5I35

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

Summary for 5I35

• Entry DOI: 10.2210/pdb5i35/pdb
• Descriptor: Atypical kinase ADCK3, mitochondrial, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (3 entities in total)
• Functional Keywords: mitochondrial protein, kinase, ubiquinone biosynthesis, ubib clade kinase, structural genomics, psi-2, protein structure initiative, mitochondrial protein partnership, mpp, transferase, adck3, coenzyme q biosynthesis, adck3_human
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 46429.56

Authors

Bingman, C.A.,Stefely, J.A.,Pagliarini, D.J.,Mitochondrial Protein Partnership (MPP) (deposition date: 2016-02-09, release date: 2016-08-17, Last modification date: 2024-10-16)

Primary citation

Stefely, J.A.,Licitra, F.,Laredj, L.,Reidenbach, A.G.,Kemmerer, Z.A.,Grangeray, A.,Jaeg-Ehret, T.,Minogue, C.E.,Ulbrich, A.,Hutchins, P.D.,Wilkerson, E.M.,Ruan, Z.,Aydin, D.,Hebert, A.S.,Guo, X.,Freiberger, E.C.,Reutenauer, L.,Jochem, A.,Chergova, M.,Johnson, I.E.,Lohman, D.C.,Rush, M.J.,Kwiecien, N.W.,Singh, P.K.,Schlagowski, A.I.,Floyd, B.J.,Forsman, U.,Sindelar, P.J.,Westphall, M.S.,Pierrel, F.,Zoll, J.,Dal Peraro, M.,Kannan, N.,Bingman, C.A.,Coon, J.J.,Isope, P.,Puccio, H.,Pagliarini, D.J.
Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.
Mol.Cell, 63:608-620, 2016

PubMed 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.

PubMed: 27499294
DOI: 10.1016/j.molcel.2016.06.030

Experimental method

X-RAY DIFFRACTION (2.3 Å)