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Special Issue "Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis"

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 (20 June 2019).

Special Issue Editor

Dr. Francesca Cantini
Website
Guest Editor
Magnetic Resonance Center (CERM)–University of Florence, Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy, and Department of Chemistry–University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
Interests: structural biology; solution NMR; protein structure determination by NMR; protein-small molecules interaction; protein-protein interaction; metalloproteins; metal homeostasis
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Special Issue Information

Dear Colleagues,

Copper is an essential transition metal ion found in many key human enzymes. Its ability to assume distinct redox states by cycling between oxidized copper(II) and reduced copper(I) makes copper an appropriate cofactor in proteins, showing a wide range of catalytic functions, such as reactive oxygen species detoxification, electron transfer and mitochondrial functions. Copper redox properties can also lead to cellular oxidative damage when it is found in excess concentrations. Copper can participate in reactions that lead to the production of highly-reactive oxidative species, which cause DNA damage and oxidation of proteins and lipids. Moreover, the ability of copper to bind at sites of other metal ions can have devastating effects for various cellular functions. In order to prevent the binding of the “wrong” copper ion, cells have developed very efficient homeostatic and trafficking mechanisms. Thus, copper distribution, exploitation and excretion is tightly regulated in cells. Molecular recognition by protein–protein interactions efficiently guarantees the correct delivery of copper to Cu-dependent enzymes.

This Special Issue, "Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis", will be comprised of original research papers and reviews covering various aspects of the field. An overview on copper proteins will be considered, and original papers aim to unravel the precise molecular nature of copper within different cellular compartments are welcome. Contributions that show recent advances in maturation of copper proteins and copper homeostasis processes will be also considered.

Dr. Francesca Cantini
Guest Editor

Manuscript Submission Information

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Published Papers (7 papers)

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Research

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Open AccessArticle
Oxidation of Human Copper Chaperone Atox1 and Disulfide Bond Cleavage by Cisplatin and Glutathione
Int. J. Mol. Sci. 2019, 20(18), 4390; https://doi.org/10.3390/ijms20184390 - 06 Sep 2019
Abstract
Cancer cells cope with high oxidative stress levels, characterized by a shift toward the oxidized form (GSSG) of glutathione (GSH) in the redox couple GSSG/2GSH. Under these conditions, the cytosolic copper chaperone Atox1, which delivers Cu(I) to the secretory pathway, gets oxidized, i.e., [...] Read more.
Cancer cells cope with high oxidative stress levels, characterized by a shift toward the oxidized form (GSSG) of glutathione (GSH) in the redox couple GSSG/2GSH. Under these conditions, the cytosolic copper chaperone Atox1, which delivers Cu(I) to the secretory pathway, gets oxidized, i.e., a disulfide bond is formed between the cysteine residues of the Cu(I)-binding CxxC motif. Switching to the covalently-linked form, sulfur atoms are not able to bind the Cu(I) ion and Atox1 cannot play an antioxidant role. Atox1 has also been implicated in the resistance to platinum chemotherapy. In the presence of excess GSH, the anticancer drug cisplatin binds to Cu(I)-Atox1 but not to the reduced apoprotein. With the aim to investigate the interaction of cisplatin with the disulfide form of the protein, we performed a structural characterization in solution and in the solid state of oxidized human Atox1 and explored its ability to bind cisplatin under conditions mimicking an oxidizing environment. Cisplatin targets a methionine residue of oxidized Atox1; however, in the presence of GSH as reducing agent, the drug binds irreversibly to the protein with ammine ligands trans to Cys12 and Cys15. The results are discussed with reference to the available literature data and a mechanism is proposed connecting platinum drug processing to redox and copper homeostasis. Full article
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Open AccessArticle
Cytosolic Copper Binding by a Bacterial Storage Protein and Interplay with Copper Efflux
Int. J. Mol. Sci. 2019, 20(17), 4144; https://doi.org/10.3390/ijms20174144 - 25 Aug 2019
Cited by 1
Abstract
Escherichia coli has a well-characterized copper (Cu) transporting ATPase (CopA) that removes this potentially toxic metal ion from the cytosol. Growth of the strain lacking CopA (ΔcopA) is inhibited above 0.5 mM Cu, whilst a similar effect does not occur in [...] Read more.
Escherichia coli has a well-characterized copper (Cu) transporting ATPase (CopA) that removes this potentially toxic metal ion from the cytosol. Growth of the strain lacking CopA (ΔcopA) is inhibited above 0.5 mM Cu, whilst a similar effect does not occur in wild type (WT) E. coli until over 2.5 mM Cu. Limited expression of CopA can restore growth to WT levels in ΔcopA E. coli in the presence of Cu. To study the influence of a bacterial cytosolic Cu storage protein (Csp3) on how E. coli handles Cu, the protein from Bacillus subtilis (BsCsp3) has been overexpressed in the WT and ΔcopA strains. BsCsp3 can protect both strains from Cu toxicity, promoting growth at up to ~1.5 and ~3.5 mM Cu, respectively. Higher levels of Csp3 expression are needed to provide resistance to Cu toxicity in ΔcopA E. coli. At 1.5 mM Cu, BsCsp3 purified from ΔcopA E. coli binds up to approximately four equivalents of Cu(I) per monomer. A similar number of Cu(I) equivalents can be bound by BsCsp3 purified from WT E. coli also grown at 1.5 mM Cu, a concentration that does not cause toxicity in this strain. Much lower amounts of BsCsp3 are produced in WT E. coli grown in the presence of 3.4 mM Cu, but the protein still counteracts toxicity and is almost half loaded with Cu(I). Csp3s can protect E. coli from Cu toxicity by sequestering cuprous ions in the cytosol. This appears to include an ability to acquire and withhold Cu(I) from the main efflux system in a heterologous host. Full article
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Open AccessArticle
Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins
Int. J. Mol. Sci. 2019, 20(14), 3462; https://doi.org/10.3390/ijms20143462 - 14 Jul 2019
Cited by 4
Abstract
Appropriate maintenance of Cu(I) homeostasis is an essential requirement for proper cell function because its misregulation induces the onset of major human diseases and mortality. For this reason, several research efforts have been devoted to dissecting the inner working mechanism of Cu(I)-binding proteins [...] Read more.
Appropriate maintenance of Cu(I) homeostasis is an essential requirement for proper cell function because its misregulation induces the onset of major human diseases and mortality. For this reason, several research efforts have been devoted to dissecting the inner working mechanism of Cu(I)-binding proteins and transporters. A commonly adopted strategy relies on mutations of cysteine residues, for which Cu(I) has an exquisite complementarity, to serines. Nevertheless, in spite of the similarity between these two amino acids, the structural and functional impact of serine mutations on Cu(I)-binding biomolecules remains unclear. Here, we applied various biochemical and biophysical methods, together with all-atom simulations, to investigate the effect of these mutations on the stability, structure, and aggregation propensity of Cu(I)-binding proteins, as well as their interaction with specific partner proteins. Among Cu(I)-binding biomolecules, we focused on the eukaryotic Atox1-ATP7B system, and the prokaryotic CueR metalloregulator. Our results reveal that proteins containing cysteine-to-serine mutations can still bind Cu(I) ions; however, this alters their stability and aggregation propensity. These results contribute to deciphering the critical biological principles underlying the regulatory mechanism of the in-cell Cu(I) concentration, and provide a basis for interpreting future studies that will take advantage of cysteine-to-serine mutations in Cu(I)-binding systems. Full article
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Open AccessArticle
The Role of the CopA Copper Efflux System in Acinetobacter baumannii Virulence
Int. J. Mol. Sci. 2019, 20(3), 575; https://doi.org/10.3390/ijms20030575 - 29 Jan 2019
Cited by 8
Abstract
Acinetobacter baumannii has emerged as one of the leading causative agents of nosocomial infections. Due to its high level of intrinsic and adapted antibiotic resistance, treatment failure rates are high, which allows this opportunistic pathogen to thrive during infection in immune-compromised patients. A. [...] Read more.
Acinetobacter baumannii has emerged as one of the leading causative agents of nosocomial infections. Due to its high level of intrinsic and adapted antibiotic resistance, treatment failure rates are high, which allows this opportunistic pathogen to thrive during infection in immune-compromised patients. A. baumannii can cause infections within a broad range of host niches, with pneumonia and bacteraemia being associated with the greatest levels of morbidity and mortality. Although its resistance to antibiotics is widely studied, our understanding of the mechanisms required for dealing with environmental stresses related to virulence and hospital persistence, such as copper toxicity, is limited. Here, we performed an in silico analysis of the A. baumannii copper resistome, examining its regulation under copper stress. Using comparative analyses of bacterial P-type ATPases, we propose that A. baumannii encodes a member of a novel subgroup of P1B-1 ATPases. Analyses of three putative inner membrane copper efflux systems identified the P1B-1 ATPase CopA as the primary mediator of cytoplasmic copper resistance in A. baumannii. Using a murine model of A. baumannii pneumonia, we reveal that CopA contributes to the virulence of A. baumannii. Collectively, this study advances our understanding of how A. baumannii deals with environmental copper toxicity, and it provides novel insights into how A. baumannii combats adversities encountered as part of the host immune defence. Full article
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Review

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Open AccessReview
Biochemistry of Copper Site Assembly in Heme-Copper Oxidases: A Theme with Variations
Int. J. Mol. Sci. 2019, 20(15), 3830; https://doi.org/10.3390/ijms20153830 - 05 Aug 2019
Cited by 4
Abstract
Copper is an essential cofactor for aerobic respiration, since it is required as a redox cofactor in Cytochrome c Oxidase (COX). This ancient and highly conserved enzymatic complex from the family of heme-copper oxidase possesses two copper sites: CuA and CuB [...] Read more.
Copper is an essential cofactor for aerobic respiration, since it is required as a redox cofactor in Cytochrome c Oxidase (COX). This ancient and highly conserved enzymatic complex from the family of heme-copper oxidase possesses two copper sites: CuA and CuB. Biosynthesis of the oxidase is a complex, stepwise process that requires a high number of assembly factors. In this review, we summarize the state-of-the-art in the assembly of COX, with special emphasis in the assembly of copper sites. Assembly of the CuA site is better understood, being at the same time highly variable among organisms. We also discuss the current challenges that prevent the full comprehension of the mechanisms of assembly and the pending issues in the field. Full article
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Open AccessReview
Copper Utilization, Regulation, and Acquisition by Aspergillus fumigatus
Int. J. Mol. Sci. 2019, 20(8), 1980; https://doi.org/10.3390/ijms20081980 - 23 Apr 2019
Cited by 7
Abstract
Copper is an essential micronutrient for the opportunistic human pathogen, Aspergillus fumigatus. Maintaining copper homeostasis is critical for survival and pathogenesis. Copper-responsive transcription factors, AceA and MacA, coordinate a complex network responsible for responding to copper in the environment and determining which [...] Read more.
Copper is an essential micronutrient for the opportunistic human pathogen, Aspergillus fumigatus. Maintaining copper homeostasis is critical for survival and pathogenesis. Copper-responsive transcription factors, AceA and MacA, coordinate a complex network responsible for responding to copper in the environment and determining which response is necessary to maintain homeostasis. For example, A. fumigatus uses copper exporters to mitigate the toxic effects of copper while simultaneously encoding copper importers and small molecules to ensure proper supply of the metal for copper-dependent processes such a nitrogen acquisition and respiration. Small molecules called isocyanides recently found to be produced by A. fumigatus may bind copper and partake in copper homeostasis similarly to isocyanide copper chelators in bacteria. Considering that the host uses copper as a microbial toxin and copper availability fluctuates in various environmental niches, understanding how A. fumigatus maintains copper homeostasis will give insights into mechanisms that facilitate the development of invasive aspergillosis and its survival in nature. Full article
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Open AccessReview
The Role of Copper Homeostasis at the Host-Pathogen Axis: From Bacteria to Fungi
Int. J. Mol. Sci. 2019, 20(1), 175; https://doi.org/10.3390/ijms20010175 - 05 Jan 2019
Cited by 13
Abstract
Copper is an essential trace element participating in many vital biological processes, however it becomes a toxic agent when in excess. Thus, precise and tight regulation of copper homeostasis processes, including transport, delivery, storage, detoxification, and efflux machineries, is important, ensuring that only [...] Read more.
Copper is an essential trace element participating in many vital biological processes, however it becomes a toxic agent when in excess. Thus, precise and tight regulation of copper homeostasis processes, including transport, delivery, storage, detoxification, and efflux machineries, is important, ensuring that only the amount needed to sustain basic biological functions and simultaneously prevent copper toxicity in the cell is maintained. Numerous exciting studies have revealed that copper plays an indispensable role at the microbial pathogen-host axis for entities ranging from pathogenic bacteria to deadly fungal species. Analyses of copper homeostases in bacteria and fungi extensively demonstrate that copper is utilized by the host immune system as an anti-microbial agent. The expression of copper efflux and detoxification from microbial pathogens is induced to counteract the host’s copper bombardment, which in turn disrupts these machineries, resulting in the attenuation of microbial survival in host tissue. We hereby review the latest work in copper homeostases in pathogenic bacteria and fungi and focus on the maintenance of a copper balance at the pathogen-host interaction axis. Full article
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