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Title: 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. 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., and Pagliarini, David J. Thu . "Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis". United States. doi: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 = {2015},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.molcel.2014.11.002

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Cited by: 23 works
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Works referencing / citing this record:

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