The Role of the L-Chain in Ferritin Iron Incorporation

Levi, Sonia; Santambrogio, Paolo; Cozzi, Anna; Rovida, Ermanna; Corsi, Barbara; Tamborini, Elena; Spada, Stefania; Albertini, Alberto; Arosio, Paolo

doi:10.1006/jmbi.1994.1325

Cited by 172 publications

(162 citation statements)

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“…However, an early attempt to construct a catalytically active site in human L ferritin led to insoluble protein that had weak mineralization activity when analyzed after solubilization and folding with guanidine in the presence of catalytically active H-ferritin subunits. Whether the solubilized chimeric protein catalyzed the formation of the DFP complex was not examined (32).…”

Section: Experimental Methods Protein Engineering and Expressionmentioning

confidence: 99%

Ferritin reactions: Direct identification of the site for the diferric peroxide reaction intermediate

Liu

Theil

2004

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

125

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Ferritins managing iron-oxygen biochemistry in animals, plants, and microorganisms belong to the diiron carboxylate protein family and concentrate iron as ferric oxide Ϸ10 14 times above the ferric Ks. Ferritin iron (up to 4,500 atoms), used for iron cofactors and heme, or to trap DNA-damaging oxidants in microorganisms, is concentrated in the protein nanocage cavity (5-8 nm) formed during assembly of polypeptide subunits, 24 in maxiferritins and 12 in miniferritins͞DNA protection during starvation proteins. I ron and oxygen are integral to life, but their chemistry requires many proteins with iron cofactors to harness them for respiration, photosynthesis, and DNA synthesis, while minimizing radical side reactions. Ferritins, cage-like nanoproteins, concentrate iron for cofactor synthesis, as a mineral (hydrated ferric oxide), in large, central cavities (5-8 nm). Ferritin nanocavities form during the spontaneous assembly of ellipsoidal, polypeptide subunits (1-3), 24 in maxiferritins (Ϸ480 kDa) and 12 in miniferritins (240 kDa), also called DNA protection during starvation proteins. The biological importance of ferritin is emphasized by the lethality of ferritin gene deletion in mammals (4), defects in the CNS from mutations in humans (5), and oxidant sensitivity after deletions of the multiple ferritins in bacteria (6)(7)(8). Reactions of iron and oxygen catalyzed by maxiferritins, in cells of higher plants, animals including humans, and microorganisms, stabilize iron with oxygen at 10 14 times above the K s to match cellular iron concentrations, whereas miniferritins protect DNA by trapping oxidants with iron in the hydrated ferric oxide mineral.Catalytic ferroxidase (F ox ) sites in ferritin catalyze the first in the series of reactions converting soluble ferrous ions to solid, concentrated ferric biomineral inside ferritin. The location of F ox sites in ferritin has been inferred to be in the center of each active subunit for maxiferritins and at junctions of subunit dimers in miniferritins, based on models of protein cocrystals with Fe 2ϩ analogues such as Mg 2ϩ or Ca 2ϩ (7-13). Such models are reasonable for the ferrous substrate, but not for ferric intermediates such as the diferric peroxo (DFP) complex or products such as diferric oxo͞hydroxo mineral precursors. There are at least four types of metal-protein sites in ferritin (iron entry, exit, nucleation, and F ox substrate). Thus, a number of assumptions are required if a crystal-metal site is assigned to one of the multiple, iron-dependent ferritin functions. Even when two Mg 2ϩ or two Ca 2ϩ ions are relatively near each other in ferritin cocrystals, the metal-metal distances in the models were much longer than the Fe 3ϩ -Fe 3ϩ distance in the functional DFP intermediate, determined by extended x-ray absorption fine structure analysis in solution (11,12,14). F ox site models have also relied on analogies to iron sites of other diiron carboxylate family members that form DFP intermediates (15-17), even when iron is a cofactor and contrasts with ferriti...

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Section: Experimental Methods Protein Engineering and Expressionmentioning

confidence: 99%

Ferritin reactions: Direct identification of the site for the diferric peroxide reaction intermediate

Liu

Theil

2004

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

125

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“…2 A and B] that is conserved among eubacterial Dps homologues and a cluster of carboxylate residues [nucleation site 1 (NI) center, Fig. 2B] that resembles the iron core nucleation site of mammalian ferritin L chains (1,25).…”

Section: Structural Comparison Of Dpsa With 24-mer Ferritins and Dps-mentioning

confidence: 99%

Iron-oxo clusters biomineralizing on protein surfaces: Structural analysis of Halobacterium salinarum DpsA in its low- and high-iron states

Zeth

Offermann

Essen

et al. 2004

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

111

122

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The crystal structure of the Dps-like (Dps, DNA-protecting protein during starvation) ferritin protein DpsA from the halophile Halobacterium salinarum was determined with low endogenous iron content at 1.6-Å resolution. The mechanism of iron uptake and storage was analyzed in this noncanonical ferritin by three highresolution structures at successively increasing iron contents. In the high-iron state of the DpsA protein, up to 110 iron atoms were localized in the dodecameric protein complex. For ultimate iron storage, the archaeal ferritin shell comprises iron-binding sites for iron translocation, oxidation, and nucleation. Initial iron-protein interactions occur through acidic residues exposed along the outer surface in proximity to the iron entry pore. This narrow pore permits translocation of ions toward the ferroxidase centers via two discrete steps. Iron oxidation proceeds by transient formation of tri-iron ferroxidase centers. Iron storage by biomineralization inside the ferritin shell occurs at two iron nucleation centers. Here, a single iron atom provides a structural seed for iron-oxide cluster formation. The clusters with up to five iron atoms adopt a geometry that is different from natural biominerals like magnetite but resembles iron clusters so far known only from bioinorganic model compounds.ferritin ͉ iron-binding ͉ inorganic cluster formation ͉ x-ray crystal structure

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“…A preferential induction of the H subunit than the L subunit of the ferritin gene was frequently observed in response to environmental and intracellular signals during inflammation (Torti et al, 1988;Miller et al, 1991;Tsuji et al, 1991;Kwak et al, 1995), and differentiation (Chou et al, 1986;Beaumont et al, 1987Beaumont et al, , 1994 in an iron-independent manner. Alterations in the subunit composition of the ferritins have a potential to alter intracellular iron balance because there are functional differences between the H and L subunits of ferritin; the ferritin heavy chain (ferritin H) subunit has ferroxidase activity that oxidizes ferrous iron to ferric iron, while the ferritin L subunit lacks the ferroxidase center but contributes to stabilization of assembled ferritin proteins (Levi et al, , 1994Santambrogio et al, 1992). Ferritin molecules that are rich in the H subunit are therefore involved in rapid iron uptake and release, contrasting the long-term iron storage by L subunit-rich ferritin molecules (Wagstaff et al, 1978;Bomford et al, 1981;Levi et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress

2005

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The Role of the L-Chain in Ferritin Iron Incorporation

Cited by 172 publications

References 0 publications

Ferritin reactions: Direct identification of the site for the diferric peroxide reaction intermediate

Ferritin reactions: Direct identification of the site for the diferric peroxide reaction intermediate

Iron-oxo clusters biomineralizing on protein surfaces: Structural analysis of Halobacterium salinarum DpsA in its low- and high-iron states

JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress

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