Interaction between Platinum Complexes and a Methionine Motif Found in Copper Transport Proteins

Arnesano, Fabio; Scintilla, Simone; Natile, Giovanni

doi:10.1002/ange.200703271

Cited by 28 publications

(27 citation statements)

References 21 publications

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“…Alternatively, Cu(I) thiolation may induce conformational changes that bring the essential amino acid residues into close proximity, creating an intermolecular surface that allows Cu(I) to permeate into the cytoplasmic compartment. Previous in vitro assays demonstrated that bindings of Cu(I) (Hassett and Kosman, 1995) and CDDP (Arnesano et al, 2007) to methionine-rich motifs require completely naked forms of the metal ions. The interaction of CDDP with methionine, like Cu(I), was mostly by means of S-thiolation (Borch and Pleasants, 1979;Guo et al, 2004;Arnesano et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Previous in vitro assays demonstrated that bindings of Cu(I) (Hassett and Kosman, 1995) and CDDP (Arnesano et al, 2007) to methionine-rich motifs require completely naked forms of the metal ions. The interaction of CDDP with methionine, like Cu(I), was mostly by means of S-thiolation (Borch and Pleasants, 1979;Guo et al, 2004;Arnesano et al, 2007). We demonstrated that both methionine mutations and membrane localization of hCtr1 are required for the dominant negative function for Cu(I) and CDDP transport.…”

Section: Discussionmentioning

confidence: 99%

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Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Zheng¹,

Stockton

Savaraj³

et al. 2009

Mol Pharmacol

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The human high-affinity copper transporter (hCtr1) plays an important role in the regulation of intracellular copper homeostasis. hCtr1 is involved in the transport of platinum-based antitumor agents such as cisplatin (CDDP); however, the mechanisms that regulate hCtr1-mediated transport of these agents have not been well elucidated. We compared the mechanisms of hCtr1-mediated transport of copper and CDDP. We found that replacements of several methionine residues that are essential for hCtr1-mediated copper transport conferred a dominant-negative effect on the endogenous hCtr1's function, resulting in reduced rates of Cu(I) and CDDP transport and increased resistance to the toxicities of copper and CDDP treatments. Kinetic constant analyses revealed that although these mutations reduced maximal transport rates (V max ) for Cu(I) and CDDP, reduction of K m only for Cu(I) but not for CDDP was observed. Mutation in Gly167, which is located in the third transmembrane domain and is involved in helix packing of hCtr1, also conferred dominant-negative property of Cu(I) transport but not of CDDP transport. Deleting the N-terminal 45 amino acids that contain two methionine-rich motifs resulted in cytoplasmic localization of the hCtr1 and abolished the dominant-negative function of these mutants. Nonetheless, these mutations did not affect the capacities of hCtr1 oligomerization induced by copper or CDDP, suggesting a distinct structural requirement between metal transport and oligomerization. Finally, we also observed that expressing the dominant-negative hCtr1 mutants up-regulates endogenous hCtr1 mRNA expression, consistent with our previous report that intracellular copper homeostasis and homeostatic levels of hCtr1 mRNA are mutually regulated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Zheng¹,

Stockton

Savaraj³

et al. 2009

Mol Pharmacol

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“…On the other hand, the highly conserved region of the translated Atox1 gene in humans can be evidence for a vital role of Atox1 protein in human metabolism or embryonic development. This also might explain the still unknown phenotype of Atox1-mutation associated diseases [2] , even though different roles and regulatory factors for Atox1 in human metabolism are emerging out of recent studies [28][29][30][31] . One might speculate about a Menkes disease like phenotype resulting from a complete disruption of both functional alleles of Atox1 as suggested by Atox1 knockout mice data [32] .…”

Section: Discussionmentioning

confidence: 99%

Analysis of the human Atox 1 homologue in Wilson patients

Simon¹,

Schaefer²,

Reichert³

et al. 2008

WJG

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AIM:To analyze the metallochaperone antioxidant-1 (Atox1) gene sequence in Wilson disease patients. METHODS:Mutation analysis of the four exons of the Atox1 gene including the intron-exon boundaries was performed in 63 Wilson disease patients by direct sequencing. RESULTS:From 63 selected patients no mutations were identified after the entire coding region including the intron-exon boundaries of Atox1 were sequenced. One known polymorphism within the Atox1 gene (5'UTR -99 T>C) in 31 (49%) of the Wilson patients as well as one previously undescribed variation (5'UTR -68 C>T) in 2 of the Wilson patients could be detected. Statistical analyses revealed that the existence of a variation within the Atox1-gene showed a tendency towards an earlier onset of the disease. CONCLUSION:Based on the data of this study, no major role can be attributed to Atox1 in the pathophysiology or clinical variation of Wilson disease.

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“…The list of cisplatin targets is constantly increasing and includes, for instance, transferrin [4], serum albumin [5][6][7], haemoglobin [3] or apo lipoproteins [7], ubiquitin [8] or metathioneins [9] or copper transport proteins [10]. Today, cisplatin-protein interactions are widely characterized by spectroscopic techniques (i.e.…”

Section: Introductionmentioning

confidence: 99%

Computational insights on the possibility of tri-coordinated cisplatinated adducts with protein models

Ortega‐Carrasco

Cossío

Lledós

et al. 2012

Journal of Inorganic Biochemistry

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Interaction between Platinum Complexes and a Methionine Motif Found in Copper Transport Proteins

Cited by 28 publications

References 21 publications

Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Analysis of the human Atox 1 homologue in Wilson patients

Computational insights on the possibility of tri-coordinated cisplatinated adducts with protein models

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