title: Pathway of binding of the intrinsically disordered mitochondrial inhibitor protein to F1-ATPase.
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.
authors: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom; and.
authors: John V
authors: JV
authors: Bason
authors: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom; and.
authors: Martin G
authors: MG
authors: Montgomery
authors: The Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.
authors: Andrew G W
authors: AG
authors: Leslie
authors: The Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom; and walker@mrc-mbu.cam.ac.uk.
authors: John E
authors: JE
authors: Walker
mesh_terms: D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D064267:Intrinsically Disordered Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000097795:ATPase Inhibitory Protein
chemical_list: D064267:Intrinsically Disordered Proteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; D011506:Proteins; D006180:Proton-Translocating ATPases; D000097795:ATPase Inhibitory Protein
keywords: binding site; folding; inhibitory path; rotary catalysis