Proteins proposed to be involved in mitochondrial copper metabolism and addition to COX subunits. (A) Copper insertion into the CuA and CuB sites in Cox2p and Cox1p, respectively. The soluble copper chaperone Cox17p transfers copper ions to two additional chaperones that facilitate copper insertion into the COX CuA and CuB active sites, respectively Sco1p and Cox11p. These proteins are anchored to the mitochondrial inner membrane through a transmembrane α-helix and expose their copper binding sides in the IMS, where copper transfer occurs. Solution structures of the apo- Cox17p, and of the globular intermembrane space domains of Sco1p and Cox11p and ligand-bound Cox1p and Cox2p structures were obtained from the protein data bank (PDB) website (http://www.rcsb.org/pdb/home/home.do) and modified to prepare the figure. The transmembrane domains of Cox11p and Sco1p were artificially generated and used to represent the tethering of these proteins to the inner membrane. The YASARA molecular-graphics, -modeling and -simulation program, developed by Elmer Krieger, was used to generate a cartoon model of the different proteins. (B) Hypothetical role of the several CX9C containing proteins in regulating copper transfer from a matrix copper pool, across the inner mitochondrial membrane through an uncharacterized transporter, towards Cox17p. The hypothetical model is explained in the text. A possible role of the CX9C containing proteins in redox homeostasis within the intermembrane space is not depicted here. OM, outer membrane, IMS, intermembrane space, IM inner membrane. Black arrows indicate experimentally proved copper transfer while grey arrows indicate strictly hypothetical copper transfer.