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

Autor:	Stefely JA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Reidenbach AG; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Ulbrich A; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Oruganty K; Department of Biochemistry, University of Georgia, Athens, GA 30602, USA., Floyd BJ; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Jochem A; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Saunders JM; Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706, USA., Johnson IE; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Minogue CE; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Wrobel RL; Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706, USA., Barber GE; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Lee D; Department of Medicine and UCSD DXMS Proteomics Resource, University of California, San Diego, La Jolla, CA 92023, USA., Li S; Department of Medicine and UCSD DXMS Proteomics Resource, University of California, San Diego, La Jolla, CA 92023, USA., Kannan N; Department of Biochemistry, University of Georgia, Athens, GA 30602, USA., Coon JJ; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Bingman CA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Mitochondrial Protein Partnership, University of Wisconsin-Madison, Madison, WI 53706, USA., Pagliarini DJ; 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.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2015 Jan 08; Vol. 57 (1), pp. 83-94. Date of Electronic Publication: 2014 Dec 11.
DOI:	10.1016/j.molcel.2014.11.002
Abstrakt:	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. (Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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