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
Volume111
Issue31
Pagination11305-10
Date Published2014 Aug 05
ISSN1091-6490
KeywordsAnimals, Cattle, Crystallography, X-Ray, Intrinsically Disordered Proteins, Mitochondrial Proteins, Protein Binding, Protein Folding, Protein Structure, Secondary, Protein Subunits, Proteins, Proton-Translocating ATPases
Abstract

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.

DOI10.1073/pnas.1411560111
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
/ / Medical Research Council / United Kingdom