Building the CuA site of cytochrome c oxidase: A complicated, redox-dependent process driven by a surprisingly large complement of accessory proteins

Cytochrome c oxidase (COX) was initially purified more than 70 years ago. A tremendous amount of insight into its structure and function has since been gleaned from biochemical, biophysical, genetic, and molecular studies. As a result, we now appreciate that COX relies on its redox-active metal centers (heme a and a(3), Cu-A and Cu-B) to reduce oxygen and pump protons in a reaction essential for most eukaryotic life. Questions persist, however, about how individual structural subunits are assembled into a functional holoenzyme. Here, we focus on what is known and what remains to be learned about the accessory proteins that facilitate Cu-A site maturation.