Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis

Journal Article · Thu Jan 01 00:00:00 EST 2015 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2014.11.002· OSTI ID:1234166

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

The ancient UbiB protein kinase-like family is involved in isoprenoid lipid biosynthesis and is implicated in human diseases, but demonstration of UbiB kinase activity has remained elusive for unknown reasons. In this paper, 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 in vivo, demonstrating functional relevance for this unique feature. Finally, 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.

• Research Organization: Univ. of Wisconsin, Madison, WI (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC02-06CH11357
• OSTI ID: 1234166
• Alternate ID(s): OSTI ID: 1344481
• Journal Information: Molecular Cell, Journal Name: Molecular Cell Vol. 57 Journal Issue: 1; ISSN 1097-2765
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES