Extrinsic conditions influence the self-association and structure of IF<sub>1</sub>, the regulatory protein of mitochondrial ATP synthase.
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Boreikaite, V., Wicky, B., Watt, I. N., Clarke, J., & Walker, J. (2019). Extrinsic conditions influence the self-association and structure of IF<sub>1</sub>, the regulatory protein of mitochondrial ATP synthase.. Proceedings of the National Academy of Sciences of the United States of America, 116 (21), 10354-10359. https://doi.org/10.1073/pnas.1903535116
The endogenous inhibitor of ATP synthase in mitochondria, known as IF1, conserves cellular energy when the proton motive force collapses by inhibiting ATP hydrolysis. Around neutrality, the 84 amino acid bovine IF1 is thought to self-assemble into active dimers, and under alkaline conditions into inactive tetramers and higher oligomers. Dimerization is mediated by formation of an anti-parallel α-helical coiled-coil involving residues 44-84. The inhibitory region of each monomer from residues 1-46 is largely α-helical in crystals, but disordered in solution. The formation of the inhibited enzyme complex requires the hydrolysis of two ATP molecules, and in the complex the disordered region from residues 8-13 is extended and is followed by an α-helix from residues 14-18, and a longer α-helix from residue 21, which continues unbroken into the coiled-coil region. From residues 21-46, the long α-helix binds to other α-helices in C-terminal region of predominantly one of the β-subunits in the most closed of the three catalytic interfaces. The definition of the factors that influence the self-association of IF1 is a key to understanding the regulation of its inhibitory properties. Therefore, we investigated the influence of pH and salt-types on the self-association of bovine IF1 and the folding of its unfolded region. We identified the equilibrium between dimers and tetramers as a potential central factor in the in vivo modulation of the inhibitory activity, and suggest that the intrinsically disordered region makes its inhibitory potency exquisitely sensitive and responsive to physiological changes that influence the capability of mitochondria to make ATP.
Mitochondria, Animals, Cattle, Mitochondrial Proton-Translocating ATPases, Amino Acids, Proteins, Protein Binding, Dimerization, Hydrolysis, Hydrogen-Ion Concentration, Protein Conformation, alpha-Helical
Wellcome Trust (095195/Z/10/Z)
Wellcome Trust (101474/Z/13/Z)
External DOI: https://doi.org/10.1073/pnas.1903535116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291817
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