Docking Study on Mammalian Copper Importer CTR1 Motifs
High affinity Cu(I) transporter CTR1 (encoded by SLC31A1) is the main candidate for the role of Cu(I)-importer. It exists as homotrimer, contains extracellular N-terminal and cytosolic C-terminal copper binding sites, separated by transmembrane cuprophylic channel. In this study the models of interaction between CTR1 and ceruloplasmin (CP), multicopper oxidase, which is the main donor of copper for nonhepatic cells, as well as CTR1 and copper binding domains of Menkes ATPase were proposed. Hex 4.5 software was used for the protein molecules docking calculations. The program utilizes 3D parametric Fourier functions for ligand and receptor modeling. Heteroatoms parametrization is implemented into the software, the model of rigid ligand is used, and the solvent is not accounted for. The calculations showed that all the reduced CTR1 extracellular N-terminal copper binding motifs, which conformations were obtained in geometry optimization by AMBER force field implemented in HyperChem 7.0 package, are strongly favoured to interact with labile Cu bound with CP molecule (PDB ID: 1KCW). That means the possibility of the CP role as the Cu donor for CTR1 N-terminus. As the control for docking specificity we used albumin, another copper binding protein. No copper containing sites in CP were found to be favourable for the interaction with albumin. The docking of C-terminal copper binding monomeric, dimeric and trimeric HCH motifs with reduced metal binding domain 4 of Menkes ATPase (PDB ID: 1AW0) revealed the sites of favoured interactions coinciding with Cu-binding site CXXC in Menkes ATPase (2AW0). The results allow us to conclude that CTR1 is able to accept Cu from extracellular transporter, CP, and transport it further into the cell to Cu binding domain of Menkes ATPase. That agrees with other in vivo and in vitro experiments suggesting CTR1 role as membrane copper importer.