Figure 7. A Proposed Model of Cu_A Site Biogenesis.

Cu_A site formation on the Cox2 subunit of CcO involves sequential transfer of Cu from Cox17 to Sco1 to Cox2. This process occurs in the mitochondrial inter-membrane space, an oxidizing environment that would promote the formation of disulfide bonds in the Cu-coordinating cysteines of apo-Cox2 and apo-Sco1 proteins and prevent Cu binding. The thioldisulfide oxidoreductase activities of Coa6 and Sco2 overcome this problem by reducing the disulfides of apo-Cox2 and apo-Sco1 to dithiols, thereby allowing for Cu binding. Previous studies and the work described here suggest that Coa6 has dual substrates in Sco1 and Cox2 and that it exhibits overlapping substrate specificity with Sco2.