How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1

Abstract

The copper transporter 1, Ctr1, is part of a major pathway for cellular copper (Cu) uptake in the intestinal epithelium, in hepatic and cardiac tissue, and likely in many other mammalian cells and tissues. Here, we summarize what is currently known about how extracellular Cu travels across the plasma membrane to enter the cytoplasm for intracellular distribution and for use by proteins and enzymes, the physiological roles of Ctr1, and its regulation. As a critical Cu importer, Ctr1 occupies a strategic position to exert a strong modifying influence on diseases and pathophysiological states caused by imbalances in Cu homeostasis. A more thorough understanding of the mechanisms that regulate Ctr1 abundance, trafficking, and function will provide new insights and opportunities for disease therapies.

Keywords: chaperones; copper homeostasis; copper trafficking; platinum; regulation; structure.

Figure 1

Schematic model depicting the key players involved in mammalian cellular acquisition, intracellular distribution, sensing, and mobilization of copper (Cu). ATOX1, antioxidant protein 1; Atp7A and B, copper transporting ATPaseA and B; CCO, cytochrome c oxidase; CCS, copper chaperone for SOD1; Ctr1 and 2, copper transporter 1 and 2; MT, metallothionein; SOD1, Cu/Zn- superoxide dismutase; tCtr1, truncated Ctr1.

Figure 2

Structural model of three fully glycosylated Ctr1 monomers in a lipid bilayer forming a functional Ctr1 transporter. The TMD 2 of all three Ctr1 monomers lines the entrance of the pore and all nine TMDs from the three monomers line the exit of the pore. Cu⁺ is bound by the Met and His rich motifs in the three Ctr1 ecto-domains probably causing a conformational change of the transporter allowing Cu⁺ to enter the pore. Met, methionine; His, histidine; Cys, cysteine; MX₃M, crucial motif for Cu transport; TMD1-3, Ctr1 monomer number 1; TMD1′-3′, Ctr1 monomer number 2.