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The Pathway of Binding of the Intrinsically Disordered Mitochondrial Inhibitor Protein to F1-ATPase
Structural highlights
FunctionATPA_BOVIN Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Subunits alpha and beta form the catalytic core in F(1). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites (By similarity). Publication Abstract from PubMedThe hydrolysis of ATP by the ATP synthase in mitochondria is inhibited by a protein called IF1. Bovine IF1 has 84 amino acids, and its N-terminal inhibitory region is intrinsically disordered. In a known structure of bovine F1-ATPase inhibited with residues 1-60 of IF1, the inhibitory region from residues 1-50 is mainly alpha-helical and buried deeply at the alphaDPbetaDP-catalytic interface, where it forms extensive interactions with five of the nine subunits of F1-ATPase but mainly with the betaDP-subunit. As described here, on the basis of two structures of inhibited complexes formed in the presence of large molar excesses of residues 1-60 of IF1 and of a version of IF1 with the mutation K39A, it appears that the intrinsically disordered inhibitory region interacts first with the alphaEbetaE-catalytic interface, the most open of the three catalytic interfaces, where the available interactions with the enzyme allow it to form an alpha-helix from residues 31-49. Then, in response to the hydrolysis of an ATP molecule and the associated partial closure of the interface to the alphaTPbetaTP state, the extent of the folded alpha-helical region of IF1 increases to residues 23-50 as more interactions with the enzyme become possible. Finally, in response to the hydrolysis of a second ATP molecule and a concomitant 120 degrees rotation of the gamma-subunit, the interface closes further to the alphaDPbetaDP-state, allowing more interactions to form between the enzyme and IF1. The structure of IF1 now extends to its maximally folded state found in the previously observed inhibited complex. Pathway of binding of the intrinsically disordered mitochondrial inhibitor protein to F1-ATPase.,Bason JV, Montgomery MG, Leslie AG, Walker JE Proc Natl Acad Sci U S A. 2014 Jul 21. pii: 201411560. PMID:25049402[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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