The copper chaperone CCS facilitates copper binding to MEK1/2 to promote kinase activation

Human copper transporters ATP7B (Wilson's disease protein) and ATP7A (Menkes' disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N-terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A.

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A putative nuclear copper chaperone promotes plant immunity in Arabidopsis

Journal of Experimental Botany ◽

10.1093/jxb/eraa401 ◽

2020 ◽

Vol 71 (20) ◽

pp. 6684-6696 ◽

Cited By ~ 1

Author(s):

Long-Xiang Chai ◽

Kai Dong ◽

Song-Yu Liu ◽

Zhen Zhang ◽

Xiao-Peng Zhang ◽

...

Keyword(s):

Pseudomonas Syringae ◽

Plant Immunity ◽

Copper Chaperone ◽

Copper Binding ◽

Nuclear Speckles ◽

Defense Gene Expression ◽

Copper Chaperones ◽

Plant Nucleus

Abstract Copper is essential for many metabolic processes but must be sequestrated by copper chaperones. It is well known that plant copper chaperones regulate various physiological processes. However, the functions of copper chaperones in the plant nucleus remain largely unknown. Here, we identified a putative copper chaperone induced by pathogens (CCP) in Arabidopsis thaliana. CCP harbors a classical MXCXXC copper-binding site (CBS) at its N-terminus and a nuclear localization signal (NLS) at its C-terminus. CCP mainly formed nuclear speckles in the plant nucleus, which requires the NLS and CBS domains. Overexpression of CCP induced PR1 expression and enhanced resistance against Pseudomonas syringae pv. tomato DC3000 compared with Col-0 plants. Conversely, two CRISPR/Cas9-mediated ccp mutants were impaired in plant immunity. Further biochemical analyses revealed that CCP interacted with the transcription factor TGA2 in vivo and in vitro. Moreover, CCP recruits TGA2 to the PR1 promoter sequences in vivo, which induces defense gene expression and plant immunity. Collectively, our results have identified a putative nuclear copper chaperone required for plant immunity and provided evidence for a potential function of copper in the salicylic pathway.

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Copper binding modulates the platination of human copper chaperone Atox1 by antitumor trans-platinum complexes

Metallomics ◽

10.1039/c3mt00338h ◽

2014 ◽

Vol 6 (3) ◽

pp. 491-497 ◽

Cited By ~ 9

Author(s):

Zhaoyong Xi ◽

Wei Guo ◽

Changlin Tian ◽

Fuyi Wang ◽

Yangzhong Liu

Keyword(s):

Platinum Complexes ◽

Copper Chaperone ◽

Copper Binding

Cu(i) coordination enhances the reactivity of Atox1 towards antitumor-active trans-platinum complexes and promotes platinum transfer from the protein to dithiothreitol.

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Copper binding promotes the interaction of cisplatin with human copper chaperone Atox1

Chemical Communications ◽

10.1039/c3cc45905e ◽

2013 ◽

Vol 49 (95) ◽

pp. 11197 ◽

Cited By ~ 31

Author(s):

Zhaoyong Xi ◽

Wei Guo ◽

Changlin Tian ◽

Fuyi Wang ◽

Yangzhong Liu

Keyword(s):

Copper Chaperone ◽

Copper Binding

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Selenocysteine Positional Variants Reveal Contributions to Copper Binding from Cysteine Residues in Domains 2 and 3 of Human Copper Chaperone for Superoxide Dismutase†

Biochemistry ◽

10.1021/bi801438g ◽

2008 ◽

Vol 47 (49) ◽

pp. 13074-13083 ◽

Cited By ~ 11

Author(s):

Amanda N. Barry ◽

Kevin M. Clark ◽

Adenike Otoikhian ◽

Wilfred A. van der Donk ◽

Ninian J. Blackburn

Keyword(s):

Superoxide Dismutase ◽

Cysteine Residues ◽

Copper Chaperone ◽

Copper Binding

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Copper-mediated dimerization of CopZ, a predicted copper chaperone from Bacillus subtilis

Biochemical Journal ◽

10.1042/bj20021036 ◽

2002 ◽

Vol 368 (3) ◽

pp. 729-739 ◽

Cited By ~ 45

Author(s):

Margaret A. KIHLKEN ◽

Andrew P. LEECH ◽

Nick E. LE BRUN

Keyword(s):

Bacillus Subtilis ◽

Metal Binding ◽

Metal Ion ◽

Complex Nature ◽

Binding Motif ◽

Copper Chaperone ◽

Ion Transfer ◽

Copper Binding ◽

Binding Properties ◽

In The Wild

Understanding the metal-binding properties and solution states of metallo-chaperones is a key step in understanding how they function in metal ion transfer. Using spectroscopic, bioanalytical and biochemical methods, we have investigated the copper-binding properties and association states of the putative copper chaperone of Bacillus subtilis, CopZ, and a variant of the protein lacking the two cysteine residues of the MXCXXC copper-binding motif. We show that copper-free CopZ exists as a monomer, but that addition of copper(I) causes the protein to associate into homodimers. The nature of the copper(I)—CopZ complex is dependent on the level of copper loading, and we report the detection of three distinct forms, containing 0.5, 1.0 and 1.5 copper(I) ions per protein. The presence of excess dithiothreitol has a significant effect on copper(I) binding to CopZ, such that, in its presence, copper(I)—CopZ occurs mainly as a monomer species. Data for copper binding to the double-cysteine variant of CopZ are consistent with an essential role for these residues in tight copper binding in the wild-type protein. We conclude that the complex nature of copper(I) binding to CopZ may underpin mechanisms of protein-to-protein copper(I) transfer.

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The YcnI protein from Bacillus subtilis contains a copper-binding domain

10.1101/2021.06.11.448128 ◽

2021 ◽

Author(s):

Madhura S Damle ◽

Stephen C Peters ◽

Veronika A Szalai ◽

Oriana S. Fisher

Keyword(s):

Bacillus Subtilis ◽

Inductively Coupled Plasma ◽

Copper Ions ◽

Bacterial Species ◽

Copper Homeostasis ◽

Copper Chaperone ◽

Copper Binding ◽

Bioinformatics Analyses ◽

Paramagnetic Resonance ◽

X Ray Crystallography

Bacteria require a precise balance of copper ions to ensure that essential cuproproteins are fully metalated while also avoiding copper-induced toxicity. The Gram positive bacterium Bacillus subtilis maintains appropriate copper homeostasis in part through its ycn operon. The ycn operon comprises genes encoding three proteins: the putative copper importer YcnJ, the copper-dependent transcriptional repressor YcnK, and the uncharacterized DUF1775 domain-containing YcnI. DUF1775 domains are found across bacterial phylogeny and bioinformatics analyses indicate that they frequently neighbor domains implicated in copper homeostasis and transport. Here, we investigated whether YcnI can interact with copper and, using electron paramagnetic resonance (EPR) and inductively-coupled plasma-mass spectrometry (ICP-MS) find that it can bind a single Cu(II) ion. We determine the structure of both the apo and copper-bound forms of the protein by X-ray crystallography, uncovering a copper binding site featuring a unique mono-histidine brace ligand set that is highly conserved among DUF1775 domains. These data suggest a possible role for YcnI as a copper chaperone and that DUF1775 domains in other bacterial species may also function in copper homeostasis.

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Evaluation of copper chaperone ATOX1 as prognostic biomarker in breast cancer

Breast Cancer ◽

10.1007/s12282-019-01044-4 ◽

2020 ◽

Vol 27 (3) ◽

pp. 505-509 ◽

Cited By ~ 5

Author(s):

Stéphanie Blockhuys ◽

Donita C. Brady ◽

Pernilla Wittung-Stafshede

Keyword(s):

Breast Cancer ◽

Prognostic Biomarker ◽

Clinicopathological Parameters ◽

Copper Chaperone ◽

Copper Binding ◽

Breast Cancer Patients ◽

Cancer Disease ◽

Data Set ◽

Expression Levels ◽

Er Positive

AbstractCopper is involved in different hallmarks of cancer, including metastasis, but responsible copper-binding proteins and pathways are not clear. The copper chaperone ATOX1 was recently shown to play a role in breast cancer cell migration, which is a key step in metastasis. Since most cancer-related deaths are due to metastasis, we hypothesized that ATOX1 mRNA expression may be associated with breast cancer disease progression and thus, a prognostic biomarker in breast cancer. We therefore studied the association of ATOX1 expression levels with clinicopathological parameters and survival for 1904 breast cancer patients using the METABRIC data set. Our results indicate ATOX1 expression levels as a potential prognostic biomarker for ER-positive subtypes and early stages of breast cancer. Pre-clinical studies and clinical trials are desired to identify the molecular roles of ATOX1 in these conditions.

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Regulation of the Copper Chaperone CCS by XIAP-Mediated Ubiquitination

Molecular and Cellular Biology ◽

10.1128/mcb.00900-09 ◽

2010 ◽

Vol 30 (8) ◽

pp. 1923-1936 ◽

Cited By ~ 48

Author(s):

Graham F. Brady ◽

Stefanie Galbán ◽

Xuwen Liu ◽

Venkatesha Basrur ◽

Jonathan D. Gitlin ◽

...

Keyword(s):

Superoxide Dismutase ◽

Ubiquitin Ligase ◽

Redox Regulation ◽

Copper Metabolism ◽

Copper Chaperone ◽

Copper Binding ◽

Superoxide Dismutase 1 ◽

Ubiquitin Ligase Activity ◽

Copper Binding Protein ◽

Copper Delivery

ABSTRACT In order to balance the cellular requirements for copper with its toxic properties, an elegant set of mechanisms has evolved to regulate and buffer intracellular copper. The X-linked inhibitor of apoptosis (XIAP) protein was recently identified as a copper-binding protein and regulator of copper homeostasis, although the mechanism by which XIAP binds copper in the cytosol is unclear. Here we describe the identification of the copper chaperone for superoxide dismutase (CCS) as a mediator of copper delivery to XIAP in cells. We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP, although interestingly, ubiquitination of CCS by XIAP was found to lead to enhancement of its chaperone activity toward its physiologic target, superoxide dismutase 1, rather than proteasomal degradation. Collectively, our results reveal novel links among apoptosis, copper metabolism, and redox regulation through the XIAP-CCS complex.

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Copper binding and reactivity at the histidine brace motif: insights from mutational analysis of the Pseudomonas fluorescens copper chaperone CopC

FEBS Letters ◽

10.1002/1873-3468.14092 ◽

2021 ◽

Author(s):

Johan Ø. Ipsen ◽

Cristina Hernández‐Rollán ◽

Sebastian J. Muderspach ◽

Søren Brander ◽

Andreas B. Bertelsen ◽

...

Keyword(s):

Pseudomonas Fluorescens ◽

Mutational Analysis ◽

Copper Chaperone ◽

Copper Binding

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