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The two most conserved subunits of the catalytic core of cytochrome c oxidase (CcO) are subunits I and III. Although equally conserved, subunit III contains no redox centers and can be removed from CcO without substantial loss of activity. Progress in deciphering its elusive function is detailed in this chapter, including evidence for its role in modulating the pH dependence of CcO activity, preventing turnover-based suicide inactivation of CcO, increasing the efficiency of proton pumping, enhancing proton backflow, providing antenna residues for proton uptake and facilitating the entry of oxygen.

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