COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating
- Andrea Gottinger
- Marco Malatesta
- Callum R. Nicoll
- Georg Ansari
- Mathieu Quinodoz
- Karolina Kaminska
- Rachael W.C. Tang
- Tien-En Tan
- Beau J. Fenner
- Pilar Barberán-Martínez
- Gema García-García
- José M. Millán
- Maximilian Pfau
- Natalie E. Burbach
- Domiziana Cecchini
- Carlo Rivolta
- Andrea Mattevi
2026-07-29
Coenzyme Q biosynthesis requires two atypical kinase-like proteins (COQ8A and COQ8B), whose detailed molecular mechanism remains unclear. Here, we show that both paralogs function as adenosine triphosphatases (ATPases) that promote coenzyme Q biosynthetic metabolon activity by engaging in loose protein-protein interactions and delivering insoluble biosynthetic intermediates. Structural bioinformatics and pathological variant–driven mutagenesis identify a previously uncharacterized pocket that selectively recognizes coenzyme Q biosynthetic intermediates via their head groups. X-ray crystallography reveals that access to this pocket is gated by long-range conformational changes controlled by adenosine 5′-triphosphate hydrolysis. Last, excess coenzyme Q suppresses binding of early-stage intermediates and thereby abolishes the promoting effect of COQ8 on the metabolon. Together, these findings support a model in which COQ8 tunes coenzyme Q biosynthesis by coupling ATPase-driven intermediate chaperoning to feedback inhibition by the final product.