The ferritins: molecular properties, iron storage function and cellular regulation

Abstract

The iron storage protein, ferritin, plays a key role in iron metabolism. Its ability to sequester the element gives ferritin the dual functions of iron detoxification and iron reserve. The importance of these functions is emphasised by ferritin's ubiquitous distribution among living species. Ferritin's three-dimensional structure is highly conserved. All ferritins have 24 protein subunits arranged in 432 symmetry to give a hollow shell with an 80 A diameter cavity capable of storing up to 4500 Fe(III) atoms as an inorganic complex. Subunits are folded as 4-helix bundles each having a fifth short helix at roughly 60 degrees to the bundle axis. Structural features of ferritins from humans, horse, bullfrog and bacteria are described: all have essentially the same architecture in spite of large variations in primary structure (amino acid sequence identities can be as low as 14%) and the presence in some bacterial ferritins of haem groups. Ferritin molecules isolated from vertebrates are composed of two types of subunit (H and L), whereas those from plants and bacteria contain only H-type chains, where 'H-type' is associated with the presence of centres catalysing the oxidation of two Fe(II) atoms. The similarity between the dinuclear iron centres of ferritin H-chains and those of ribonucleotide reductase and other proteins suggests a possible wider evolutionary linkage. A great deal of research effort is now concentrated on two aspects of ferritin: its functional mechanisms and its regulation. These form the major part of the review. Steps in iron storage within ferritin molecules consist of Fe(II) oxidation, Fe(III) migration and the nucleation and growth of the iron core mineral. H-chains are important for Fe(II) oxidation and L-chains assist in core formation. Iron mobilisation, relevant to ferritin's role as iron reserve, is also discussed. Translational regulation of mammalian ferritin synthesis in response to iron and the apparent links between iron and citrate metabolism through a single molecule with dual function are described. The molecule, when binding a [4Fe-4S] cluster, is a functioning (cytoplasmic) aconitase. When cellular iron is low, loss of the [4Fe-4S] cluster allows the molecule to bind to the 5'-untranslated region (5'-UTR) of the ferritin m-RNA and thus to repress translation. In this form it is known as the iron regulatory protein (IRP) and the stem-loop RNA structure to which it binds is the iron regulatory element (IRE). IREs are found in the 3'-UTR of the transferrin receptor and in the 5'-UTR of erythroid aminolaevulinic acid synthase, enabling tight co-ordination between cellular iron uptake and the synthesis of ferritin and haem. Degradation of ferritin could potentially lead to an increase in toxicity due to uncontrolled release of iron. Degradation within membrane-encapsulated "secondary lysosomes' may avoid this problem and this seems to be the origin of another form of storage iron known as haemosiderin. However, in certain pathological states, massive deposits of "haemosiderin' are f...

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

“…1,2 For example, the induction of ferritin by free iron has been shown to inhibit leukocyte migration, 27 proliferation of T cells 28 and to promote the development of DCs capable of inhibiting MLRs. 29 Bilirubin and biliverdin have been demonstrated to inhibit complement activation 30 and bilirubin has been described as a potent antioxidant, 31 as well as been shown to inhibit lymphocyte proliferation, IL-2 production and cytotoxicity.…”

The role of lysosomes in iron metabolism and recycling

“…Ferritin is a high molecular weight 24-mer consisting of heavy (H-ferritin) and light (L-ferritin) subunits (Harrison and Arosio, 1996). The ferroxidase activity of the H-chain is responsible for converting Fe(II) to Fe(III) and then together with the L-form for its storage as a ferric oxohydroxide mineral (Arosio et al, 2009).…”

Multiple Pathways for Mineral Core Formation in Mammalian Apoferritin. The Role of Hydrogen Peroxide

“…4 As the amount of iron added to the apoprotein in a single shot increased from 48 to 800 Fe(II), the percentage of iron oxidized by the ferroxidase reaction 1 decreased from ∼100 to ∼30% (Figure 6, X 1 curve). Figure 7 shows the dependence of the measured Fe(II)/O 2 stoichiometry on single additions of Fe(II) to HuHF samples having protein concentrations of 0.5, 1.0, and 3.0 µM under O 2 atmospheres of 21, 21, and 100%, respectively, for curves a-c. Each point represents a separate protein sample.…”

“…5 Fe(III) mineral cores have recently been shown to form with H 2 O 2 as the Fe(II) oxidant in E. coli bacterioferritin (EcBFR) (33) 7 The stopped-flow and oximetry data were then used to estimate the fractions of iron oxidized by eqs 1-3. The net Fe(II)/O 2 stoichiometry S from Fe(II) oxidation through eqs 1-3 is given by 1/S ) 1 / 2 X 1 + 1 / 4 X 2 as before but in this 4 The total amount of iron processed through the ferroxidase site mechanism was calculated from the integrated rate equations for the concentrations of the species in the sequential reaction depicted by eq 1. The kinetic analysis to be reported elsewhere (G. Zhao, F. BouAbdallah, H. B. Mayne, P. Arosio, and N. D. Chasteen, manuscript in preparation) indicates that the half-life for iron turnover at the ferroxidase center (i.e., decay time for the µ-1,2-oxodiFe(III) complex) is approximately 1 s at Fe(III) loadings greater than 48 Fe(II)/HuHF.…”

“…Mammalian ferritins are generally heteropolymers composed of 24 subunits of two types, H and L, that assemble into nearly spherical protein shells within which iron is stored as a hydrous ferric oxide mineral phase. The H-and L-subunit composition of ferritins is tissue specific, with ferritins from tissues involved in long-term storage of iron being richer in L-subunits, whereas those from tissues with more active iron metabolism have more Hsubunits (4). The H-and L-subunits are about 50% homologous in amino acid sequence and have comparable molecular weights and tertiary structures (3,4).…”