Sci Adv. 2026 Jul 31;12(31):eaeg1124. doi: 10.1126/sciadv.aeg1124. Epub 2026 Jul 29.
ABSTRACT
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.
PMID:42525751 | DOI:10.1126/sciadv.aeg1124