Cytochrome c Oxidase

Shelagh Ferguson-Miller group (Michigan State University)

The group of Shelagh Ferguson-Miller at Michigan State University published two papers, including a cover article in Biochemistry, on mechanistic studies of the complex and challenging membrane protein, cytochrome c oxidase (CcO). CcO couples electron and proton transport to reduction of O₂ to H₂O at its active site (heme a₃ and Cu_B), meanwhile pumping protons across membranes for ATP synthesis. Structures are known for bacterial and for bovine CcOs, but questions remain about the complicated chemistry of coupled electron/proton transport, and about the binding sites for effector molecules. Two pathways in CcO take up protons; the D pathway transports protons across the membrane and also donates protons to the reduction of O₂, while the K pathway only donates protons to reduction of O2. A binding site for deoxycholate was identified in the CcO K path, leading to the proposal that this is a conserved site for binding steroids and other physiological effectors (Qin, L. et al., Biochemistry, 47, 9931-9933 (2008)). In the structure of the reduced CcO (Qin, L. et al., Biochemistry, 48, 5121-5130 (2009)), redox-induced shifts in the active site and changes in water locations in the D and K paths suggest a conformational gate for cycling between proton paths in the catalytic cycle.

Figure: Channels in cytochrome c oxidase. On the left, a deoxycholate binding site and a detergent binding site were identified in the K path of R. sphaeroids CcO. On the right, comparisons of structures of the reduced and oxidized forms of R. sphaeroides CcO show the loss of a strategically located water from the D path in the reduced state.

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