Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q Biosynthesis

Jonathan A. Stefely, Andrew G. Reidenbach, Arne Ulbrich, Krishnadev Oruganty, Brendan J. Floyd, Adam Jochem, Jaclyn M. Saunders, Isabel E. Johnson, Catherine E. Minogue, Russell L. Wrobel, Grant E. Barber, David Lee, Sheng Li, Natarajan Kannan, Joshua J. Coon, Craig A. Bingman, David J. Pagliarini

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

The ancient UbiB protein kinase-like family is involved in isoprenoid lipid biosynthesis and is implicated in human diseases, but demonstration ofUbiB kinase activity has remained elusive for unknown reasons. Here, we quantitatively define UbiB-specific sequence motifs and reveal their positions within the crystal structure of a UbiB protein, ADCK3. We find that multiple UbiB-specific features are poised to inhibit protein kinase activity, including an N-terminal domain that occupies the typical substrate binding pocket and a unique A-rich loop that limits ATP binding by establishing an unusual selectivity for ADP. A single alanine-to-glycine mutation of this loop flips this coenzyme selectivity and enables autophosphorylation but inhibits coenzyme Q biosynthesis invivo, demonstrating functional relevance for this unique feature. Our work provides mechanistic insight into UbiB enzyme activity and establishes a molecular foundation for further investigation of how UbiB family proteins affect diseases and diverse biological pathways.

Original languageEnglish
Pages (from-to)83-94
Number of pages12
JournalMolecular cell
Volume57
Issue number1
DOIs
StatePublished - Jan 8 2015

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