Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis
Abstract
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.
- Authors:
- Publication Date:
- Research Org.:
- Univ. of Wisconsin, Madison, WI (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1234166
- Alternate Identifier(s):
- OSTI ID: 1344481
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Published Article
- Journal Name:
- Molecular Cell
- Additional Journal Information:
- Journal Name: Molecular Cell Journal Volume: 57 Journal Issue: 1; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
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., and Pagliarini, David J. Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis. United States: N. p., 2015.
Web. doi:10.1016/j.molcel.2014.11.002.
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. Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis. United States. https://doi.org/10.1016/j.molcel.2014.11.002
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., and Pagliarini, David J. Thu .
"Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis". United States. https://doi.org/10.1016/j.molcel.2014.11.002.
@article{osti_1234166,
title = {Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis},
author = {Stefely, Jonathan A. and Reidenbach, Andrew G. and Ulbrich, Arne and Oruganty, Krishnadev and Floyd, Brendan J. and Jochem, Adam and Saunders, Jaclyn M. and Johnson, Isabel E. and Minogue, Catherine E. and Wrobel, Russell L. and Barber, Grant E. and Lee, David and Li, Sheng and Kannan, Natarajan and Coon, Joshua J. and Bingman, Craig A. and Pagliarini, David J.},
abstractNote = {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.},
doi = {10.1016/j.molcel.2014.11.002},
journal = {Molecular Cell},
number = 1,
volume = 57,
place = {United States},
year = {Thu Jan 01 00:00:00 EST 2015},
month = {Thu Jan 01 00:00:00 EST 2015}
}
https://doi.org/10.1016/j.molcel.2014.11.002
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