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Conserved Lipid and Small-Molecule Modulation of COQ8 Reveals Regulation of the Ancient Kinase-like UbiB Family.
Reidenbach, Andrew G; Kemmerer, Zachary A; Aydin, Deniz; Jochem, Adam; McDevitt, Molly T; Hutchins, Paul D; Stark, Jaime L; Stefely, Jonathan A; Reddy, Thiru; Hebert, Alex S; Wilkerson, Emily M; Johnson, Isabel E; Bingman, Craig A; Markley, John L; Coon, Joshua J; Dal Peraro, Matteo; Pagliarini, David J.
Affiliation
  • Reidenbach AG; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Kemmerer ZA; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Aydin D; Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  • Jochem A; Morgridge Institute for Research, Madison, WI 53715, USA.
  • McDevitt MT; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Hutchins PD; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Stark JL; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Stefely JA; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Reddy T; Morgridge Institute for Research, Madison, WI 53715, USA.
  • Hebert AS; Genome Center of Wisconsin, Madison, WI 53706, USA.
  • Wilkerson EM; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Johnson IE; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Bingman CA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Markley JL; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Coon JJ; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Genome Center of Wisconsin, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Dal Peraro M; Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  • Pagliarini DJ; Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: dpagliarini@morgridge.org.
Cell Chem Biol ; 25(2): 154-165.e11, 2018 02 15.
Article in En | MEDLINE | ID: mdl-29198567
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Saccharomyces cerevisiae Proteins / Mitochondrial Proteins / Small Molecule Libraries / Lipids Limits: Humans Language: En Journal: Cell Chem Biol Year: 2018 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Saccharomyces cerevisiae Proteins / Mitochondrial Proteins / Small Molecule Libraries / Lipids Limits: Humans Language: En Journal: Cell Chem Biol Year: 2018 Document type: Article Affiliation country: Estados Unidos