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Mol Cell. 2015 Jan 8;57(1):83-94. doi: 10.1016/j.molcel.2014.11.002. Epub 2014 Dec 11.

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

Author information

1
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
2
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Department of Biochemistry, University of Georgia, Athens, GA 30602, USA.
4
Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706, USA.
5
Department of Medicine and UCSD DXMS Proteomics Resource, University of California, San Diego, La Jolla, CA 92023, USA.
6
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
7
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706, USA.
8
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: pagliarini@wisc.edu.

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. 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 in vivo, 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.

PMID:
25498144
PMCID:
PMC4289473
DOI:
10.1016/j.molcel.2014.11.002
[Indexed for MEDLINE]
Free PMC Article

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