Origin of the Unusual Kinetics of Iron Deposition in Human H-Chain Ferritin

Bou-Abdallah, Fadi; Zhao, Guanghua; Mayne, Howard R.; Arosio, Paolo; Chasteen, N. Dennis

doi:10.1021/ja044355k

Cited by 81 publications

(140 citation statements)

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“…8C). Additionally, it is evident that the initial rate of iron oxidation catalyzed by ferritin is generally proportional to iron concentration, a result that accords with previous observations (30,32).…”

Section: H-1 and H-2 In Oxidative Deposition Of Iron In Proteinsupporting

confidence: 90%

“…Iron Oxidative Deposition in rH-1, rH-2, WT SSF, and rH-1H-2-UV absorption in the 300 -330 nm spectral region has been traditionally used to monitor the formation of Fe 3ϩ species during oxidative deposition of iron in the ferritins (13,17,20,30,31). Spectrophotometric kinetic measurements of iron deposition in rH-1, rH-2, WT SSF, and rH-1H-2 were conducted to evaluate the role of the H-1 and H-2 subunits in the formation of the mineral core of ferritin at different iron loadings (48, 200, and 400 irons/protein).…”

Section: H-1 and H-2 In Oxidative Deposition Of Iron In Proteinmentioning

confidence: 99%

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Role of H-1 and H-2 Subunits of Soybean Seed Ferritin in Oxidative Deposition of Iron in Protein

Deng

Liao

Yang

et al. 2010

Journal of Biological Chemistry

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Naturally occurring phytoferritin is a heteropolymer consisting of two different H-type subunits, H-1 and H-2. Prior to this study, however, the function of the two subunits in oxidative deposition of iron in ferritin was unknown. The data show that, upon aerobic addition of 48 -200 Fe 2؉ /shell to apoferritin, iron oxidation occurs only at the diiron ferroxidase center of recombinant H1 (rH-1). In addition to the diiron ferroxidase mechanism, such oxidation is catalyzed by the extension peptide (a specific domain found in phytoferritin) of rH-2, because the H-1 subunit is able to remove Fe 3؉ from the center to the inner cavity better than the H-2 subunit. These findings support the idea that the H-1 and H-2 subunits play different roles in iron mineralization in protein. Interestingly, at medium iron loading (200 irons/shell), wild-type (WT) soybean seed ferritin (SSF) exhibits a stronger activity in catalyzing iron oxidation (1.10 ؎ 0.13 M iron/subunit/s) than rH-1 (0.59 ؎ 0.07 M iron/subunit/s) and rH-2 (0.48 ؎ 0.04 M iron/subunit/s), demonstrating that a synergistic interaction exists between the H-1 and H-2 subunits in SSF during iron mineralization. Such synergistic interaction becomes considerably stronger at high iron loading (400 irons/shell) as indicated by the observation that the iron oxidation activity of WT SSF is ϳ10 times larger than those of rH-1 and rH-2. This helps elucidate the widespread occurrence of heteropolymeric ferritins in plants.Iron and oxygen chemistry, in a variety of non-heme diiron proteins, has drawn considerable attention because of their various roles in reversible O 2 binding for respiration in hemerythrin, oxidation and desaturation of organic substrates in methane monooxygenase, R2 subunit of ribonucleotide reductase, stearoyl-acyl carrier protein ⌬-9 desaturase, as well as the detoxification and concentration of iron in Dps and ferritin (1-6). Diiron centers have similar structural motifs containing a combination of carboxylate and histidine ligands that either bind or bridge the two metal ions of the dinuclear active site. Although the dinuclear centers of the protein are very similar in structure, each of the proteins fulfills a different biological function that appears to be mediated by the nature of the first and second coordination sphere of the diiron center.Ferritins are a special class of diiron proteins that play a role in both iron housekeeping and iron detoxification. They are widely distributed in animals, plants, and bacteria (but not in yeast) and are typically composed of 24 similar or identical subunits assembled into a shell-like structure. In vertebrates, ferritins consist of two types of subunits, H and L, respectively. The two types have about 55% identity in amino acid sequence.

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Section: H-1 and H-2 In Oxidative Deposition Of Iron In Proteinsupporting

confidence: 90%

Section: H-1 and H-2 In Oxidative Deposition Of Iron In Proteinmentioning

confidence: 99%

Role of H-1 and H-2 Subunits of Soybean Seed Ferritin in Oxidative Deposition of Iron in Protein

Deng

Liao

Yang

et al. 2010

Journal of Biological Chemistry

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“…One of the residues at the ferritin-specific Fe2 site, residue 140, varies coincidentally with tissue-specific or organellespecific ferritin expression (24,25), without altering the reaction pathway (Scheme 1) (9,10,29). However, each ferritin active site in the homologous background had variable k cat and DFP kinetic stability, but constant K app (Table 1).…”

Section: Natural Asp 140 Variants In Ferritin Fe2mentioning

confidence: 99%

The ferritin Fe2 site at the diiron catalytic center controls the reaction with O ₂ in the rapid mineralization pathway

Tosha¹,

Hasan²,

Theil

2008

Proc. Natl. Acad. Sci. U.S.A.

108

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Oxidoreduction in ferritin protein nanocages occurs at sites that bind two Fe(II) substrate ions and O2, releasing Fe(III)2-O products, the biomineral precursors. Diferric peroxo intermediates form in ferritins and in the related diiron cofactor oxygenases. Cofactor iron is retained at diiron sites throughout catalysis, contrasting with ferritin. Four of the 6 active site residues are the same in ferritins and diiron oxygenases; ferritin-specific Gln 137 products (diiron substrates). The results and the coding similarities for cofactor and substrate site residues-e.g., Glu/Gln and His/Asp pairs share 2 of 3 nucleotides-illustrate the potential simplicity of evolving active sites for diiron cofactors or diiron substrates. diiron protein catalysts ͉ dioxygen ͉ iron biominerals ͉ protein nanocages ͉ Differic peroxo F erritins are protein nanocages with multiple sites that catalyze the oxidoreduction of Fe(II) and O 2 to produce diferric mineral precursors; the mineral precursors migrate into a central cavity 8 nm in diameter and form Fe(III) hydrated oxo mineral. Iron minerals in ferritins serve to concentrate iron to the high levels needed for the synthesis of iron-containing cofactors. The Fe(II) oxidation reactions in ferritins consume dioxygen or hydrogen peroxide, thereby minimizing dangerous Fenton chemistry (1). Ferritin protein nanocages self-assemble from 24 or 12, 4-␣-helix-bundle, subunits in maxiferritin or miniferritin, respectively; miniferritins were named, historically, Dps (DNA protection during starvation) proteins and, to date, are known only in bacteria and archaea; heme-containing ferritins in bacteria are called bacterioferritins (Bfr) (2). The biological importance of ferritin is reflected by wide distribution in most cells of humans, other animals, bacteria, and archaea, by the lethality of gene deletion in mice (3), by mutation effects on the central nervous system (4), and by protection during oxidant stress (5). In addition, the unusual physical stability of ferritin nanocages to temperature and chaotropes has application to materials and protein engineering (6, 7).Oxidoreductase/ferroxidase (F ox ) catalytic centers with diferrous binding sites, Fe1 and Fe2, occur in each ferritin subunit except in animals, where a second gene encodes a catalytically inactive subunit (ferritin L) that co-assembles with the active subunits in various ratios that depend on the tissue. The ferritin oxidoreductase sites share properties with diiron cofactor catalysts that include the first detectable reaction intermediate in ferritin, a diferric peroxo (DFP) complex, characterized by UV/visible (UV/vis), resonance Raman, Mössbauer, and extended X-ray absorption fine structure (EXAFS) spectroscopies (8)(9)(10)(11)(12)(13)(14). The reaction in ferritins is shown in Scheme 1.DFP decays to Fe(III) oxo or hydroxo dimers or multimers (15), representing reaction products from multiple sites, that move across the protein cage to the cavity where the Fe(III) oxide mineral forms. Parallel formation of diferric dimer...

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“…Based on the above reactions and on identification of intermediates by resonance Raman spectroscopy, Mössbauer spectroscopy, and EXAFS (extended x-ray absorption fine structure), the mechanism of mineral core formation in mammalian ferritins has been reasonably well established (18,(21)(22)(23) dimer(s) then translocates from the ferroxidase center to the inner cavity to form an incipient core, which ultimately leads to the formation of the mineral core itself. However, this mechanism of oxidative deposition of iron is only applicable to ferritins such as horse spleen ferritin and human H-chain ferritin, which regenerate activity at their ferroxidase centers.…”

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confidence: 99%

Protein Association and Dissociation Regulated by Ferric Ion

et al. 2009

Journal of Biological Chemistry

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Iron stored in phytoferritin plays an important role in the germination and early growth of seedlings. The protein is located in the amyloplast where it stores large amounts of iron as a hydrated ferric oxide mineral core within its shell-like structure. The present work was undertaken to study alternate mechanisms of core formation in pea seed ferritin (PSF). The data reveal a new mechanism for mineral core formation in PSF involving the binding and oxidation of iron at the extension peptide (EP) located on the outer surface of the protein shell. This binding induces aggregation of the protein into large assemblies of ϳ400 monomers. The bound iron is gradually translocated to the mineral core during which time the protein dissociates back into its monomeric state. Either the oxidative addition of Fe 2؉ to the apoprotein to form Fe 3؉ or the direct addition of Fe 3؉ to apoPSF causes protein aggregation once the binding capacity of the 24 ferroxidase centers (48 Fe 3؉ /shell) is exceeded. When the EP is enzymatically deleted from PSF, aggregation is not observed, and the rate of iron oxidation is significantly reduced, demonstrating that the EP is a critical structural component for iron binding, oxidation, and protein aggregation. These data point to a functional role for the extension peptide as an iron binding and ferroxidase center that contributes to mineralization of the iron core. As the iron core grows larger, the new pathway becomes less important, and Fe 2؉ oxidation and deposition occurs directly on the surface of the iron core.The chemistry of iron and oxygen in a number of non-heme di-iron proteins has been a subject of intense interest because of their varied roles in oxygen activation and catalysis, substrate hydrolysis, oxygen transport, redox reactions, H 2 O 2 , and iron detoxification and iron storage. Di-iron centers have similar structural motifs consisting of a combination of carboxylate and histidine ligands that either bind or bridge the two metal ions of the di-nuclear active site; di-iron proteins containing these centers include methane monooxygenase, ribonucleotide reductase, rubrerythrin, stearoyl desaturase, purple acid phosphatase, hemerythrin, the Dps proteins, and ferritins (1-6). Despite their similar di-nuclear centers, each of these proteins fulfills a distinct biological role that seems to be mediated by the nature of the first and second coordination sphere of the di-iron center.Ferritins are a class of intracellular iron storage and detoxification proteins that facilitate the oxidation of iron by molecular oxygen or hydrogen peroxide to form a hydrous ferric oxide mineral core within their interiors (1-3). Rapid Fe 2ϩ oxidation occurs at the di-iron ferroxidase center located on the H-subunit of the mammalian protein. Unlike the H-chain, the more acidic L-subunit lacks the ferroxidase center but contains a putative nucleation site responsible for slower iron oxidation and mineralization (7). The shapes of both the H-and L-subunit are nearly cylindrical and composed of a four...

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Origin of the Unusual Kinetics of Iron Deposition in Human H-Chain Ferritin

Cited by 81 publications

References 37 publications

Role of H-1 and H-2 Subunits of Soybean Seed Ferritin in Oxidative Deposition of Iron in Protein

Role of H-1 and H-2 Subunits of Soybean Seed Ferritin in Oxidative Deposition of Iron in Protein

The ferritin Fe2 site at the diiron catalytic center controls the reaction with O ₂ in the rapid mineralization pathway

Protein Association and Dissociation Regulated by Ferric Ion

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Origin of the Unusual Kinetics of Iron Deposition in Human H-Chain Ferritin

Cited by 81 publications

References 37 publications

Role of H-1 and H-2 Subunits of Soybean Seed Ferritin in Oxidative Deposition of Iron in Protein

Role of H-1 and H-2 Subunits of Soybean Seed Ferritin in Oxidative Deposition of Iron in Protein

The ferritin Fe2 site at the diiron catalytic center controls the reaction with O 2 in the rapid mineralization pathway

Protein Association and Dissociation Regulated by Ferric Ion

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The ferritin Fe2 site at the diiron catalytic center controls the reaction with O ₂ in the rapid mineralization pathway