scholarly journals The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin

2009 ◽  
Vol 419 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Nataliya V. Dolgova ◽  
Doug Olson ◽  
Svetlana Lutsenko ◽  
Oleg Y. Dmitriev
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Active Drug ◽  
Binding Domain ◽  
Copper Binding ◽  
Protein Fragment ◽  
Copper Transporter ◽  
Metal Binding Domain ◽  
Cell Expression

Wilson disease ATPase (ATP7B) has been implicated in the resistance of cancer cells to cisplatin. Using a simple in vivo assay in bacterial culture, in the present study we demonstrate that ATP7B can confer resistance to cisplatin by sequestering the drug in its N-terminal metal-binding domain without active drug extrusion from the cell. Expression of a protein fragment containing four N-terminal MBRs (metal-binding repeats) of ATP7B (MBR1–4) protects cells from the toxic effects of cisplatin. One MBR1–4 molecule binds up to three cisplatin molecules at the copper-binding sites in the MBRs. The findings of the present study suggest that suppressing enzymatic activity of ATP7B may not be an effective way of combating cisplatin resistance. Rather, the efforts should be directed at preventing cisplatin binding to the protein.

Mechanism of tumor resistance to cisplatin mediated by the copper transporter ATP7BThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 138-147 ◽  
Author(s):  
Oleg Y. Dmitriev
Keyword(s):  
Metal Binding ◽  
Peer Review Process ◽  
Alternative Mechanism ◽  
Copper Binding ◽  
Cancer Resistance ◽  
Tumor Resistance ◽  
Copper Transporter ◽  
Metal Binding Domain ◽  
Disease Protein

The Wilson disease protein (ATP7B) is a copper-transporting ATPase that is responsible for regulating copper homeostasis in human tissues. ATP7B is associated with cancer resistance to cisplatin, one of the most widely used anticancer drugs. This minireview discusses the possible mechanisms of tumor resistance to cisplatin mediated by ATP7B. Cisplatin binds to the N-terminal cytosolic domain of ATP7B, which contains multiple copper-binding sites. Active platinum efflux catalyzed by ATP7B is unlikely to significantly contribute to cisplatin resistance in vivo. Transient platinum sequestration in the metal-binding domain followed by transfer to an acceptor protein or a low molecular weight compound is proposed as an alternative mechanism of cisplatin detoxification in the cell.

Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification

2013 ◽  
Vol 454 (1) ◽  
pp. 147-156 ◽  
Author(s):  
Nataliya V. Dolgova ◽  
Sergiy Nokhrin ◽  
Corey H. Yu ◽  
Graham N. George ◽  
Oleg Y. Dmitriev
Keyword(s):  
Metal Binding ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Binding Domain ◽  
Binding Motif ◽  
Copper Chaperone ◽  
Copper Binding ◽  
Copper Transporters ◽  
Metal Binding Domain ◽  
Disease Protein

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.

Expression, purification and copper-binding studies of the first metal-binding domain of Menkes protein

1999 ◽  
Vol 264 (3) ◽  
pp. 890-896 ◽  
Author(s):  
Pia Y. Jensen ◽  
Nicklas Bonander ◽  
Nina Horn ◽  
Zeynep Tumer ◽  
Ole Farver
Keyword(s):  
Metal Binding ◽  
Binding Domain ◽  
Copper Binding ◽  
Binding Studies ◽  
Metal Binding Domain ◽  
Menkes Protein

In silico modeling of the Menkes copper-translocating P-type ATPase 3rd metal binding domain predicts that phosphorylation regulates copper-binding

BioMetals ◽  
2011 ◽  
Vol 24 (3) ◽  
pp. 477-487 ◽  
Author(s):  
N. A. Veldhuis ◽  
M. J. Kuiper ◽  
R. C. J. Dobson ◽  
R. B. Pearson ◽  
J. Camakaris
Keyword(s):  
Metal Binding ◽  
In Silico ◽  
Binding Domain ◽  
Copper Binding ◽  
Metal Binding Domain ◽  
In Silico Modeling ◽  
P Type

Copper and Zinc Promote Interactions between Membrane-Anchored Peptides of the Metal Binding Domain of the Prion Protein†

Biochemistry ◽  
2007 ◽  
Vol 46 (14) ◽  
pp. 4261-4271 ◽  
Author(s):  
Angela G. Kenward ◽  
Libero J. Bartolotti ◽  
Colin S. Burns
Keyword(s):  
Prion Protein ◽  
Metal Binding ◽  
Binding Domain ◽  
Copper And Zinc ◽  
Metal Binding Domain

The βE-Domain of Wheat Ec-1 Metallothionein: A Metal-Binding Domain with a Distinctive Structure

2009 ◽  
Vol 387 (1) ◽  
pp. 207-218 ◽  
Author(s):  
Estevão A. Peroza ◽  
Roland Schmucki ◽  
Peter Güntert ◽  
Eva Freisinger ◽  
Oliver Zerbe
Keyword(s):  
Metal Binding ◽  
Binding Domain ◽  
Metal Binding Domain ◽  
Distinctive Structure

scholarly journals A possible regulatory role for the metal-binding domain of CadA, the Listeria monocytogenes Cd2+ -ATPase

FEBS Letters ◽  
2001 ◽  
Vol 506 (3) ◽  
pp. 249-252 ◽  
Author(s):  
Nathalie Bal ◽  
Elisabeth Mintz ◽  
Florent Guillain ◽  
Patrice Catty
Keyword(s):  
Listeria Monocytogenes ◽  
Metal Binding ◽  
Binding Domain ◽  
Regulatory Role ◽  
Metal Binding Domain
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