Regulation of Oxidative Phosphorylation: -An Inhibitory Protein Prevents ATP Hydrolysis during Ischemia
We have already encountered ATP synthase as an ATP driven proton pump, catalyzing the reverse of ATP synthesis. When a cell is ischemic (deprived of oxygen), as in a heart attack or stroke, electron transfer to oxygen ceases, and so does the pumping of protons. The proton-motive force soon collapses. Under these conditions, the ATP synthase could operate in reverse, hydrolyzing ATP to pump pro tons outward and causing a disastrous drop in ATP levels. This is prevented by a small (84 amino acids) protein inhibitor, IF1, which simultaneously binds to two ATP synthase molecules, inhibiting their ATPase activity (Fig. 19–29). IF1 is inhibitory only in its dimeric form, which is favored at pH lower than 6.5. In a cell starved for oxygen, the main source of ATP becomes glycolysis, and the pyruvic or lactic acid thus formed lowers the pH in the cytosol and the mitochondrial matrix. This favors IF1 dimerization, leading to inhibition of the ATPase activity of ATP synthase, thereby preventing wasteful hydrolysis of ATP. When aerobic metabolism resumes, production of pyruvic acid slows, the pH of the cytosol rises, the IF1 dimer is destabilized, and the inhibition of ATP synthase is lifted.
FIGURE 19–29 Structure of bovine F1-ATPase in a complex with its regulatory protein IF1. (Derived from PDB ID 1OHH) Two F1 molecules are viewed here as in Figure 19–23c. The inhibitor IF1 (red) binds to the αβ interface of the subunits in the diphosphate (ADP) conformation (αADP and ADP), freezing the two F1 complexes and thereby blocking ATP hydrolysis (and synthesis). (Parts of IF1 that failed to resolve in crystals of F1 are shown in white outline as they occur in crystals of isolated IF1.) This complex is stable only at the low cytosolic pH characteristic of cells that are producing ATP by glycolysis; when aerobic metabolism resumes, the cytosolic pH rises, the inhibitor is destabilized, and ATP synthase becomes active.
