Ferritin: iron storage in biological systems

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Bernacchioni, Caterina Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Florence, Italy.

Turano, Paola Magnetic Resonance Center (CERM) and Department of Chemistry, University of Florence, Sesto Fiorentino, Florence, Italy.

Last reviewed:2014

DOI:https://doi.org/10.1036/1097-8542.YB150546

Iron is essential in virtually all living organisms; it is required for the functioning of proteins and enzymes involved in many key biological processes, including oxygen (O₂) transport and activation, electron transfer, and substrate hydroxylation/oxidation. Iron is the fourth most abundant element on Earth, but its bioavailability is rather limited. Under aerobic conditions, Fe³⁺ is the dominant oxidation state, but it is characterized by extremely low solubility (about 10⁻¹⁸ M at pH 7.4). While Fe²⁺ is more soluble, it is toxic under aerobic conditions because of its redox chemistry, which leads to the formation of Fe³⁺ and reactive oxygen species. Therefore biological systems tightly regulate iron metabolism, preventing its toxicity by sequestering it within high-affinity iron-binding proteins. Many proteins have evolved to carry out the uptake and transport of iron or to modulate its redox chemistry, but only one protein, ferritin, is able to catalytically oxidize Fe²⁺ and concentrate and store Fe³⁺ in a bioavailable but redox-controlled form. The reversible formation and dissolution of iron (ferric) oxide biominerals is the main function of ferritin, which additionally eliminates excess iron and prevents the generation of free radicals. Maxiferritins are nanocage proteins found in eukaryotes and prokaryotes. The nanocage is generated by the self-assembly of 24 peptide subunits, each with a four-helix bundle structure. Pairing of the subunits in an antiparallel fashion along the C2 symmetry axes generates an almost spherical protein shell with 432-point symmetry (Fig. 1). The resulting nanocage has an outer diameter of about 12 nanometers (nm) and an internal cage diameter of about 8 nm (Fig. 1a and b); this large cavity can accommodate up to 4500 iron atoms. The biomineral is a hydrous ferric oxide mineral, ferrihydrite (5Fe₂O₃ċ9H₂O), with varying degrees of crystallinity and the presence of some inorganic phosphate. In each subunit, helices H1-H2 and H3-H4 form antiparallel pairs, with H1 and H3 at the external surface and H2 and H4 providing the inner cage wall. Helices H2 and H3 are connected by a solvent-exposed long loop that extends along the helix bundle. Each subunit is completed by a short fifth helix (H5) [Fig. 1c]. Dimers interacting along the C2 symmetry axes are generated by extended intersubunit contacts involving helices H1, H2, and the long loop. The sphere surface is pierced by pores at the threefold (C3) and fourfold (C4) symmetry axes, where three and four subunits come in contact (Fig. 1d). Vertebrates have two main ferritin genes that encode subunits with different properties, named H (heavy) and L (light), and coassemble to form heteropolymers. H subunits have catalytic ferroxidase activity (oxidization of Fe²⁺ to Fe³⁺), while L subunits are catalytically inactive. The two subunit types assemble in different proportions, thus originating a large number of ferritins (isoferritins) with a tissue-specific distribution. Amphibians have an additional M (middle) type of ferritin that, like the H subunits, has catalytic activity. All the subunits that are composed of bacterial and plant maxiferritins are catalytically active. The catalytic activity of H and M subunits of maxiferritins derives from a ferroxidase (or oxidoreductase) site hosted in the central part of the four-helix bundle.

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