Identification of catalytic residues involved in iron uptake by L-chain ferritins

Crichton, Robert R.; Herbas, Adelina; Chavez-Alba, Octavio; Roland, Francine

doi:10.1007/s007750050093

Cited by 49 publications

(48 citation statements)

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“…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-␣-helix bundle containing two antiparallel helix pairs (A, B and C, D) connected by a long non-helical stretch, the BC-loop, between B and C helices.…”

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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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“…Iron oxidation/mineralization in human ferritin occurs by at least three reaction pathways (16,17 (1,7,17).…”

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Protein Association and Dissociation Regulated by Ferric Ion

et al. 2009

Journal of Biological Chemistry

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“…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)(2)(3)(4)(5)(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.…”

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“…The H-type subunit of vertebrate ferritins contains a dinuclear iron "ferroxidase site" at which the rapid oxidation of Fe 2ϩ to Fe 3ϩ by dioxygen occurs; subsequent hydrolysis of the Fe 3ϩ and its migration away from the ferroxidase site leads to formation of the Fe 3ϩ mineral core. Unlike the H-subunit, the L-subunit lacks a ferroxidase center but has a greater negative charge; in the assembled ferritin, the negative charge presents itself on the interior surface as clusters of acidic residues (Glu and Asp) that comprise the mineral nucleation site (6). Ferritins from lower vertebrates, such as bullfrogs and fish, contain a third subunit type, named the M(HЈ) chain, which harbors the residues forming both the ferroxidase center and the nucleation site (1,7).…”

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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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“…Three categories of iron sites can be defined according to function (1): (i) pore residues § (Asp-127, Glu-130, Cys-126, ¶ His-114, Leu-110 and -134, and Arg-72 ͞Asp-122) (9-18); (ii) protein-catalyzed iron oxidation (Glu-23, Glu-57, Glu-58, His-61, Glu-103, Gln-137, and Asp-140) (4,(19)(20)(21)(22)(23); and (iii) Fe(III) nucleation͞chelation in the interior surface of the protein cavity (Glu-56, Glu-57, Glu-60, and Glu-63 in H subunits and Glu-53, Glu-56, Glu-57, Glu-60, and Glu-63 in L subunits) (24,25).…”

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Iron uptake in ferritin is blocked by binding of [Cr(TREN)(H ₂ O)(OH)] ²⁺ , a slow dissociating model for [Fe(H ₂ O) ₆ ] ²⁺

Barnes

Theil

Raymond

2002

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

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Identification of catalytic residues involved in iron uptake by L-chain ferritins

Cited by 49 publications

References 1 publication

Protein Association and Dissociation Regulated by Ferric Ion

Protein Association and Dissociation Regulated by Ferric Ion

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

Iron uptake in ferritin is blocked by binding of [Cr(TREN)(H ₂ O)(OH)] ²⁺ , a slow dissociating model for [Fe(H ₂ O) ₆ ] ²⁺

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Identification of catalytic residues involved in iron uptake by L-chain ferritins

Cited by 49 publications

References 1 publication

Protein Association and Dissociation Regulated by Ferric Ion

Protein Association and Dissociation Regulated by Ferric Ion

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

Iron uptake in ferritin is blocked by binding of [Cr(TREN)(H 2 O)(OH)] 2+ , a slow dissociating model for [Fe(H 2 O) 6 ] 2+

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Iron uptake in ferritin is blocked by binding of [Cr(TREN)(H ₂ O)(OH)] ²⁺ , a slow dissociating model for [Fe(H ₂ O) ₆ ] ²⁺