Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1

Crider, S.; Holbrook, Robert J.; Franz, Katherine J.

doi:10.1039/b916899k

Cited by 63 publications

(49 citation statements)

References 62 publications

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“…It is noteworthy that the Pt(II) species loses from the early beginning both ammine ligands, which are replaced by methionine residues of Mets7. The final adducts are identical to those observed when Mets7 was reacted directly with cisplatin [32,45].…”

Section: Interaction Of 1-4 Complexes With Copper Transporterssupporting

confidence: 74%

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Ravera

Gabano

Zanellato

et al. 2015

Journal of Inorganic Biochemistry

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Section: Interaction Of 1-4 Complexes With Copper Transporterssupporting

confidence: 74%

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Ravera

Gabano

Zanellato

et al. 2015

Journal of Inorganic Biochemistry

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“…Here, we demonstrate that tCtr1 is generated by proteolytic cleavage of full-length Ctr1, which is initiated by the cysteine cathepsins L and B, and that this cleavage occurs in a Ctr2-dependent manner. We also demonstrate that truncation of Ctr1 by these cathepsins has a functional impact on cellular accumulation of both Cu ϩ and cisplatin, both of which bind directly to the metal ligand-rich ectodomain (24,26,27,29). Our results establish cathepsin L/B cleavage as a direct and rate-limiting step in the generation of tCtr1.…”

Section: Discussionmentioning

confidence: 62%

“…Similar to Cu ϩ , platinum binds to Met-rich motifs within the Ctr1 ectodomain (27), but studies using Ctr1 mutants that are defective in Cu ϩ transport, but competent for cisplatin acquisition, suggest that Ctr1 delivers platinum into cells via receptor-mediated endocytosis rather than acting as a membrane channel as it does for Cu ϩ (15,26). Cancer patient survival after treatment with platinum-based drugs is associated with high levels of CTR1 expression and lower CTR1 levels associated with decreased survival to cisplatin (62,63).…”

Section: Discussionmentioning

confidence: 99%

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Öhrvik

Logeman

Turk

et al. 2016

Journal of Biological Chemistry

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Copper is an essential metal ion for embryonic development, iron acquisition, cardiac function, neuropeptide biogenesis, and other critical physiological processes. Ctr1 is a high affinity Cu ؉ transporter on the plasma membrane and endosomes that exists as a full-length protein and a truncated form of Ctr1 lacking the methionine-and histidine-rich metal-binding ectodomain, and it exhibits reduced Cu ؉ transport activity. Here, we identify the cathepsin L/B endolysosomal proteases functioning in a direct and rate-limiting step in the Ctr1 ectodomain cleavage. Cells and mice lacking cathepsin L accumulate full-length Ctr1 and hyper-accumulate copper. As Ctr1 also transports the chemotherapeutic drug cisplatin via direct binding to the ectodomain, we demonstrate that the combination of cisplatin with a cathepsin L/B inhibitor enhances cisplatin uptake and cell killing. These studies identify a new processing event and the key protease that cleaves the Ctr1 metal-binding ectodomain, which functions to regulate cellular Cu ؉ and cisplatin acquisition.Copper is essential for key biological processes, including electron transfer, iron acquisition, dopamine hydrolysis, and superoxide disproportionation, and defects in copper metabolism are associated with cardiomyopathy, anemia, peripheral neuropathy, and neutropenia (1-6). Although many proteins involved in the acquisition and intracellular distribution of copper have been identified, little is known about the regulation of copper import. The transport of Cu ϩ from the extracellular environment is accomplished by the evolutionarily conserved homotrimeric integral membrane protein, copper transporter 1 (Ctr1) (7-13), which resides on the plasma membrane and in endosomal compartments (14 -18). High affinity Cu ϩ import via Ctr1 requires a methionine-and histidine-rich metal-binding extracellular domain (ectodomain) that is thought to concentrate extracellular Cu ϩ near the ion trans-membrane pore (19 -23). Additionally, Ctr1 binds the chemotherapeutic agent cisplatin via the methionine ligands in the ectodomain and imports cisplatin and other platinum-based chemotherapeutic agents via an endocytic mechanism (24 -28). Despite a critical role for the Ctr1 ectodomain in both Cu ϩ and cisplatin import, both a full-length form and a truncated form of Ctr1 (tCtr1) 4 are present in cultured cells and tissues (18,29,30). The latter lacks the ectodomain and drives ϳ50% of the Cu ϩ uptake as compared with full-length Ctr1 (31).Previously, an integral membrane protein similar to Ctr1, denoted Ctr2, was shown to both interact with and regulate the ratio of full-length Ctr1 to tCtr1 in mouse embryonic fibroblasts (MEFs) and in specific tissues in Ctr2 knock-out mice (32). In the absence of Ctr2, MEFs possess dramatically lower levels of tCtr1, while simultaneously expressing high levels of full-length Ctr1 and accumulating Cu ϩ and cisplatin. A large fraction of the Cu ϩ accumulated in Ctr2 Ϫ/Ϫ MEFs and mouse tissues is found in endosomal compartments (32). The mechanism by which Ct...

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“…6A). Notably, cleavage of mouse Ctr1 at these positions results in the removal of all 11 His residues and 10-13 Met residues in the Ctr1 ecto-domain, many of which have been shown to serve as Cu and cisplatin ligands in model peptides (32,33,47). Interestingly, Mets 49 and 51, which remain in the truncated Ctr1 protein, are essential for human Ctr1 function in Cu + transport (31).…”

Section: Truncated Ctr1 Facilitates Endosomal Copper Mobilizationmentioning

confidence: 99%

“…Mutagenic and truncation studies in the context of intact yeast or human Ctr1 indicate that the ecto-domain in general, and the Met residues in particular, play an important role in high-affinity cellular Cu + import, yet all but one key Met near the first transmembrane domain appear to be dispensable for function in cellular Cu + import (31). Studies using model peptides suggest that the Ctr1 Met residues are direct ligands for both Cu + and cisplatin (32)(33)(34). In contrast to Cu + uptake, the Met-rich ectodomain of yeast Ctr1 is required for cisplatin import (27).…”

mentioning

confidence: 99%

Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain

Öhrvik

Nose

Wood

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

141

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Significance Copper is essential for normal growth and development because it serves roles in catalysis, signaling, and structure. Cells acquire copper through the copper transporter 1 (Ctr1) protein, a copper transporter that localizes to the cell membrane and intracellular vesicles. Both copper and the anticancer drug cisplatin are imported by Ctr1 by virtue of an extracellular domain rich in metal-binding amino acids. In this report we demonstrate that a protein structurally related to Ctr1, called Ctr2, plays a role in the generation or stability of a truncated form of Ctr1 lacking a large portion of the extracellular domain. Retention of this domain in mice or cells lacking Ctr2 enhances copper and cisplatin uptake, thereby establishing Ctr2 as a regulator of Ctr1 function.

show abstract

Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1

Cited by 63 publications

References 62 publications

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain

Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain

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