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Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis 2.0

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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 13550

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Dr. Francesca Cantini

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1. Magnetic Resonance Center, University of Florence, Sesto Fiorentino, 50019 Firenze, Italy
2. Department of Chemistry, University of Florence, Sesto Fiorentino, 50019 Firenze, Italy
Interests: protein higher order structure; structural biology; solution NMR; protein-small molecules interaction; protein-protein interaction
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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

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Published Papers (4 papers)

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Research

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19 pages, 2157 KiB

Open AccessArticle

A Deeper Insight in Metal Binding to the hCtr1 N-terminus Fragment: Affinity, Speciation and Binding Mode of Binuclear Cu²⁺ and Mononuclear Ag⁺ Complex Species

by Antonio Magrì, Giovanni Tabbì, Irina Naletova, Francesco Attanasio, Giuseppe Arena and Enrico Rizzarelli

Int. J. Mol. Sci. 2022, 23(6), 2929; https://doi.org/10.3390/ijms23062929 - 08 Mar 2022

Cited by 7 | Viewed by 1627

Abstract

Ctr1 regulates copper uptake and its intracellular distribution. The first 14 amino acid sequence of the Ctr1 ectodomain Ctr1_(1-14) encompasses the characteristic Amino Terminal Cu²⁺ and Ni²⁺ binding motif (ATCUN) as well as the bis-His binding motif (His5 and His6). We report a combined thermodynamic and spectroscopic (UV-vis, CD, EPR) study dealing with the formation of Cu²⁺ homobinuclear complexes with Ctr1_(1-14), the percentage of which is not negligible even in the presence of a small Cu²⁺ excess and clearly prevails at a M/L ratio of 1.9. Ascorbate fails to reduce Cu²⁺ when bound to the ATCUN motif, while it reduces Cu²⁺ when bound to the His5-His6 motif involved in the formation of binuclear species. The histidine diade characterizes the second binding site and is thought to be responsible for ascorbate oxidation. Binding constants and speciation of Ag⁺ complexes with Ctr1_(1-14), which are assumed to mimic Cu⁺ interaction with N-terminus of Ctr1_(1-14), were also determined. A preliminary immunoblot assay evidences that the anti-Ctr1 extracellular antibody recognizes Ctr1_(1-14) in a different way from the longer Ctr1_(1-25) that encompasses a second His and Met rich domain. Full article

(This article belongs to the Special Issue Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis 2.0)

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21 pages, 6168 KiB

Open AccessArticle

Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells

by Ssu-Yu Chen, Yung-Lung Chang, Shu-Ting Liu, Gunng-Shinng Chen, Shiao-Pieng Lee and Shih-Ming Huang

Int. J. Mol. Sci. 2021, 22(7), 3711; https://doi.org/10.3390/ijms22073711 - 02 Apr 2021

Cited by 22 | Viewed by 2690

Abstract

Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We explored the potential mechanism behind the cytotoxicity of DSF-Cu⁺/Cu²⁺ complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl₂ or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu⁺/Cu²⁺ induced cell death in OECM-1 cells, but not SG cells. DSF-Cu⁺/Cu²⁺ also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu⁺/Cu²⁺ in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu⁺/Cu²⁺-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu⁺/Cu²⁺ induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl₂ increased but DSF- Cu²⁺ impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl₂ stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu⁺/Cu²-treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl₂ complex as a repurposed agent for OSCC cancer therapy. Full article

(This article belongs to the Special Issue Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis 2.0)

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Review

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14 pages, 1346 KiB

Open AccessReview

Copper as a Collaborative Partner of Zinc-Induced Neurotoxicity in the Pathogenesis of Vascular Dementia

by Masahiro Kawahara, Ken-ichiro Tanaka and Midori Kato-Negishi

Int. J. Mol. Sci. 2021, 22(14), 7242; https://doi.org/10.3390/ijms22147242 - 06 Jul 2021

Cited by 10 | Viewed by 3123

Abstract

Copper is an essential trace element and possesses critical roles in various brain functions. A considerable amount of copper accumulates in the synapse and is secreted in neuronal firings in a manner similar to zinc. Synaptic copper and zinc modulate neuronal transmission and contribute to information processing. It has been established that excess zinc secreted during transient global ischemia plays central roles in ischemia-induced neuronal death and the pathogenesis of vascular dementia. We found that a low concentration of copper exacerbates zinc-induced neurotoxicity, and we have demonstrated the involvement of the endoplasmic reticulum (ER) stress pathway, the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) signaling pathway, and copper-induced reactive oxygen species (ROS) production. On the basis of our results and other studies, we discuss the collaborative roles of copper in zinc-induced neurotoxicity in the synapse and the contribution of copper to the pathogenesis of vascular dementia. Full article

(This article belongs to the Special Issue Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis 2.0)

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23 pages, 2038 KiB

Open AccessReview

Advances in Understanding of the Copper Homeostasis in Pseudomonas aeruginosa

by Lukas Hofmann, Melanie Hirsch and Sharon Ruthstein

Int. J. Mol. Sci. 2021, 22(4), 2050; https://doi.org/10.3390/ijms22042050 - 19 Feb 2021

Cited by 13 | Viewed by 5143

Abstract

Thirty-five thousand people die as a result of more than 2.8 million antibiotic-resistant infections in the United States of America per year. Pseudomonas aeruginosa (P. aeruginosa) is classified a serious threat, the second-highest threat category of the U.S. Department of Health and Human Services. Among others, the World Health Organization (WHO) encourages the discovery and development of novel antibiotic classes with new targets and mechanisms of action without cross-resistance to existing classes. To find potential new target sites in pathogenic bacteria, such as P. aeruginosa, it is inevitable to fully understand the molecular mechanism of homeostasis, metabolism, regulation, growth, and resistances thereof. P. aeruginosa maintains a sophisticated copper defense cascade comprising three stages, resembling those of public safety organizations. These stages include copper scavenging, first responder, and second responder. Similar mechanisms are found in numerous pathogens. Here we compare the copper-dependent transcription regulators cueR and copRS of Escherichia coli (E. coli) and P. aeruginosa. Further, phylogenetic analysis and structural modelling of mexPQ-opmE reveal that this efflux pump is unlikely to be involved in the copper export of P. aeruginosa. Altogether, we present current understandings of the copper homeostasis in P. aeruginosa and potential new target sites for antimicrobial agents or a combinatorial drug regimen in the fight against multidrug resistant pathogens. Full article

(This article belongs to the Special Issue Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis 2.0)

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