applied as an assay in cases where cerebrospinal fluid leakage is...
- Transferrin receptorTransferrin receptorTransferrin receptor is a carrier protein for transferrin. It is needed for the import of iron into the cell and is regulated in response to intracellular iron concentration...
- Total iron-binding capacityTotal iron-binding capacityTotal iron-binding capacity is a medical laboratory test that measures the blood's capacity to bind iron with transferrin. It is performed by drawing blood and measuring the maximum amount of iron that it can carry, which indirectly measures transferrin since transferrin is the most dynamic carrier...
- Transferrin saturationTransferrin saturationTransferrin saturation, abbreviated as TSAT and measured as a percentage, is a medical laboratory value. It is the ratio of serum iron and total iron-binding capacity, multiplied by 100. Of the transferrin that is available to bind iron, this value tells a clinician how much serum iron is actually...
- FerritinFerritinFerritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...