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

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 mean...

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Published in:Molecular cell 2016-08, Vol.63 (4), p.608-620
Main Authors: Stefely, Jonathan A., Licitra, Floriana, Laredj, Leila, Reidenbach, Andrew G., Kemmerer, Zachary A., Grangeray, Anais, Jaeg-Ehret, Tiphaine, Minogue, Catherine E., Ulbrich, Arne, Hutchins, Paul D., Wilkerson, Emily M., Ruan, Zheng, Aydin, Deniz, Hebert, Alexander S., Guo, Xiao, Freiberger, Elyse C., Reutenauer, Laurence, Jochem, Adam, Chergova, Maya, Johnson, Isabel E., Lohman, Danielle C., Rush, Matthew J.P., Kwiecien, Nicholas W., Singh, Pankaj K., Schlagowski, Anna I., Floyd, Brendan J., Forsman, Ulrika, Sindelar, Pavel J., Westphall, Michael S., Pierrel, Fabien, Zoll, Joffrey, Dal Peraro, Matteo, Kannan, Natarajan, Bingman, Craig A., Coon, Joshua J., Isope, Philippe, Puccio, Hélène, Pagliarini, David J.
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal
Biochemistry, Molecular Biology
Cerebellar Ataxia - enzymology
Cerebellar Ataxia - genetics
Cerebellar Ataxia - physiopathology
Cerebellar Ataxia - psychology
Cerebellum - enzymology
Cerebellum - physiopathology
Cerebellum - ultrastructure
Chlorocebus aethiops
COS Cells
Disease Models, Animal
Exercise Tolerance
Female
Genetic Predisposition to Disease
HEK293 Cells
Humans
Life Sciences
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
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Summary: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. [Display omitted] •Coq8a–/– mice recapitulate the most frequent form of human genetic CoQ deficiency•COQ8A maintains a mammalian coenzyme Q (ubiquinone) biosynthesis complex•COQ8 stabilizes complex Q through unorthodox kinase-like mechanisms•COQ8 binds lipid CoQ intermediates with a conserved structural feature (KxGQ domain) The ancient UbiB protein kinase-like (PKL) family has five human members (ADCK1–5), which are largely uncharacterized. Stefely et al. demonstrate that COQ8A (ADCK3) possesses conserved unorthodox PKL functionalities essential for maintaining a CoQ biosynthesis complex. Loss of COQ8A disrupts this complex, causing CoQ deficiency and cerebellar ataxia.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2016.06.030