30 research outputs found

    Distribution of the frequently occurring Fe-S families of aerobes and HC anaerobes within facultative anaerobes (A) and LC aerotolerant anaerobes (B).

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    <p>The black part of the column indicates the occurrence of the families of the three groups defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171279#pone.0171279.g002" target="_blank">Fig 2</a> within facultative anaerobes (A) and LC aerotolerant anaerobes (B). The grey part of the column indicates the absent families. The last columns correspond to Fe-S families unique to facultative anaerobes (A) and LC aerotolerant anaerobes (B), i.e. not mapping to any family in the Venn diagram of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171279#pone.0171279.g002" target="_blank">Fig 2</a>.</p

    The Relationship between Environmental Dioxygen and Iron-Sulfur Proteins Explored at the Genome Level

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    <div><p>About 2 billion years ago, the atmosphere of the Earth experienced a great change due to the buildup of dioxygen produced by photosynthetic organisms. This transition caused a reduction of iron bioavailability and at the same time exposed living organisms to the threat of oxidative stress. Iron-sulfur (Fe-S) clusters require iron ions for their biosynthesis and are labile if exposed to reactive oxygen species. To assess how the above transition influenced the usage of Fe-S clusters by organisms, we compared the distribution of the Fe-S proteins encoded by the genomes of more than 400 prokaryotic organisms as a function of their dioxygen requirements. Aerobic organisms use less Fe-S proteins than the majority of anaerobic organisms with a similar genome size. Furthermore, aerobes have evolved specific Fe-S proteins that bind the less iron-demanding and more chemically stable Fe<sub>2</sub>S<sub>2</sub> clusters while reducing the number of Fe<sub>4</sub>S<sub>4</sub>-binding proteins in their genomes. However, there is a shared core of Fe-S protein families composed mainly by Fe<sub>4</sub>S<sub>4</sub>-binding proteins. Members of these families are present also in humans. The distribution of human Fe-S proteins within cell compartments shows that mitochondrial proteins are inherited from prokaryotic proteins of aerobes, whereas nuclear and cytoplasmic Fe-S proteins are inherited from anaerobic organisms.</p></div

    The occurrence of (A) and the Fe-S cluster type (B) in the Fe-S families of humans, aerobes and HC anaerobes.

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    <p>In panel A, human Fe-S families that did not map to any prokaryotic family of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171279#pone.0171279.g002" target="_blank">Fig 2</a> are classified as “Human”. Panel B displays the average fraction of proteins binding at least one cluster of the Fe<sub>2</sub>S<sub>2</sub> or of the Fe<sub>4</sub>S<sub>4</sub> type.</p

    Exploiting Bacterial Operons To Illuminate Human Iron–Sulfur Proteins

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    Organisms from all kingdoms of life use iron–sulfur proteins (FeS-Ps) in a multitude of functional processes. We applied a bioinformatics approach to investigate the human portfolio of FeS-Ps. Sixty-one percent of human FeS-Ps bind Fe<sub>4</sub>S<sub>4</sub> clusters, whereas 39% bind Fe<sub>2</sub>S<sub>2</sub> clusters. However, this relative ratio varies significantly depending on the specific cellular compartment. We compared the portfolio of human FeS-Ps to 12 other eukaryotes and to about 700 prokaryotes. The comparative analysis of the organization of the prokaryotic homologues of human FeS-Ps within operons allowed us to reconstruct the human functional networks involving the conserved FeS-Ps common to prokaryotes and eukaryotes. These functional networks have been maintained during evolution and thus presumably represent fundamental cellular processes. The respiratory chain and the ISC machinery for FeS-P biogenesis are the two conserved processes that involve the majority of human FeS-Ps. Purine metabolism is another process including several FeS-Ps, in which BOLA proteins possibly have a regulatory role. The analysis of the co-occurrence of human FeS-Ps with other proteins highlighted numerous links between the iron–sulfur cluster machinery and the response mechanisms to cell damage, from repair to apoptosis. This relationship probably relates to the production of reactive oxygen species within the biogenesis and degradation of FeS-Ps

    Dependence of the number of Fe-S proteins and Fe-S families on the genome size of the organisms.

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    <p><b>A)</b> Number of putative Fe-S proteins as a function of the genome size in aerotolerant anaerobes (orange crosses), obligate anaerobes (red squares), aerobes (light blue triangles) and obligate aerobes (royal blue circles). The black line represent the threshold (3% of the genome content) used to separate LC aerotolerant anaerobes from HC aerotolerant anaerobes. <b>B)</b> Average number of distinct Fe-S families as a function of the genome size in HC aerotolerant anaerobes (orange crosses), obligate anaerobes (red squares), aerobes (light blue triangles) and obligate aerobes (royal blue circles).</p

    Frequently occurring (i.e. present in at least 30% organisms) families of Fe-S proteins in aerobes and HC anaerobes.

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    <p>(A): Venn diagram showing the distribution of the 116 frequently occurring Fe-S families within aerobes and HC anaerobes. (B), (C), and (D): Pie charts showing the types of Fe-S cluster (blue: Fe<sub>2</sub>S<sub>2</sub>; orange: Fe<sub>4</sub>S<sub>4</sub>; green: Fe<sub>3</sub>S<sub>4</sub>; yellow: two or more of Fe<sub>2</sub>S<sub>2</sub>-Fe<sub>4</sub>S<sub>4</sub>-Fe<sub>3</sub>S<sub>4</sub>; red: FeCys<sub>4</sub>; grey: unknown type) associated with families conserved in aerobes (B), in anaerobes (D), and in both (C). (E), (F), and (G): histograms showing the number of families associated with specific functional processes in aerobes (E), in anaerobes (G), and in both (F). More than one functional process may be associated with a family. Unknown functional processes are excluded from the count.</p

    Average percentage of Fe-S proteins encoded in the genome of each group of organisms, divided per dioxygen requirement.

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    <p>Columns 3–5 report the total number of organisms and the number of eubacterial and archaeal organisms of each type analyzed.</p

    Anamorsin/Ndor1 Complex Reduces [2Fe–2S]-MitoNEET via a Transient Protein–Protein Interaction

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    Human mitoNEET is a homodimeric protein anchored to the outer mitochondrial membrane and has a C-terminal [2Fe–2S] binding domain located in the cytosol. Recently, human mitoNEET has been shown to be implicated in Fe/S cluster repair of cytosolic iron regulatory protein 1 (IRP1), a key regulator of cellular iron homeostasis in mammalian cells. The Fe/S cluster repair function of mitoNEET is based on an Fe/S redox switch mechanism: under normal cellular conditions, reduced [2Fe–2S]<sup>+</sup>-mitoNEET is present and is inactive as an Fe/S cluster transfer protein; under conditions of oxidative cellular stress, the clusters of mitoNEET become oxidized, and the formed [2Fe–2S]<sup>2+</sup>-mitoNEET species reacts promptly to initiate Fe/S cluster transfer to IRP1, recycling the cytosolic <i>apo</i>-IRP1 into <i>holo</i>-aconitase. Until now, no clear data have been available on which is the system that reduces the mitoNEET clusters back once oxidative stress is not present anymore. In the present work, we used UV–vis and NMR spectroscopies to investigate the electron transfer process between mitoNEET and the cytosolic electron-donor Ndor1/anamorsin complex, a component of the cytosolic iron–sulfur protein assembly (CIA) machinery. The [2Fe–2S] clusters of mitoNEET are reduced via the formation of a transient complex that brings the [2Fe–2S] clusters of mitoNEET close to the redox-active [2Fe–2S] cluster of anamorsin. Our data provide in vitro evidence of a possible direct link between the CIA machinery and the mitoNEET cluster transfer repair pathway. This link might contribute to recovery of CIA machinery efficiency to mature cytosolic and nuclear Fe/S proteins

    Elucidating the Molecular Function of Human BOLA2 in GRX3-Dependent Anamorsin Maturation Pathway

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    In eukaryotes, the interaction between members of the monothiol glutaredoxin family and members of the BolA-like protein family has been involved in iron metabolism. To investigate the still unknown functional role of the interaction between human glutaredoxin-3 (GRX3) and its protein partner BOLA2, we characterized at the atomic level the interaction of apo BOLA2 with the apo and holo states of GRX3 and studied the role of BOLA2 in the GRX3-dependent anamorsin maturation pathway. From these studies, it emerged that apo GRX3 and apo BOLA2 form a heterotrimeric complex, composed by two BOLA2 molecules and one GRX3 molecule. This complex is able to bind two [2Fe-2S]<sup>2+</sup> clusters, each being bridged between a BOLA2 molecule and a monothiol glutaredoxin domain of GRX3, and to transfer both [2Fe-2S]<sup>2+</sup> clusters to apo anamorsin producing its mature holo state. Collectively, the data suggest that the heterotrimeric complex can work as a [2Fe-2S]<sup>2+</sup> cluster transfer component in cytosolic Fe/S protein maturation pathways

    [4Fe-4S] Cluster Assembly in Mitochondria and Its Impairment by Copper

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    The cellular toxicity of copper is usually associated with its ability to generate reactive oxygen species. However, recent studies in bacterial organisms showed that copper toxicity is also strictly connected to iron–sulfur cluster proteins and to their assembly processes. Mitochondria of eukaryotic cells contain a labile copper­(I) pool localized in the matrix where also the mitochondrial iron–sulfur (Fe/S) cluster assembly machinery resides to mature mitochondrial Fe/S cluster-containing proteins. Misregulation of copper homeostasis might therefore damage mitochondrial Fe/S protein maturation. To describe, from a molecular perspective, the effects of copper­(I) toxicity on such a maturation process, we have here investigated the still unknown mechanism of [4Fe-4S] cluster formation conducted by the mitochondrial ISCA1/ISCA2 and GLRX5 proteins, and defined how copper­(I) can impair this process. The molecular model here proposed indicates that the copper­(I) and Fe/S protein maturation cellular pathways need to be strictly regulated to avoid copper­(I) ion from blocking mitochondrial [4Fe-4S] protein maturation
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