Ferritin

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including algae, bacteria, higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload. Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body, hence serum ferritin is used as a diagnostic test for iron-deficiency anemia. Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including algae, bacteria, higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload. Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body, hence serum ferritin is used as a diagnostic test for iron-deficiency anemia. Ferritin is a globular protein complex consisting of 24 protein subunits forming a nanocage with multiple metal–protein interactions. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. Ferritin that is not combined with iron is called apoferritin. Ferritin genes are highly conserved between species. All vertebrate ferritin genes have three introns and four exons. In human ferritin, introns are present between amino acid residues 14 and 15, 34 and 35, and 82 and 83; in addition, there are one to two hundred untranslated bases at either end of the combined exons. The tyrosine residue at amino acid position 27 is thought to be associated with biomineralization. Ferritin is a hollow globular protein of 474 kDa consisting of 24 subunits that is present in every cell type. Typically it has internal and external diameters of about 8 and 12 nm, respectively. In vertebrates, these subunits are both the light (L) and the heavy (H) type with an apparent molecular weight of 19 kDa or 21 kDa respectively; their sequences are homologous (about 50% identical). Amphibians have an additional ('M') type of ferritin; the single ferritin of plants and bacteria most closely resembles the vertebrate H-type. Two types have been recovered in the gastropod Lymnaea, the somatic ferritin being distinct from the yolk ferritin (see below). An additional subunit resembling Lymnaea soma ferritin is associated with shell formation in the pearl oyster. Two types are present in the parasite Schistosoma, one in males, the other in females. All the aforementioned ferritins are similar, in terms of their primary sequence, with the vertebrate H-type. In E. coli, a 20% similarity to human H-ferritin is observed. Inside the ferritin shell, iron ions form crystallites together with phosphate and hydroxide ions. The resulting particle is similar to the mineral ferrihydrite. Each ferritin complex can store about 4500 iron (Fe3+) ions. Some ferritin complexes in vertebrates are hetero-oligomers of two highly related gene products with slightly different physiological properties. The ratio of the two homologous proteins in the complex depends on the relative expression levels of the two genes. Mitochondrial ferritin was recently identified as a protein precursor, and is classified as a metal-binding protein that is located within the mitochondria. After the protein is taken up by the mitochondria it can be processed into a mature protein and assemble to form functional ferritin shells. Its structure was determined at 1.70 angstroms through the use of X-ray diffraction and contains 182 residues. It is 67% helical. The Ramachandran plot shows that the structure of mitochondrial ferritin is mainly alpha helical with a low prevalence of beta sheets. Unlike other human ferritin, it appears to have no introns in its genetic code. Ferritin serves to store iron in a non-toxic form, to deposit it in a safe form, and to transport it to areas where it is required. The function and structure of the expressed ferritin protein varies in different cell types. This is controlled primarily by the amount and stability of mRNA. mRNA concentration is further tweaked by changes to how it is stored and how efficiently it is transcribed. The presence of iron itself is a major trigger for the production of ferritin, with some exceptions (such as the yolk ferritin of the gastropod Lymnaea, which lacks an iron-responsive unit). Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species via the Fenton reaction. Hence vertebrates evolve an elaborate set of protective mechanisms to bind iron in various tissue compartments. Within cells, iron is stored in a protein complex as ferritin or hemosiderin. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the reticuloendothelial system, protein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderin can be extracted for release by the RE cells although hemosiderin is less readily available. Under steady state conditions, the serum ferritin level correlates with total body iron stores; thus, the serum ferritin FR5Rl is the most convenient laboratory test to estimate iron stores. Because iron is an important mineral in mineralization, ferritin is employed in the shells of organisms such as molluscs to control the concentration and distribution of iron, thus sculpting shell morphology and colouration. It also plays a role in the haemolymph of the polyplacophora where it serves to rapidly transport iron to the mineralizing radula.