Copper transporter protein 1 (CTR1)

Copper transporter protein 1 (CTR1), encoded by the SLC31A1 gene, is a high-affinity copper transporter that mediates copper uptake across cell membranes and plays a critical role in copper homeostasis across eukaryotes ranging from yeast to humans. CTR1 functions as a trimeric complex with three transmembrane domains and contains conserved methionine-rich metal-binding motifs that recognize and transport copper(I) ions through a mechanism involving sequential copper exchange reactions between defined binding sites. The protein is ubiquitously expressed with highest levels in the liver and is absolutely essential for normal mammalian embryonic development and proper functioning of copper-dependent enzymes including cytochrome c oxidase and superoxide dismutase. Beyond its physiological role in copper acquisition, CTR1 is a significant determinant of platinum-based chemotherapy efficacy, as cisplatin and related antitumor drugs exploit the copper transport machinery by binding to CTR1 and being carried intracellularly for their cytotoxic effects. Therapeutic targeting of CTR1 faces substantial challenges due to its essential role in development and the ubiquitous requirement for copper-dependent enzymes, though modulating CTR1 activity or expression may offer strategies to enhance chemotherapy sensitivity or address certain copper metabolism disorders.

Other names

High affinity copper uptake protein 1SLC31A1 gene producthCTR1 (human CTR1)COPT1 (in plant nomenclature)

CTR1 operates as a high-affinity copper transporter with energy-independent, potassium-dependent transport. It functions as a trimeric complex with a membrane-spanning pore created by symmetry-related transmembrane segments. The protein contains conserved methionine-rich (MPM and MxxxM) motifs in the N-terminus and transmembrane domain 2 that bind copper(I) ions. Copper transport occurs through a chain of copper exchange reactions between defined Cu(I)-binding sites with conformational switching. Cisplatin binds to extracellular domains and is carried intracellularly via CTR1 internalization. C-terminal cysteine-rich motifs bind copper and are essential for rapid inactivation in response to excess copper.