Functional Properties of Threefold and Fourfold Channels in Ferritin Deduced from Electrostatic Calculations

Takahashi, Takuya; Kuyucak, Serdar

doi:10.1016/s0006-3495(03)75031-0

Cited by 100 publications

(128 citation statements)

References 36 publications

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“…to catalysis or mineralization (5,38). Previously, conserved amino acids in ferritin that were not in localized clusters such as the oxidoreductase sites were assigned roles in folding and stabilizing the unique ferritin cage structure, with the exception of those around the 3-fold channels shown to regulate Fe 2ϩ release from the mineral and the cage (5) or those theoretically shown to create local electrostatic gradients for Fe 2ϩ entry through the ion channels (32). The amino acids studied here, which all have functional effects on iron oxidation and mineralization, are distributed over a distance of ϳ50 Å.…”

Section: Discussionmentioning

confidence: 99%

Moving Iron through Ferritin Protein Nanocages Depends on Residues throughout Each Four α-Helix Bundle Subunit

Haldar¹,

Bevers²,

Tosha³

et al. 2011

Journal of Biological Chemistry

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Ferritins are an ancient superfamily of protein nanocages that synthesize, reversibly, iron concentrates for cellular use, heme, FeS cluster, and Fe-protein synthesis and provide oxidant protection by consumption of dioxygen or hydrogen peroxide and ferrous iron during stress; the protein cavities containing the minerals are ϳ60% of the cage volume (1-4). Ferritins differ in cage size, location, and mechanism of catalytic sites, mineral size, and mineral crystallinity; the Fe 2ϩ /O 2 oxidoreductase sites are also called ferroxidase sites or FC (ferroxidase centers) sites (1-5). In eukaryotic H ferritins, Fe 2ϩ and dioxygen are substrates for oxidoreductase sites and are catalytically coupled at multiple protein sites to synthesize diferric oxo mineral precursors (Fig. 1). Consumption of both iron and oxygen by ferritins accounts for the antioxidant response and iron-controlled gene regulation of ferritins in eukaryotes (6). Many catalytic proteins use iron and oxygen to produce a variety of organic products. Such products include unsaturated fatty acids such as oleate stearoyl-CoA desaturase-1 (7), deoxyribose (ribonucleotide reductase), and prolyhydroxyl modification of oxygen-sensing DNA transcription factors, e.g. hypoxia-inducible factor-␣ (8). Only in ferritins are both substrates inorganic. The exclusive use of inorganic substrates may relate to the ancient origins of the ferritins, which are distributed in all kingdoms and in both anaerobes and aerobes; ferritin gene deletion is lethal early in mammalian embryogenesis (9).There are two types of protein channels that move iron into and through the 24 subunit cages during synthesis of [Fe 3ϩ O] n in eukaryotic ferritins. The two functional types of ferritin channels are: (i) ion entry channels around the 3-fold axes, for , where diferric oxo mineral precursors produced by oxidoreduction fuse to tetramers and larger multimers before exiting from the protein cage for mineral growth.Recent high resolution structural studies show that ferritin is a soluble ion channel protein with lines of multiple metal ions (10), much like K ϩ and other membrane ion channel proteins. The eight Fe 2ϩ entry channels (Fig. 1) suggest roles beyond just electrostatics for the conserved carboxylates, such as ion selectivity at the channel constriction or directing Fe 2ϩ substrate ions to active sites in three subunits that also form the entry channels (10). The Fe 3ϩ O nucleation channels were recently identified using 13 C-13 C solution NMR spectroscopy in the presence and absence of Fe 3ϩ , by the disappearance of resonances within 5 Å of Fe 3ϩ O moving away from the active sites (11). Nucleation channel exits into the cavity are clustered around the 4-fold axes of the cage, which facilitates ordered mineral growth. 4 The abbreviations used are: DFP, diferric peroxo; MCD, magnetic circular dichroism; bis-Tris, bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane.

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Section: Discussionmentioning

confidence: 99%

Moving Iron through Ferritin Protein Nanocages Depends on Residues throughout Each Four α-Helix Bundle Subunit

Haldar¹,

Bevers²,

Tosha³

et al. 2011

Journal of Biological Chemistry

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“…The mechanisms governing the exit of the metal from the protein deposit are not clear yet and the physiological relevance of the data obtained in vitro is still debated. The 3-fold channels seem to be the main route of both iron entry and exit from the protein shell (Wardeska et al 1986), with the negatively charged amino acids paving their surface playing a fundamental role in determining the types of ions and molecules that can access inside the cage (Takahashi and Kuyucak 2003). In vitro, the removal of iron is efficient in the presence of reducing agents and chelators, even those larger than the diameter of the channel (Jones et al 1978;Watt et al 1988); this could be explained by a direct transfer of electrons from the exterior reductants to the inner mineral core through the 2 nm ferritin wall.…”

Section: Mammalian Ferritin Structurementioning

confidence: 99%

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

2014

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Iron is an abundant transition metal that is essential for life, being associated to many enzyme and oxygen carrier proteins involved in a variety of fundamental cellular processes. At the same time the metal is potentially toxic due to its capacity to engage in the catalytic production of noxious reactive oxygen species. The control of iron availability in the cells is largely dependent on ferritins, ubiquitous proteins with storage and detoxification capacity. In mammals, cytosolic ferritins are composed of two types of subunits, the H and the L chain, assembled to form a 24-mer spherical cage. Ferritin is present also in mitochondria, in the form of a complex with 24 identical chains. Even though the proteins have been known for a long time, their study is a very active and interesting field yet. In this review we will focus our attention to mammalian cytosolic and mitochondrial ferritins, describing the most recent advancement regarding their storage and antioxidant function, the effects of their genetic mutations in human pathology, and also the possible involvement in non-iron related activities. We will also discuss recent evidence connecting ferritins and the toxicity of iron in a set of neurodegenerative disorder characterized by focal cerebral siderosis. IntroductionThe adaptation of life to an oxic environment required the development of mechanisms to deal with the transformation of the water soluble ferrous ion (Fe 2+ ) to the insoluble ferric ion (Fe 3+ ) and with the concomitant generation of dangerous reactive oxygen species (ROS). The ferritin molecules represent an important and ancient mean developed by organisms in the three domains of life to safely handle the necessary, yet potentially toxic metal. Their ability to detoxify and store the metal through safe oxidation processes protects the cells from undue iron-dependent redox chemistry, while a controlled release of the metal guarantees its availability for different and essential enzymatic reactions. Storage and detoxification of iron represent the main functions of these molecules, and much work has been done to understand the chemical and molecular details of this

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“…These fourfold hydrophobic channels are found to be impermeable to all cations with the possible exception of protons. It is suggested that these fourfold channels facilitate proton transfer in and out of ferritin in order to maintain electroneutrality during iron deposition (Takahashi & Kuyucak, 2003). However, the substitution of leucine for histidine in the H-subunit may confer iron transfer properties to the hydrophobic channel of the H-subunit since histidine has a strong affinity for iron (Boyd et al, 1985).…”

Section: Structure Of the Ferritin Protein Shellmentioning

confidence: 99%

Ferritin and ferritin isoforms I: Structure–function relationships, synthesis, degradation and secretion

Koorts

Viljoen

2007

Archives of Physiology and Biochemistry

127

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Ferritin is the intracellular protein responsible for the sequestration, storage and release of iron. Ferritin can accumulate up to 4500 iron atoms as a ferrihydrite mineral in a protein shell and releases these iron atoms when there is an increase in the cell's need for bioavailable iron. The ferritin protein shell consists of 24 protein subunits of two types, the H-subunit and the L-subunit. These ferritin subunits perform different functions in the mineralization process of iron. The ferritin protein shell can exist as various combinations of these two subunit types, giving rise to heteropolymers or isoferritins. Isoferritins are functionally distinct and characteristic populations of isoferritins are found depending on the type of cell, the proliferation status of the cell and the presence of disease. The synthesis of ferritin is regulated both transcriptionally and translationally. Translation of ferritin subunit mRNA is increased or decreased, depending on the labile iron pool and is controlled by an ironresponsive element present in the 5'-untranslated region of the ferritin subunit mRNA. The transcription of the genes for the ferritin subunits is controlled by hormones and cytokines, which can result in a change in the pool of translatable mRNA. The levels of intracellular ferritin are determined by the balance between synthesis and degradation. Degradation of ferritin in the cytosol results in complete release of iron, while degradation in secondary lysosomes results in the formation of haemosiderin and protection against iron toxicity. The majority of ferritin is found in the cytosol. However, ferritin with slightly different properties can also be found in organelles such as nuclei and mitochondria. Most of the ferritin produced intracellularly is harnessed for the regulation of iron bioavailability; however, some of the ferritin is secreted and internalized by other cells. In addition to the regulation of iron bioavailability ferritin may contribute to the control of myelopoiesis and immunological responses.

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Functional Properties of Threefold and Fourfold Channels in Ferritin Deduced from Electrostatic Calculations

Cited by 100 publications

References 36 publications

Moving Iron through Ferritin Protein Nanocages Depends on Residues throughout Each Four α-Helix Bundle Subunit

Moving Iron through Ferritin Protein Nanocages Depends on Residues throughout Each Four α-Helix Bundle Subunit

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

Ferritin and ferritin isoforms I: Structure–function relationships, synthesis, degradation and secretion

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