Structure and functionality of a multimeric human COQ7:COQ9 complex

Coenzyme Q (CoQ) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined “complex Q” metabolon. Here, we present structure-function analyses of a lipid-, substrate-, and NADH-bound complex compr...

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Veröffentlicht in:Molecular cell 2022-11, Vol.82 (22), p.4307-4323.e10
Hauptverfasser: Manicki, Mateusz, Aydin, Halil, Abriata, Luciano A., Overmyer, Katherine A., Guerra, Rachel M., Coon, Joshua J., Dal Peraro, Matteo, Frost, Adam, Pagliarini, David J.
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Sprache:eng
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Zusammenfassung:Coenzyme Q (CoQ) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined “complex Q” metabolon. Here, we present structure-function analyses of a lipid-, substrate-, and NADH-bound complex comprising two complex Q subunits: the hydroxylase COQ7 and the lipid-binding protein COQ9. We reveal that COQ7 adopts a ferritin-like fold with a hydrophobic channel whose substrate-binding capacity is enhanced by COQ9. Using molecular dynamics, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for the CoQ intermediates to translocate from the bilayer to the proteins’ lipid-binding sites. Two such tetramers assemble into a soluble octamer with a pseudo-bilayer of lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors within the membrane and coordinate subsequent synthesis steps toward producing CoQ. [Display omitted] •Molecular architecture of a human COQ7:COQ9 complex with bound membrane lipids•CoQ precursors bound to COQ7 reveal details of substrate selection and loading•COQ7 NADH binding suggests a sequential electron-proton-electron donation mechanism•Tetrameric complex reshapes lipid membranes to access substrates within the bilayer Manicki et al. report an atomic model of a human COQ7:COQ9 complex and provide mechanistic insights into its molecular functions that facilitate CoQ biosynthesis. MD simulations further show how this metabolon-like CoQ complex can surmount hydrophobic challenges at the aqueous/membrane interface to access CoQ precursors.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2022.10.003