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5i35

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Structure of the Human mitochondrial kinase COQ8A R611K with AMPPNP (Cerebellar Ataxia and Ubiquinone Deficiency Through Loss of Unorthodox Kinase Activity)

Structural highlights

5i35 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

COQ8A_HUMAN Autosomal recessive ataxia due to ubiquinone deficiency. The disease is caused by variants affecting the gene represented in this entry.

Function

COQ8A_HUMAN Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration (PubMed:21296186, PubMed:25498144, PubMed:25540914, PubMed:27499294). Its substrate specificity is unclear: does not show any protein kinase activity (PubMed:25498144, PubMed:27499294). Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway, as suggested by its ability to bind coenzyme Q lipid intermediates (PubMed:25498144, PubMed:27499294). Shows an unusual selectivity for binding ADP over ATP (PubMed:25498144).^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stefely JA, Reidenbach AG, Ulbrich A, Oruganty K, Floyd BJ, Jochem A, Saunders JM, Johnson IE, Minogue CE, Wrobel RL, Barber GE, Lee D, Li S, Kannan N, Coon JJ, Bingman CA, Pagliarini DJ. Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis. Mol Cell. 2015 Jan 8;57(1):83-94. doi: 10.1016/j.molcel.2014.11.002. Epub 2014, Dec 11. PMID:25498144 doi:http://dx.doi.org/10.1016/j.molcel.2014.11.002
↑ 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
↑ 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
↑ Wheeler B, Jia Z. Preparation and characterization of human ADCK3, a putative atypical kinase. Protein Expr Purif. 2015 Apr;108:13-17. doi: 10.1016/j.pep.2014.12.008. Epub 2014 , Dec 22. PMID:25540914 doi:http://dx.doi.org/10.1016/j.pep.2014.12.008
↑ 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