The role of Ctr1 and Ctr2 in mammalian copper homeostasis and platinum-based chemotherapy

Abstract

Copper (Cu) is an essential metal for growth and development that has the potential to be toxic if levels accumulate beyond the ability of cells to homeostatically balance uptake with detoxification. One system for Cu acquisition is the integral membrane Cu(+) transporter, Ctr1, which has been quite well characterized in terms of its function and physiology. The mammalian Ctr2 protein has been a conundrum for the copper field, as it is structurally closely related to the high affinity Cu transporter Ctr1, sharing important motifs for Cu transport activity. However, in contrast to mammalian Ctr1, Ctr2 fails to suppress the Cu-dependent growth phenotype of yeast cells defective in Cu(+) import, nor does it appreciably stimulate Cu acquisition when over-expressed in mammalian cells, underscoring important functional dissimilarities between the two proteins. Several roles for the mammalian Ctr2 have been suggested both in vitro and in vivo. Here, we summarize and discuss current insights into the Ctr2 protein and its interaction with Ctr1, its functions in mammalian Cu homeostasis and platinum-based chemotherapy.

Keywords: Copper trafficking; Copper transporter, Ctr; Platinum-based chemotherapy; Regulation; Structure.

Figure 1

Alignment of human Ctr1 and Ctr2 showing trans-membrane domains in yellow and glycosylation sites in the ecto-domain of Ctr1 in orange. Cleavage sites of Ctr1 protein ecto-domain are indicated with vertical black arrowheads. The Met-X₃-Met motif in second trans-membrane domain, crucial for Cu⁺ transport activity, is boxed in red and the Gly-X₃-Gly in third trans-membrane domain, involved in helix packing, is boxed in blue. The Cys-His-Cys motif at the carboxyl-terminus of Ctr1, involved in trafficking Cu to the chaperones CCS and Atox1, is boxed in green.

Figure 2

Schematic figure depicting Ctr1 and Ctr2 homotrimers, and a possible way for their interaction; heterotrimerization. Adapted and modified from Öhrvik, H. & D.J. Thiele. 2014. How Copper Traverses Cellular Membranes Through the Mammalian Copper Transporter 1, Ctr1. Ann. N.Y. Acad. Sci. (In press).