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Title: Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis

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:
 [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [3] ;  [3] ;  [2] ;  [1] ;  [1] ;  [1]
  1. Univ. of Wisconsin, Madison, WI (United States)
  2. Univ. of Georgia, Athens, GA (United States)
  3. Univ. of California, San Diego, La Jolla, CA (United States)
Publication Date:
OSTI Identifier:
1234166
Grant/Contract Number:
AC02-06CH11357
Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 57; Journal Issue: 1; Journal ID: ISSN 1097-2765
Publisher:
Elsevier - Cell Press
Research Org:
Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES