Figure 7.

Double function of mitochondrial IF₁as intrinsic F₁F_O-ATPase inhibitor and as dimerizing and oligomerizing factor of the mitochondrial F-ATP synthase. (A) The first EM 2D structure of bovine mitochondrial dimeric F₁F_O-IF₁ complex [102] is shown as an average of the complete set of collected images, indicating the originally proposed sites for IF₁ as a central protein bridge structure connecting the F₁–F₁ moieties. On the other hand, the proposed dimerizing subunits e and g form a “hanging bridge” at the Fo-Fo dimer interface [102]. (B) Two-dimensional cartoon model of the mitochondrial F-ATP synthase dimer showing the proposed positions of IF₁ (yellow) and e and g subunits (red/blue) according to functional and mutagenesis studies [103,104,105,106,107]. (C) The structure of tetrameric mitochondrial F-ATP synthase of pig Sus scrofa as resolved by Cryo-EM depicted as two small-angle (≈40°) V-shaped homodimers bridged by an antiparallel coiled-coil homodimer of the IF₁ inhibitor (red). Two large-angle dimers (≈60°–90°) form another, more open V-shaped dimer connected through F_O-F_O dimerizing subunits (e, g, and others) at the center of the tetramer. The dimerizing and oligomerizing function of mitochondrial IF₁ lies on its C-terminal domain forming an antiparallel IF₁-IF₁ coiled-coil (red F₁-F₁ bridge and see Figure 1D and Figure 7), and its inhibitory domain is inserted in the α_DPβ_DPγ interface of each monomer (see Figure 1C). The dimerizing function of IF₁ was also demonstrated functionally by some of us with removal and reconstitution of IF₁, which promoted, respectively, monomerization and dimerization/oligomerization of the mitochondrial rat liver F-ATP synthase. See Ref. [108] and text for further details.