Structure and functionality of a multimeric human COQ7:COQ9 complex

Manicki, M.; Aydin, H.; Abriata, L. A.; Overmyer, K. A.; Guerra, R. M.; Coon, J. J.; Dal Peraro, M.; Frost, A. S.; Pagliarini, D. J.

doi:10.1101/2021.11.15.468694

bioRxiv · 10.1101/2021.11.15.468694

Structure and functionality of a multimeric human COQ7:COQ9 complex

Manicki, M.·Aydin, H.·Abriata, L. A.·Overmyer, K. A.·Guerra, R. M.·Coon, J. J.·Dal Peraro, M.·Frost, A. S.·Pagliarini, D. J.

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Abstract

Coenzyme Q (CoQ, ubiquinone) 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 a structure and functional analyses of a substrate- and NADH-bound oligomeric complex comprised of two complex Q subunits: the hydroxylase COQ7, which performs the penultimate step in CoQ biosynthesis, and the prenyl lipid-binding protein COQ9. We reveal that COQ7 adopts a modified ferritin-like fold with an extended hydrophobic access channel whose substrate binding capacity is enhanced by COQ9. Using molecular dynamics simulations, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for CoQ intermediates to translocate from within the bilayer to the proteins lipid-binding sites. Two such tetramers assemble into a soluble octamer, closed like a capsid, with lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors and coordinate subsequent synthesis steps toward producing mature CoQ.

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Manicki, M., Aydin, H., Abriata, L. A., Overmyer, K. A., Guerra, R. M., Coon, J. J., Dal Peraro, M., Frost, A. S., Pagliarini, D. J.. 2021-11-15. Structure and functionality of a multimeric human COQ7:COQ9 complex. https://doi.org/10.1101/2021.11.15.468694

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