1.A.56.1.2
High affinity copper (Cu⁺) and silver (Ag⁺) uptake transporter, Ctr1 of 190 aas and 3 TMSs.  The trimeric channel (Eisses and Kaplan, 2005) forms an oligomeric pore with each subunit displaying 3 TMSs and 2 metal binding motifs (Lee et al., 2007). TMS2 is sufficient to form the trimer, and the MXXM motif bind Ag⁺ (Dong et al. 2015). Ctr1 mediates basolateral uptakes of Cu⁺ in enterocytes (Zimnicka et al., 2007) and shows copper-dependent internalization and recycling which provides a reversible mechanism for the regulation of cellular copper entry (Molloy and Kaplan, 2009). It acts as a receptor for the two extinct viruses, CERV1 and CERV2 (Soll et al., 2010). Ctr1 takes up platinum anticancer drugs, cisplatin and carboplatin (Du et al., 2012). The 3-d structure is known (Yang et al., 2012).  Ctr1 has a low turn over number of about 10 ions/second/trimer (Maryon et al. 2013).  Methionine and histidine residues in the transmembrane domain are essential for transport of copper, but when mutated, they stimulated uptake of cisplatin (Larson et al. 2010).  Plays important roles in the developing embryo as well as in adult ionic homeostasis (Wee et al. 2013). (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells. EGCG inhibits the rapid degradation of CTR1 induced by cisplatin (cDDP). The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer (Wang et al. 2015). Steroid inhibitors may be able to overcome cycplatin resistance (Kadioglu et al. 2015).  ctr1 is upregulated in colorectal cancer cells (Barresi et al. 2016). The N-terminus of CTR1 binds Cu²⁺ following transfer from blood copper carriers such as human serum albumin to the transporter (Bossak et al. 2018). Once in the cytosol, enzyme-specific chaperones receive copper from the CTR1 C-terminal domain and deliver it to their apoenzymes (Ilyechova et al. 2019). Ctr1 is part of the Sp1-Slc31a1/Ctr1 copper-sensing system, and carnosine, a brain dipeptide, influences copper homeostasis in murine CNS-derived cells (Barca et al. 2019). A proteomic view of cellular responses of macrophages to copper has appeared (Dalzon et al. 2021). Tetrahedral framework nucleic acid delivered RNA therapeutics significantly attenuate pancreatic cancer progression via inhibition of CTR1-dependent copper absorption (Song et al. 2021). Electron paramagnetic resonance (EPR) has been used to study conformational changes during transport (Hofmann and Ruthstein 2022). Ctr1 is the main entry point for Cu' ions in eukaryotes. It  contains intrinsically disordered regions, IDRs, both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. Aupič et al. 2022 showed that Cu⁺ ions and a lipidic environment drive the insertion of the N-terminus into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Polymorphic renal transporters and cisplatin's toxicity in urinary bladder cancer patients have been reviewed (Selim et al. 2023).  Rosmarinic acid has a protective effect on Ctr1 expression in cisplatin-treated mice (Akhter et al. 2023).  Disorders of copper metabolism can be caused by variants in CTR1 (Batzios et al. 2022).