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. JohnsonDanielle 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

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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.

Original languageEnglish
Pages (from-to)608-620
Number of pages13
JournalMolecular cell
Issue number4
StatePublished - Aug 18 2016


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