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Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):755-62. doi: 10.1016/j.bbabio.2010.03.007. Epub 2010 Mar 15.

ATP hydrolysis in ATP synthases can be differently coupled to proton transport and modulated by ADP and phosphate: a structure based model of the mechanism.

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Department of Biology, Laboratory of Biochemistry and Biophysics, University of Bologna, Via Irnerio 42, 40126 Bologna, Italy.


In the ATP synthases of Escherichia coli ADP and phosphate exert an apparent regulatory role on the efficiency of proton transport coupled to the hydrolysis of ATP. Both molecules induce clearly biphasic effects on hydrolysis and proton transfer. At intermediate concentrations (approximately 0.5-1 microM and higher) ADP inhibits hydrolysis and proton transfer; a quantitative analysis of the fluxes however proves that the coupling efficiency remains constant in this concentration range. On the other hand at nanomolar concentrations of ADP (a level obtainable only using an enzymatic ATP regenerating system) the efficiency of proton transport drops progressively, while the rate of hydrolysis remains high. Phosphate, at concentrations>or=0.1 mM, inhibits hydrolysis only if ADP is present at sufficiently high concentrations, keeping the coupling efficiency constant. At lower ADP levels phosphate is, however, necessary for an efficiently coupled catalytic cycle. We present a model for a catalytic cycle of ATP hydrolysis uncoupled from the transport of protons. The model is based on the available structures of bovine and yeast F1 and on the known binding affinities for ADP and Pi of the catalytic sites in their different functional states. The binding site related to the inhibitory effects of Pi (in association with ADP) is identified as the alphaHCbetaHC site, the pre-release site for the hydrolysis products. We suggest, moreover, that the high affinity site, associated with the operation of an efficient proton transport, could coincide with a conformational state intermediate between the alphaTPbetaTP and the alphaDPbetaDP (similar to the transition state of the hydrolysis/synthesis reaction) that does not strongly bind the ligands and can exchange them rather freely with the external medium. The emptying of this site can lead to an unproductive hydrolysis cycle that occurs without a net rotation of the central stalk and, consequently, does not translocate protons.

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