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Oxidation of human copper chaperone Atox1 and disulfide bond cleavage by cisplatin and glutathione

DOI: 10.3390/ijms20184390 DOI Help

Authors: Maria I. Nardella (University of Bari) , Antonio Rosato (University of Bari) , Benny D. Belviso (CNR) , Rocco Caliandro (CNR) , Giovanni Natile (University of Bari) , Fabio Arnesano (University of Bari)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: International Journal Of Molecular Sciences , VOL 20

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 15832

Open Access Open Access

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., 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.

Journal Keywords: copper; cisplatin; Atox1; disulfide bond; metallochaperones; oxidative stress

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF