RT Journal Article
SR Electronic
T1 Conserved lipid and small molecule modulation of COQ8 reveals regulation of the ancient UbiB family
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 149823
DO 10.1101/149823
A1 Andrew G. Reidenbach
A1 Zachary A. Kemmerer
A1 Deniz Aydin
A1 Adam Jochem
A1 Molly T. McDevitt
A1 Paul D. Hutchins
A1 Emily M. Wilkerson
A1 Jaime L. Stark
A1 Jonathan A. Stefely
A1 Isabel E. Johnson
A1 Craig A. Bingman
A1 John L. Markley
A1 Joshua J. Coon
A1 Matteo Dal Peraro
A1 David J. Pagliarini
YR 2017
UL http://biorxiv.org/content/early/2017/06/13/149823.abstract
AB 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.