Complex structure of cytochrome c-cytochrome c oxidase reveals a novel protein-protein interaction mode

Mitochondrial cytochrome c oxidase (CcO) transfers electrons from cytochrome c (Cyt. c) to O-2 to generate H2O, a process coupled to proton pumping. To elucidate the mechanism of electron transfer, we determined the structure of the mammalian Cyt.c-CcO complex at 2.0- resolution and identified an electron transfer pathway from Cyt.c to CcO. The specific interaction between Cyt.c and CcO is stabilized by a few electrostatic interactions between side chains within a small contact surface area. Between the two proteins are three water layers with a long inter-molecular span, one of which lies between the other two layers without significant direct interaction with either protein. Cyt.c undergoes large structural fluctuations, using the interacting regions with CcO as a fulcrum. These features of the protein-protein interaction at the docking interface represent the first known example of a new class of protein-protein interaction, which we term soft and specific. This interaction is likely to contribute to the rapid association/ dissociation of the Cyt.c-CcO complex, which facilitates the sequential supply of four electrons for the O-2 reduction reaction.