How the regulatory protein, IF(1), inhibits F(1)-ATPase from bovine mitochondria.

TitleHow the regulatory protein, IF(1), inhibits F(1)-ATPase from bovine mitochondria.
Publication TypeJournal Article
Year of Publication2007
AuthorsGledhill, JR, Montgomery, MG, Leslie, AGW, Walker, JE
JournalProc Natl Acad Sci U S A
Volume104
Issue40
Pagination15671-6
Date Published2007 Oct 02
ISSN0027-8424
KeywordsAdenosine Triphosphate, Animals, Binding Sites, Cattle, Dimerization, Hydrolysis, Mitochondria, Models, Molecular, Peptide Fragments, Protein Conformation, Proteins, Proton-Translocating ATPases
Abstract

The structure of bovine F(1)-ATPase inhibited by a monomeric form of the inhibitor protein, IF(1), known as I1-60His, lacking most of the dimerization region, has been determined at 2.1-A resolution. The resolved region of the inhibitor from residues 8-50 consists of an extended structure from residues 8-13, followed by two alpha-helices from residues 14-18 and residues 21-50 linked by a turn. The binding site in the beta(DP)-alpha(DP) catalytic interface is complex with contributions from five different subunits of F(1)-ATPase. The longer helix extends from the external surface of F(1) via a deep groove made from helices and loops in the C-terminal domains of subunits beta(DP), alpha(DP), beta(TP), and alpha(TP) to the internal cavity surrounding the central stalk. The linker and shorter helix interact with the gamma-subunit in the central stalk, and the N-terminal region extends across the central cavity to interact with the nucleotide binding domain of the alpha(E) subunit. To form these complex interactions and penetrate into the core of the enzyme, it is likely that the initial interaction of the inhibitor with F(1) forms via the open conformation of the beta(E) subunit. Then, as two ATP molecules are hydrolyzed, the beta(E)-alpha(E) interface converts to the beta(DP)-alpha(DP) interface via the beta(TP)-alpha(TP) interface, trapping the inhibitor progressively in its binding site and a nucleotide in the catalytic site of subunit beta(DP). The inhibition probably arises by IF(1) imposing the structure and properties of the beta(TP)-alpha(TP) interface on the beta(DP)-alpha(DP) interface, thereby preventing it from hydrolyzing the bound ATP.

DOI10.1073/pnas.0707326104
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.0707326104
PubMed ID17895376
PubMed Central IDPMC1994141
Grant ListMC_U105184325 / / Medical Research Council / United Kingdom
MC_U105663150 / / Medical Research Council / United Kingdom