title: Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.
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.
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Jonathan A
authors: JA
authors: Stefely
authors: 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.
authors: Floriana
authors: F
authors: Licitra
authors: 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.
authors: Leila
authors: L
authors: Laredj
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Andrew G
authors: AG
authors: Reidenbach
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Zachary A
authors: ZA
authors: Kemmerer
authors: Université de Strasbourg, 67081 Strasbourg, France; Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, 67084 Strasbourg, France.
authors: Anais
authors: A
authors: Grangeray
authors: 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.
authors: Tiphaine
authors: T
authors: Jaeg-Ehret
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Catherine E
authors: CE
authors: Minogue
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Arne
authors: A
authors: Ulbrich
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Paul D
authors: PD
authors: Hutchins
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Emily M
authors: EM
authors: Wilkerson
authors: Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA; Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors: Zheng
authors: Z
authors: Ruan
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors: Deniz
authors: D
authors: Aydin
authors: Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Alexander S
authors: AS
authors: Hebert
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Xiao
authors: X
authors: Guo
authors: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Elyse C
authors: EC
authors: Freiberger
authors: 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.
authors: Laurence
authors: L
authors: Reutenauer
authors: Morgridge Institute for Research, Madison, WI 53715, USA.
authors: Adam
authors: A
authors: Jochem
authors: 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.
authors: Maya
authors: M
authors: Chergova
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Isabel E
authors: IE
authors: Johnson
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Danielle C
authors: DC
authors: Lohman
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Matthew J P
authors: MJP
authors: Rush
authors: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Nicholas W
authors: NW
authors: Kwiecien
authors: 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.
authors: Pankaj K
authors: PK
authors: Singh
authors: Fédération de Medicine Translationnelle de Strasbourg, EA3072, Faculté de Médicine et Faculté des Sciences du Sport, Université de Strasbourg, 67084 Strasbourg, France.
authors: Anna I
authors: AI
authors: Schlagowski
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Brendan J
authors: BJ
authors: Floyd
authors: University Grenoble Alpes, LCBM, UMR 5249, 38000 Grenoble, France.
authors: Ulrika
authors: U
authors: Forsman
authors: University Grenoble Alpes, LCBM, UMR 5249, 38000 Grenoble, France; Laboratoire de Chimie des Processus Biologiques, CNRS UMR 8229, Collège de France, 75252 Paris, France.
authors: Pavel J
authors: PJ
authors: Sindelar
authors: Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Michael S
authors: MS
authors: Westphall
authors: University Grenoble Alpes, LCBM, UMR 5249, 38000 Grenoble, France; TIMC-IMAG, CNRS UMR 5525, UFR de Médecine, University Joseph Fourier, 38706 La Tronche, France.
authors: Fabien
authors: F
authors: Pierrel
authors: Fédération de Medicine Translationnelle de Strasbourg, EA3072, Faculté de Médicine et Faculté des Sciences du Sport, Université de Strasbourg, 67084 Strasbourg, France.
authors: Joffrey
authors: J
authors: Zoll
authors: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors: Matteo
authors: M
authors: Dal Peraro
authors: Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA; Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors: Natarajan
authors: N
authors: Kannan
authors: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Craig A
authors: CA
authors: Bingman
authors: 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.
authors: Joshua J
authors: JJ
authors: Coon
authors: Université de Strasbourg, 67081 Strasbourg, France; Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, 67084 Strasbourg, France.
authors: Philippe
authors: P
authors: Isope
authors: 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.
authors: Hélène
authors: H
authors: Puccio
authors: Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: dpagliarini@morgridge.org.
authors: David J
authors: DJ
authors: Pagliarini
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D019556:COS Cells; D002524:Cerebellar Ataxia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D002531:Cerebellum / Q000201:enzymology* / Q000503:physiopathology / Q000648:ultrastructure; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D017079:Exercise Tolerance; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D008958:Models, Molecular; D009043:Motor Activity; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000503:physiopathology; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D040901:Proteomics / Q000379:methods; D021641:Recognition, Psychology; D045442:Rotarod Performance Test; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection; D014451:Ubiquinone / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics
chemical_list: C099891:COQ8 protein, S cerevisiae; C553453:COQ8A protein, human; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D014451:Ubiquinone; C030778:ubiquinone 8