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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. In this work 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:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); Searle Scholars; Vilas Associates Awards; National Institutes of Health (NIH); European Research Council (ERC); National Science Foundation (NSF); Swiss National Science Foundation (SNF); French National Research Agency (ANR); Michigan Economic Development Corporation; National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS)
OSTI Identifier:
1393679
Alternate Identifier(s):
OSTI ID: 1357649
Grant/Contract Number:  
AC02-06CH11357; U01GM94622; R01DK098672; R01GM112057; R01GM115591; 206634/ ISCATAXIA; F30AG043282; T32GM008505; 5T32GM08349; DGE-1256259; T32DK007665; R35GM118110; 200021_157217; pABACoQ
Resource Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Name: Molecular Cell Journal Volume: 63 Journal Issue: 4; Journal ID: ISSN 1097-2765
Publisher:
Cell Press - Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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, and Pagliarini, David J. Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity. United States: N. p., 2016. Web. doi:10.1016/j.molcel.2016.06.030.
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. Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity. United States. doi:10.1016/j.molcel.2016.06.030.
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, and Pagliarini, David J. Thu . "Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity". United States. doi:10.1016/j.molcel.2016.06.030.
@article{osti_1393679,
title = {Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity},
author = {Stefely, Jonathan A. and Licitra, Floriana and Laredj, Leila and Reidenbach, Andrew G. and Kemmerer, Zachary A. and Grangeray, Anais and Jaeg-Ehret, Tiphaine and Minogue, Catherine E. and Ulbrich, Arne and Hutchins, Paul D. and Wilkerson, Emily M. and Ruan, Zheng and Aydin, Deniz and Hebert, Alexander S. and Guo, Xiao and Freiberger, Elyse C. and Reutenauer, Laurence and Jochem, Adam and Chergova, Maya and Johnson, Isabel E. and Lohman, Danielle C. and Rush, Matthew J. P. and Kwiecien, Nicholas W. and Singh, Pankaj K. and Schlagowski, Anna I. and Floyd, Brendan J. and Forsman, Ulrika and Sindelar, Pavel J. and Westphall, Michael S. and Pierrel, Fabien and Zoll, Joffrey and Dal Peraro, Matteo and Kannan, Natarajan and Bingman, Craig A. and Coon, Joshua J. and Isope, Philippe and Puccio, Hélène and Pagliarini, David J.},
abstractNote = {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. In this work 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.},
doi = {10.1016/j.molcel.2016.06.030},
journal = {Molecular Cell},
number = 4,
volume = 63,
place = {United States},
year = {2016},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1016/j.molcel.2016.06.030

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