If ATP is the universal currency of free energy in biological systems then the F1F0 ATP synthase is the mint. This enzyme can synthesize ATP using a transmembrane proton gradient. The ATP synthase is a multisubunit complex with a water-soluble F1 domain, the crystal structure of which has been solved, and a transmembrane F0 domain about which there is very little structural information. The F0 domain is made up of three types of subunits, in an a1b2 c12 stoichiometry. Low-resolution images and biochemical experiments suggest that the 12 c subunits are in a cylindrical arrangement with the a (purple) and b (not shown) subunits on the periphery. While it is clear that the F1 core subunit γ rotates during catalysis, the mechanism by which proton translocation through F0 is coupled to F1 subunit rotation is unknown.

Several models have been proposed in which ATP synthesis in the F1 domain is coupled to proton movement through F0 via movements of the c subunits. To explore this possibility, Rastogi and Girvin examined the structural changes induced by deprotonating a specific aspartic acid (Asp 61) on the c subunit known to be essential for proton transport (Nature; in the press). They combined their studies of the NMR structures of the deprotonated and protonated forms of the c subunit with distance constraints from crosslinking experiments to come up with a model for the c12 oligomer. The a subunit was modeled using biochemical data and then positioned with respect to the c12 oligomer using crosslinking data. Interestingly, this model places Asp 61 (shown in red and black) in a position to interact with Arg 210 (shown in blue and gray) in subunit a that is also essential for proton translocation.

The model proposes the following scenario. The flow of protons down the gradient (towards the F1 face) would drive protonation of Asp 61. The C-terminal helix of this newly protonated monomer (green) would rotate. As a result subunit a would then be in a position to interact with the next (blue) monomer. This local rotation within subunit c would drive larger scale rotations of the c12 ring as a whole. Translocation of a single proton would lead to rotation of the c12 oligomer by 30° with respect to the static elements (for example, a in F0). Because the F1 core, which includes the ε subunit (red) is linked to the c12 ring it would rotate in concert with the ring. Four steps would result in the observed 120° rotation of the F1 core that has been shown to drive the catalytic conformational changes in the active sites of F1 that result in ATP synthesis.