Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

Jonathan A Stefely; Floriana Licitra; Leila Laredj; Andrew G Reidenbach; Zachary A Kemmerer; Anais Grangeray; Tiphaine Jaeg-Ehret; Catherine E Minogue; Arne Ulbrich; Paul D Hutchins; Emily M Wilkerson; Zheng Ruan; Deniz Aydin; Alexander S Hebert; Xiao Guo; Elyse C Freiberger; Laurence Reutenauer; Adam Jochem; Maya Chergova; Isabel E Johnson; Danielle C Lohman; Matthew J P Rush; Nicholas W Kwiecien; Pankaj K Singh; Anna I Schlagowski; Brendan J Floyd; Ulrika Forsman; Pavel J Sindelar; Michael S Westphall; Fabien Pierrel; Joffrey Zoll; Matteo Dal Peraro; Natarajan Kannan; Craig A Bingman; Joshua J Coon; Philippe Isope; Hélène Puccio; David J Pagliarini

doi:10.1016/j.molcel.2016.06.030

Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

Mol Cell. 2016 Aug 18;63(4):608-620. doi: 10.1016/j.molcel.2016.06.030. Epub 2016 Aug 4.

Authors

Jonathan A Stefely¹, Floriana Licitra², Leila Laredj², Andrew G Reidenbach¹, Zachary A Kemmerer¹, Anais Grangeray³, Tiphaine Jaeg-Ehret², Catherine E Minogue⁴, Arne Ulbrich⁴, Paul D Hutchins⁴, Emily M Wilkerson⁴, Zheng Ruan⁵, Deniz Aydin⁶, Alexander S Hebert⁷, Xiao Guo⁸, Elyse C Freiberger⁹, Laurence Reutenauer², Adam Jochem¹⁰, Maya Chergova², Isabel E Johnson¹, Danielle C Lohman¹, Matthew J P Rush⁴, Nicholas W Kwiecien⁴, Pankaj K Singh², Anna I Schlagowski¹¹, Brendan J Floyd¹, Ulrika Forsman¹², Pavel J Sindelar¹³, Michael S Westphall⁷, Fabien Pierrel¹⁴, Joffrey Zoll¹¹, Matteo Dal Peraro⁶, Natarajan Kannan⁵, Craig A Bingman⁹, Joshua J Coon¹⁵, Philippe Isope³, Hélène Puccio¹⁶, David J Pagliarini¹⁷

Affiliations

¹ Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
² Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U596, CNRS UMR 7104, 67400 Illkirch, France; Université de Strasbourg, 67081 Strasbourg, France; Chaire de Génétique Humaine, Collège de France, 67404 Illkirch, France.
³ Université de Strasbourg, 67081 Strasbourg, France; Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, 67084 Strasbourg, France.
⁴ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁵ Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA; Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
⁶ Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
⁷ Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁸ Morgridge Institute for Research, Madison, WI 53715, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁹ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹⁰ Morgridge Institute for Research, Madison, WI 53715, USA.
¹¹ Fédération de Medicine Translationnelle de Strasbourg, EA3072, Faculté de Médicine et Faculté des Sciences du Sport, Université de Strasbourg, 67084 Strasbourg, France.
¹² University Grenoble Alpes, LCBM, UMR 5249, 38000 Grenoble, France.
¹³ University Grenoble Alpes, LCBM, UMR 5249, 38000 Grenoble, France; Laboratoire de Chimie des Processus Biologiques, CNRS UMR 8229, Collège de France, 75252 Paris, France.
¹⁴ University Grenoble Alpes, LCBM, UMR 5249, 38000 Grenoble, France; TIMC-IMAG, CNRS UMR 5525, UFR de Médecine, University Joseph Fourier, 38706 La Tronche, France.
¹⁵ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
¹⁶ Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U596, CNRS UMR 7104, 67400 Illkirch, France; Université de Strasbourg, 67081 Strasbourg, France; Chaire de Génétique Humaine, Collège de France, 67404 Illkirch, France. Electronic address: hpuccio@igbmc.fr.
¹⁷ Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: dpagliarini@morgridge.org.

Abstract

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.

MeSH terms

Animals
Behavior, Animal*
COS Cells
Cerebellar Ataxia / enzymology*
Cerebellar Ataxia / genetics
Cerebellar Ataxia / physiopathology
Cerebellar Ataxia / psychology
Cerebellum / enzymology*
Cerebellum / physiopathology
Cerebellum / ultrastructure
Chlorocebus aethiops
Disease Models, Animal
Exercise Tolerance
Female
Genetic Predisposition to Disease
HEK293 Cells
Humans
Lipid Metabolism
Male
Maze Learning
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Proteins / chemistry
Mitochondrial Proteins / deficiency*
Mitochondrial Proteins / genetics
Models, Molecular
Motor Activity
Muscle Strength
Muscle, Skeletal / enzymology*
Muscle, Skeletal / physiopathology
Phenotype
Protein Binding
Protein Conformation
Proteomics / methods
Recognition, Psychology
Rotarod Performance Test
Saccharomyces cerevisiae / enzymology
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Seizures / enzymology
Seizures / genetics
Seizures / physiopathology
Structure-Activity Relationship
Time Factors
Transfection
Ubiquinone / chemistry
Ubiquinone / deficiency*
Ubiquinone / genetics

Substances

COQ8 protein, S cerevisiae
COQ8A protein, human
Mitochondrial Proteins
Saccharomyces cerevisiae Proteins
Ubiquinone
ubiquinone 8

Abstract

MeSH terms

Substances

Grants and funding