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

Date publication

août 2016

Journal

Molecular cell

Auteurs

Membres identifiés du Cancéropôle Est :
Dr ZOLL Joffrey

Tous les auteurs :
Stefely JA, Licitra F, Laredj L, Reidenbach AG, Kemmerer ZA, Grangeray A, Jaeg-Ehret T, Minogue CE, Ulbrich A, Hutchins PD, Wilkerson EM, Ruan Z, Aydin D, Hebert AS, Guo X, Freiberger EC, Reutenauer L, Jochem A, Chergova M, Johnson IE, Lohman DC, Rush MJP, Kwiecien NW, Singh PK, Schlagowski AI, Floyd BJ, Forsman U, Sindelar PJ, Westphall MS, Pierrel F, Zoll J, Dal Peraro M, Kannan N, Bingman CA, Coon JJ, Isope P, Puccio H, Pagliarini DJ

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/27499294

Résumé

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.

Mots clés

Animals, Behavior, Animal, COS Cells, Cerebellar Ataxia, enzymology, Cerebellum, enzymology, 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, Models, Molecular, Motor Activity, Muscle Strength, Muscle, Skeletal, enzymology, Phenotype, Protein Binding, Protein Conformation, Proteomics, methods, Recognition, Psychology, Rotarod Performance Test, Saccharomyces cerevisiae, enzymology, Saccharomyces cerevisiae Proteins, genetics, Seizures, enzymology, Structure-Activity Relationship, Time Factors, Transfection, Ubiquinone, chemistry

Référence

Mol Cell. 2016 08 18;63(4):608-620