TY - JOUR T1 - Conserved lipid and small molecule modulation of COQ8 reveals regulation of the ancient UbiB family JF - bioRxiv DO - 10.1101/149823 SP - 149823 AU - Andrew G. Reidenbach AU - Zachary A. Kemmerer AU - Deniz Aydin AU - Adam Jochem AU - Molly T. McDevitt AU - Paul D. Hutchins AU - Emily M. Wilkerson AU - Jaime L. Stark AU - Jonathan A. Stefely AU - Isabel E. Johnson AU - Craig A. Bingman AU - John L. Markley AU - Joshua J. Coon AU - Matteo Dal Peraro AU - David J. Pagliarini Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/13/149823.abstract N2 - Human COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 and its direct role in CoQ production remain unclear, in part due to lack of known endogenous regulators of COQ8 function and of effective small molecules for probing its activity in vivo. Here we demonstrate that COQ8 possesses evolutionarily conserved ATPase activity that is activated by binding to membranes containing cardiolipin and by phenolic compounds that resemble CoQ pathway intermediates. We further create an analog-sensitive version of Coq8p and reveal that acute chemical inhibition of its endogenous activity in yeast is sufficient to cause respiratory deficiency concomitant with CoQ depletion. Collectively, this work defines lipid and small molecule modulators of an ancient family of atypical kinase-like proteins and establishes a chemical genetic system for further exploring the mechanistic role of COQ8 in CoQ biosynthesis. ER -