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

doi:10.1016/j.chembiol.2017.11.001

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.

Authors

Andrew G Reidenbach¹, Zachary A Kemmerer¹, Deniz Aydin², Adam Jochem³, Molly T McDevitt¹, Paul D Hutchins⁴, Jaime L Stark⁵, Jonathan A Stefely¹, Thiru Reddy³, Alex S Hebert⁶, Emily M Wilkerson⁴, Isabel E Johnson¹, Craig A Bingman⁵, John L Markley⁵, Joshua J Coon⁷, Matteo Dal Peraro², David J Pagliarini⁸

Affiliations

¹ Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
² Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
³ Morgridge Institute for Research, Madison, WI 53715, USA.
⁴ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁵ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁶ Genome Center of Wisconsin, Madison, WI 53706, USA.
⁷ 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.
⁸ Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: [email protected].

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

COQ8 protein, S cerevisiae
COQ8A protein, human
Lipids
Mitochondrial Proteins
Saccharomyces cerevisiae Proteins
Small Molecule Libraries
Adenosine Triphosphatases

Abstract

Publication types

MeSH terms

Substances

Grants and funding