Structures and Interactions of Proteins Involved in the Coupling Function of the Protonmotive FoF1-ATP Synthase

Author(s): A. Gaballo, F. Zanotti, S. Papa

Journal Name: Current Protein & Peptide Science

Volume 3 , Issue 4 , 2002

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The mitochondrial F1Fo ATP synthase complex has a key role in cellular energy metabolism. The general architecture of the enzyme is conserved among species and consists of a globular catalytic moiety F1, protruding out of the inner side of the membrane, a membrane integral proton translocating moiety Fo, and a stalk connecting F1 to F o. The Xray crystallographic analysis of the structure of the bovine mitochondrial F1 ATPase has provided a structural basis for the binding-change rotary mechanism of the catalytic process in F1, in which the γ subunit rotates in the central cavity of the F1 α3 / β3 hexamer. Rotation of γ and ε subunits in the E. coli enzyme and of, γ and δ subunits in the mitochondrial enzyme, is driven, during ATP synthesis, by proton motive rotation of an oligomer of c subunits (10-12 copies) within the Fo base piece. Average analysis of electron microscopy images and cross-linking results have revealed that, in addition to a central stalk, contributed by γ and δ / ε subunits, there is a second lateral one connecting the peripheries of Fo and F1. To gain deeper insight into the mechanism of coupling between proton translocation and catalytic activity (ATP synthesis and hydrolysis), studies have been undertaken on the role of F1 and Fo subunits which contribute to the structural and functional connection between the catalytic sector F1 and the proton translocating moiety Fo. These studies, which employed limited proteolysis, chemical cross-linking and functional analysis of the native and reconstituted F1Fo complex, as well as isolated F1, have shown that the N-terminus of α subunits, located at the top of the F1 hexamer is essential for energy coupling in the F1Fo complex. The α N-terminus domain appears to be connected to Fo by OSCP (Fo subunit conferring sensitivity of the complex to oligomycin). In turn, OSCP contacts FoI-PVP(b) and d subunits, with which it constitutes a structure surrounding the central γ and δ rotary shaft. Cross-linking of FoI-PVP(b) and γ subunits causes a dramatic enhancement of downhill proton translocation decoupled from ATP synthesis but is without effect on ATP driven uphill proton transport. This would indicate the existence of different rate-limiting steps in the two directions of proton translocation through Fo. In mitochondria, futile ATP hydrolysis by the F1Fo complex is inhibited by the ATPase inhibitor protein (IF1), which reversibly binds at one side of the F1Fo connection. The trans-membrane ΔpH component of the respiratory Δp displaces IF1 from the complex, in particular the matrix pH is the critical factor for IF1 association and its related inhibitory activity. The 42L-58K segment of the IF1 has been shown to be the most active segment of the protein, it interacts with the surface of one α / β pairs of F1, thus inhibiting, with the same pH dependence as the natural IF1, the conformational interconversions of the catalytic sites involved in ATP hydrolysis. IF1 has a relevant physiopathological role for the conservation of the cellular ATP pool in ischemic tissues. Under these conditions IF1, which appears to be over expressed, prevents dissipation of the glycolytic ATP.

Keywords: FoF1-ATP Synthase, enzyme, mitochondrial, oligomycin, physiopathological

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Article Details

Year: 2002
Page: [451 - 460]
Pages: 10
DOI: 10.2174/1389203023380558
Price: $65

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