Pathway of binding of the intrinsically disordered mitochondrial inhibitor protein to F1-ATPase.

TitlePathway of binding of the intrinsically disordered mitochondrial inhibitor protein to F1-ATPase.
Publication TypeJournal Article
Year of Publication2014
AuthorsBason, JV, Montgomery, MG, Leslie, AGW, Walker, JE
JournalProc Natl Acad Sci U S A
Date Published2014 Aug 05
KeywordsAnimals, Cattle, Crystallography, X-Ray, Intrinsically Disordered Proteins, Mitochondrial Proteins, Protein Binding, Protein Folding, Protein Structure, Secondary, Protein Subunits, Proteins, Proton-Translocating ATPases

The 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 α-helical and buried deeply at the α(DP)β(DP)-catalytic interface, where it forms extensive interactions with five of the nine subunits of F1-ATPase but mainly with the β(DP)-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 αEβE-catalytic interface, the most open of the three catalytic interfaces, where the available interactions with the enzyme allow it to form an α-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 αTPβTP state, the extent of the folded α-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° rotation of the γ-subunit, the interface closes further to the α(DP)β(DP)-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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.1411560111
PubMed ID25049402
PubMed Central IDPMC4128166
Grant ListMC_U105184325 / / Medical Research Council / United Kingdom
MC_U105663150 / / Medical Research Council / United Kingdom