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Iron-Sulfur Clusters and Proteins
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Iron-Sulfur Clusters and Proteins

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 14804

Special Issue Editor

Dr. Paola Costantini

E-Mail Website
Guest Editor
Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
Interests: mitochondrial diseases caused by FeS-clusters deficiency; neurodegenerative disease; Friedreich ataxia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Iron–sulfur (FeS) clusters are inorganic cofactors that are essential in several major biochemical processes in prokaryotic and eukaryotic organisms, including catalysis, electron transfer, determining of protein structure, and regulation of gene expression. Different FeS centers may exist in nature, ranging from the simplest [2Fe-2S] and [4Fe-4S] units, found in plant and bacterial ferredoxins, as well as in respiratory complexes I-III of bacteria and mitochondria, to more complex polymetallic clusters characterized in metalloproteins, such as nitrogenase and hydrogenase, involved in nitrogen fixation and hydrogen metabolism respectively. The biosynthesis of FeS clusters and their transfer to the target apoproteins are highly complex and strictly coordinated processes driven by different, phylogenetically unrelated molecular systems, all sharing common biosynthetic principles. These pathways are key events in the overall cellular physiology, and, according to their crucial role, an increasing number of human diseases are related to impaired biogenesis of FeS proteins.

In this Special Issue of IJMS, the focus will be on the most recent research advances in the field of FeS cluster assembly molecular mechanisms, FeS protein biogenesis and its regulation in numerous organisms, from bacteria to humans, and disease-associated FeS protein defects.

Dr. Paola Costantini
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • typical and atypical FeS clusters: biogenesis diversity and evolution
  • FeS cluster assembly factors: structure and function
  • ISC and CIA assembly machinery
  • models and strategies for studying FeS proteins biogenesis
  • FeS proteins diseases

Published Papers (5 papers)

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Research

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18 pages, 3113 KiB  
Article
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation
by Giovanni Saudino, Dafne Suraci, Veronica Nasta, Simone Ciofi-Baffoni and Lucia Banci
Int. J. Mol. Sci. 2021, 22(9), 4848; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094848 - 03 May 2021
Cited by 5 | Viewed by 2068
Abstract
Multiple mitochondrial dysfunctions syndrome (MMDS) is a rare neurodegenerative disorder associated with mutations in genes with a vital role in the biogenesis of mitochondrial [4Fe–4S] proteins. Mutations in one of these genes encoding for BOLA3 protein lead to MMDS type 2 (MMDS2). Recently, [...] Read more.
Multiple mitochondrial dysfunctions syndrome (MMDS) is a rare neurodegenerative disorder associated with mutations in genes with a vital role in the biogenesis of mitochondrial [4Fe–4S] proteins. Mutations in one of these genes encoding for BOLA3 protein lead to MMDS type 2 (MMDS2). Recently, a novel phenotype for MMDS2 with complete clinical recovery was observed in a patient containing a novel variant (c.176G > A, p.Cys59Tyr) in compound heterozygosity. In this work, we aimed to rationalize this unique phenotype observed in MMDS2. To do so, we first investigated the structural impact of the Cys59Tyr mutation on BOLA3 by NMR, and then we analyzed how the mutation affects both the formation of a hetero-complex between BOLA3 and its protein partner GLRX5 and the iron–sulfur cluster-binding properties of the hetero-complex by various spectroscopic techniques and by experimentally driven molecular docking. We show that (1) the mutation structurally perturbed the iron–sulfur cluster-binding region of BOLA3, but without abolishing [2Fe–2S]2+ cluster-binding on the hetero-complex; (2) tyrosine 59 did not replace cysteine 59 as iron–sulfur cluster ligand; and (3) the mutation promoted the formation of an aberrant apo C59Y BOLA3–GLRX5 complex. All these aspects allowed us to rationalize the unique phenotype observed in MMDS2 caused by Cys59Tyr mutation. Full article
(This article belongs to the Special Issue Iron-Sulfur Clusters and Proteins)
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20 pages, 3406 KiB  
Article
Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies
by Davide Doni, Leonardo Passerini, Gérard Audran, Sylvain R. A. Marque, Marvin Schulz, Javier Santos, Paola Costantini, Marco Bortolus and Donatella Carbonera
Int. J. Mol. Sci. 2020, 21(24), 9619; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249619 - 17 Dec 2020
Cited by 7 | Viewed by 2447
Abstract
Frataxin is a highly conserved protein whose deficiency results in the neurodegenerative disease Friederich’s ataxia. Frataxin’s actual physiological function has been debated for a long time without reaching a general agreement; however, it is commonly accepted that the protein is involved in the [...] Read more.
Frataxin is a highly conserved protein whose deficiency results in the neurodegenerative disease Friederich’s ataxia. Frataxin’s actual physiological function has been debated for a long time without reaching a general agreement; however, it is commonly accepted that the protein is involved in the biosynthetic iron-sulphur cluster (ISC) machinery, and several authors have pointed out that it also participates in iron homeostasis. In this work, we use site-directed spin labeling coupled to electron paramagnetic resonance (SDSL EPR) to add new information on the effects of ferric and ferrous iron binding on the properties of human frataxin in vitro. Using SDSL EPR and relating the results to fluorescence experiments commonly performed to study iron binding to FXN, we produced evidence that ferric iron causes reversible aggregation without preferred interfaces in a concentration-dependent fashion, starting at relatively low concentrations (micromolar range), whereas ferrous iron binds without inducing aggregation. Moreover, our experiments show that the ferrous binding does not lead to changes of protein conformation. The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions. Full article
(This article belongs to the Special Issue Iron-Sulfur Clusters and Proteins)
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22 pages, 5059 KiB  
Article
The Arabidopsis Mitochondrial Glutaredoxin GRXS15 Provides [2Fe-2S] Clusters for ISCA-Mediated [4Fe-4S] Cluster Maturation
by Tamanna Azam, Jonathan Przybyla-Toscano, Florence Vignols, Jérémy Couturier, Nicolas Rouhier and Michael K. Johnson
Int. J. Mol. Sci. 2020, 21(23), 9237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239237 - 03 Dec 2020
Cited by 10 | Viewed by 2505
Abstract
Iron-sulfur (Fe-S) proteins are crucial for many cellular functions, particularly those involving electron transfer and metabolic reactions. An essential monothiol glutaredoxin GRXS15 plays a key role in the maturation of plant mitochondrial Fe-S proteins. However, its specific molecular function is not clear, and [...] Read more.
Iron-sulfur (Fe-S) proteins are crucial for many cellular functions, particularly those involving electron transfer and metabolic reactions. An essential monothiol glutaredoxin GRXS15 plays a key role in the maturation of plant mitochondrial Fe-S proteins. However, its specific molecular function is not clear, and may be different from that of the better characterized yeast and human orthologs, based on known properties. Hence, we report here a detailed characterization of the interactions between Arabidopsis thaliana GRXS15 and ISCA proteins using both in vivo and in vitro approaches. Yeast two-hybrid and bimolecular fluorescence complementation experiments demonstrated that GRXS15 interacts with each of the three plant mitochondrial ISCA1a/1b/2 proteins. UV-visible absorption/CD and resonance Raman spectroscopy demonstrated that coexpression of ISCA1a and ISCA2 resulted in samples with one [2Fe-2S]2+ cluster per ISCA1a/2 heterodimer, but cluster reconstitution using as-purified [2Fe-2S]-ISCA1a/2 resulted in a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer. Cluster transfer reactions monitored by UV-visible absorption and CD spectroscopy demonstrated that [2Fe-2S]-GRXS15 mediates [2Fe-2S]2+ cluster assembly on mitochondrial ferredoxin and [4Fe-4S]2+ cluster assembly on the ISCA1a/2 heterodimer in the presence of excess glutathione. This suggests that ISCA1a/2 is an assembler of [4Fe-4S]2+ clusters, via two-electron reductive coupling of two [2Fe-2S]2+ clusters. Overall, the results provide new insights into the roles of GRXS15 and ISCA1a/2 in effecting [2Fe-2S]2+ to [4Fe-4S]2+ cluster conversions for the maturation of client [4Fe-4S] cluster-containing proteins in plants. Full article
(This article belongs to the Special Issue Iron-Sulfur Clusters and Proteins)
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25 pages, 4341 KiB  
Article
A Highly Conserved Iron-Sulfur Cluster Assembly Machinery between Humans and Amoeba Dictyostelium discoideum: The Characterization of Frataxin
by Justo Olmos, María Florencia Pignataro, Ana Belén Benítez dos Santos, Mauro Bringas, Sebastián Klinke, Laura Kamenetzky, Francisco Velazquez and Javier Santos
Int. J. Mol. Sci. 2020, 21(18), 6821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186821 - 17 Sep 2020
Cited by 3 | Viewed by 2777
Abstract
Several biological activities depend on iron–sulfur clusters ([Fe-S]). Even though they are well-known in several organisms their function and metabolic pathway were poorly understood in the majority of the organisms. We propose to use the amoeba Dictyostelium discoideum, as a biological model [...] Read more.
Several biological activities depend on iron–sulfur clusters ([Fe-S]). Even though they are well-known in several organisms their function and metabolic pathway were poorly understood in the majority of the organisms. We propose to use the amoeba Dictyostelium discoideum, as a biological model to study the biosynthesis of [Fe-S] at the molecular, cellular and organism levels. First, we have explored the D. discoideum genome looking for genes corresponding to the subunits that constitute the molecular machinery for Fe-S cluster assembly and, based on the structure of the mammalian supercomplex and amino acid conservation profiles, we inferred the full functionality of the amoeba machinery. After that, we expressed the recombinant mature form of D. discoideum frataxin protein (DdFXN), the kinetic activator of this pathway. We characterized the protein and its conformational stability. DdFXN is monomeric and compact. The analysis of the secondary structure content, calculated using the far-UV CD spectra, was compatible with the data expected for the FXN fold, and near-UV CD spectra were compatible with the data corresponding to a folded protein. In addition, Tryptophan fluorescence indicated that the emission occurs from an apolar environment. However, the conformation of DdFXN is significantly less stable than that of the human FXN, (4.0 vs. 9.0 kcal mol−1, respectively). Based on a sequence analysis and structural models of DdFXN, we investigated key residues involved in the interaction of DdFXN with the supercomplex and the effect of point mutations on the energetics of the DdFXN tertiary structure. More than 10 residues involved in Friedreich’s Ataxia are conserved between the human and DdFXN forms, and a good correlation between mutational effect on the energetics of both proteins were found, suggesting the existence of similar sequence/function/stability relationships. Finally, we integrated this information in an evolutionary context which highlights particular variation patterns between amoeba and humans that may reflect a functional importance of specific protein positions. Moreover, the complete pathway obtained forms a piece of evidence in favor of the hypothesis of a shared and highly conserved [Fe-S] assembly machinery between Human and D. discoideum. Full article
(This article belongs to the Special Issue Iron-Sulfur Clusters and Proteins)
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Review

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23 pages, 3605 KiB  
Review
Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly
by Courtney J. Campbell, Ashley E. Pall, Akshata R. Naik, Lindsey N. Thompson and Timothy L. Stemmler
Int. J. Mol. Sci. 2021, 22(11), 6006; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116006 - 02 Jun 2021
Cited by 10 | Viewed by 4118
Abstract
Iron–sulfur clusters are essential to almost every life form and utilized for their unique structural and redox-targeted activities within cells during many cellular pathways. Although there are three different Fe–S cluster assembly pathways in prokaryotes (the NIF, SUF and ISC pathways) and two [...] Read more.
Iron–sulfur clusters are essential to almost every life form and utilized for their unique structural and redox-targeted activities within cells during many cellular pathways. Although there are three different Fe–S cluster assembly pathways in prokaryotes (the NIF, SUF and ISC pathways) and two in eukaryotes (CIA and ISC pathways), the iron–sulfur cluster (ISC) pathway serves as the central mechanism for providing 2Fe–2S clusters, directly and indirectly, throughout the entire cell in eukaryotes. Proteins central to the eukaryotic ISC cluster assembly complex include the cysteine desulfurase, a cysteine desulfurase accessory protein, the acyl carrier protein, the scaffold protein and frataxin (in humans, NFS1, ISD11, ACP, ISCU and FXN, respectively). Recent molecular details of this complex (labeled NIAUF from the first letter from each ISC protein outlined earlier), which exists as a dimeric pentamer, have provided real structural insight into how these partner proteins arrange themselves around the cysteine desulfurase, the core dimer of the (NIAUF)2 complex. In this review, we focus on both frataxin and the scaffold within the human, fly and yeast model systems to provide a better understanding of the biophysical characteristics of each protein alone and within the FXN/ISCU complex as it exists within the larger NIAUF construct. These details support a complex dynamic interaction between the FXN and ISCU proteins when both are part of the NIAUF complex and this provides additional insight into the coordinated mechanism of Fe–S cluster assembly. Full article
(This article belongs to the Special Issue Iron-Sulfur Clusters and Proteins)
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