Cellular distribution of copper to superoxide dismutase involves scaffolding by membranes

Pope, Christopher R.; Feo, Christopher J. De; Unger, Vinzenz M.

doi:10.1073/pnas.1309820110

Cited by 51 publications

(63 citation statements)

References 41 publications

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“…Therefore, the only way to transport the metal to another protein is via direct protein-protein interactions. Whereas CCS has been shown to interact with membranes and to receive Cu directly from Ctr1 (Pope et al 2013), Ctr1-Atox1 interactions have not been described except for the yeast protein pair (Xiao and Wedd 2002). Thus, it is a possibility that Cu delivery to Atox1 goes via CCS.…”

Section: Discussionmentioning

confidence: 99%

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Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro

et al. 2015

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After Ctr1-mediated copper ion (Cu) entry into the human cytoplasm, chaperones Atox1 and CCS deliver Cu to P1B-type ATPases and to superoxide dismutase, respectively, via direct protein-protein interactions. Although the two Cu chaperones are presumed to work along independent pathways, we here assessed cross-reactivity between Atox1 and the first domain of CCS (CCS1) using biochemical and biophysical methods in vitro. By NMR we show that CCS1 is monomeric although it elutes differently from Atox1 in size exclusion chromatography (SEC). This property allows separation of Atox1 and CCS1 by SEC and, combined with the 254/280 nm ratio as an indicator of Cu loading, we demonstrate that Cu can be transferred from one protein to the other. Cu exchange also occurs with full-length CCS and, as expected, the interaction involves the metal binding sites since mutation of Cu-binding cysteine in Atox1 eliminates Cu transfer from CCS1. Cross-reactivity between CCS and Atox1 may aid in regulation of Cu distribution in the cytoplasm.

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Section: Discussionmentioning

confidence: 99%

“…Since both Atox1 and CCS possess the capacity to interact with lipid bilayers, membrane scaffolding may facilitate the interaction between Ctr1 and the chaperones (Pope et al 2013). In yeast, Ctr1 has a cytosolic C-terminal domain that was shown to interact with the yeast Atx1 chaperone and deliver Cu (Xiao and Wedd 2002).…”

mentioning

confidence: 99%

Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro

et al. 2015

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“…It has been suggested that virtually all cellular Cu is tightly bound, and intracellular Cu trafficking is carried out by Cu chaperones to different cellular compartments, i.e, CCS to superoxide dismutase in the cytoplasm [12], Cox17 to mitochondrial cytochrome C oxidase, and Atox1 to two trans -Golgi P1B-type ATPases (ATP7A and ATP7B) [13]. It has been reported that ZF domain is involved in nuclear targeting of Sp1 [14].…”

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confidence: 99%

Effects of Cu(II) and cisplatin on the stability of Specific protein 1 (Sp1)-DNA binding: Insights into the regulation of copper homeostasis and platinum drug transport

Dong

Aiba

Chen

et al. 2016

Journal of Inorganic Biochemistry

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The human high-affinity copper transporter 1 (hCtr1) transports both Cu(I) and cisplatin (cDDP). Because Cu deficiency is lethal yet Cu overload is poisonous, hCtr1 expression is transcriptionally upregulated in response to Cu deficiency but is downregulated under Cu replete conditions in controlling Cu homeostasis. The up- and down-regulation of hCtr1 is regulated by Specific protein 1 (Sp1), which itself is also correspondingly regulated under these Cu conditions. hCtr1 expression is also upregulated by cDDP via upregulation of Sp1. The underlying mechanisms of these regulations are unknown. Using gel-electrophoretic mobility shift assays, we demonstrated here that Sp1-DNA binding affinity is reduced under Cu replete conditions but increased under reduced Cu conditions. Similarly, Sp1-DNA binding affinity is increased by cDDP treatment. This in vitro system demonstrated, for the first time, that regulation of Sp1/hCtr1 expression by these agents is modulated by the stability of Sp1-DNA binding, the first step in the Sp1-mediated transcriptional regulation process.

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“…Recent studies demonstrated that both CCS [32] and Atox1 [33] interact with hCtr1, suggesting a direct transfer of Cu +1 from hCtr1 to these carrier proteins (Figs. 1B & 1C).…”

Section: Mechanisms Of Cddp Transportmentioning

confidence: 99%

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

Chen

Liang

et al. 2015

Expert Opinion on Therapeutic Targets

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Introduction Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy. Area covered Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated. Expert opinion While both transcriptional and posttranslational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.

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Cellular distribution of copper to superoxide dismutase involves scaffolding by membranes

Cited by 51 publications

References 41 publications

Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro

Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro

Effects of Cu(II) and cisplatin on the stability of Specific protein 1 (Sp1)-DNA binding: Insights into the regulation of copper homeostasis and platinum drug transport

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

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