Molecular Cell
Volume 63, Issue 4, 18 August 2016, Pages 608-620
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Article
Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

https://doi.org/10.1016/j.molcel.2016.06.030Get rights and content
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Highlights

  • 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)

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.

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