PT  - JOURNAL ARTICLE
AU  - Mateusz Manicki
AU  - Halil Aydin
AU  - Luciano A. Abriata
AU  - Katherine A. Overmyer
AU  - Rachel M. Guerra
AU  - Joshua J. Coon
AU  - Matteo Dal Peraro
AU  - Adam Frost
AU  - David J. Pagliarini
TI  - Structure and functionality of a multimeric human COQ7:COQ9 complex
AID  - 10.1101/2021.11.15.468694
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.15.468694
4099  - http://biorxiv.org/content/early/2021/11/15/2021.11.15.468694.short
4100  - http://biorxiv.org/content/early/2021/11/15/2021.11.15.468694.full
AB  - 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.Competing Interest StatementJoshua J. Coon is a consultant for Thermo Scientific. Adam Frost is a shareholder and consultant for Relay Therapeutics, LLC.