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

Cell Chem Biol. 2018 Feb 15;25(2):154-165.e11. doi: 10.1016/j.chembiol.2017.11.001. Epub 2017 Nov 30.

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.

Keywords: 2-alkylphenols; ATPase; COQ8A; Coq8p; UbiB; analog-sensitive; atypical kinase; cardiolipin; coenzyme Q; mitochondrial chemical biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Humans
  • Lipids / chemistry*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Saccharomyces cerevisiae / chemistry
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism*

Substances

  • ADCK3 protein, human
  • COQ8 protein, S cerevisiae
  • Lipids
  • Mitochondrial Proteins
  • Saccharomyces cerevisiae Proteins
  • Small Molecule Libraries
  • Adenosine Triphosphatases