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Flexible coupling in mitochondrial F1Fo-ATP synthase resolved by single-particle cryo-EM

ATP synthase is an intricate molecular machine that uses energy from down-gradient proton translocation in the Fo rotor to power ATP synthesis in the F1 head. A stoichiometric mismatch between processes in Fo (8-17 protons per rotation) and F1 (three molecules of ATP per rotation) poses a challenge to efficient energy conversion within the complex. A long-standing proposal suggests that flexibility within the complex mediates efficient coupling, but the structural basis of this flexibility is unresolved, with most previous proposals involving central stalk flexion. We have used single-particle cryo-EM in order to study the structure and conformational variability of dimeric mitochondrial ATP synthase from the green alga Polytomella.  Using 3D classification of half-dimers, we resolve 13 distinct rotary substates, revealing substantial flexibility in the inter-domain hinge region of the oligomycin-sensitivity conferring protein (OSCP) which connects the F1 head to the peripheral stalk. This flexibility allows the F1 head to rotate together with the central stalk through an angle of ~30°, or one c-subunit. This flexibility provides a novel mechanism for flexible F1/Fo coupling, and gives much-needed context to many studies finding that OSCP is an important point of metabolic control within the cell. 3D classification also provides important insight into the role of a newly-described metal ion within the lumenal channel of Fo.


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