Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family

Andrew G. Reidenbach, Zachary A. Kemmerer, Deniz Aydin, Adam Jochem, Molly T. McDevitt, Paul D. Hutchins, Jaime L. Stark, Jonathan A. Stefely, Thiru Reddy, Alex S. Hebert, Emily M. Wilkerson, Isabel E. Johnson, Craig A. Bingman, John L. Markley, Joshua J. Coon, Matteo Dal Peraro, David J. Pagliarini

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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. Reidenbach et al. discover small-molecule and lipid ligands for the atypical kinase-like protein COQ8 that enhance its ATPase activity. They develop an analog-sensitive version of COQ8 that can be covalently inhibited, enabling acute inhibition of COQ8 ATPase activity in vitro and coenzyme Q biosynthesis in vivo.

Original languageEnglish
Pages (from-to)154-165.e11
JournalCell Chemical Biology
Volume25
Issue number2
DOIs
StatePublished - Feb 15 2018

Keywords

  • 2-alkylphenols
  • ATPase
  • COQ8A
  • Coq8p
  • UbiB
  • analog-sensitive
  • atypical kinase
  • cardiolipin
  • coenzyme Q
  • mitochondrial chemical biology

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