| Structural highlights
Disease
[ADCK3_HUMAN] Autosomal recessive ataxia due to ubiquinone deficiency. The disease is caused by mutations affecting the gene represented in this entry.
Function
[ADCK3_HUMAN] Putative protein kinase involved in the biosynthesis of coenzyme Q since it is able to rescue partially coenzyme Q6 biosynthesis of yeast COQ8 mutants. May be a chaperone-like protein essential for the proper conformation and functioning of protein complexes in the respiratory chain.[1]
Publication Abstract from PubMed
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.
Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.,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 MJ, 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 Mol Cell. 2016 Aug 18;63(4):608-20. doi: 10.1016/j.molcel.2016.06.030. Epub 2016 , Aug 4. PMID:27499294[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Xie LX, Hsieh EJ, Watanabe S, Allan CM, Chen JY, Tran UC, Clarke CF. Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants. Biochim Biophys Acta. 2011 May;1811(5):348-60. doi: 10.1016/j.bbalip.2011.01.009., Epub 2011 Feb 4. PMID:21296186 doi:http://dx.doi.org/10.1016/j.bbalip.2011.01.009
- ↑ 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 MJ, 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. Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity. Mol Cell. 2016 Aug 18;63(4):608-20. doi: 10.1016/j.molcel.2016.06.030. Epub 2016 , Aug 4. PMID:27499294 doi:http://dx.doi.org/10.1016/j.molcel.2016.06.030
|
