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Cell. 2018 Oct 18;175(3):809-821.e19. doi: 10.1016/j.cell.2018.08.046. Epub 2018 Sep 27.

Protein AMPylation by an Evolutionarily Conserved Pseudokinase.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Howard Hughes Medical Institute, Dallas, TX 75390, USA.
3
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw 02-106, Poland.
4
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Faculty of Agriculture and Biology, Warsaw University of Life Sciences, Warsaw 02-776, Poland.
6
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw 02-106, Poland; Faculty of Agriculture and Biology, Warsaw University of Life Sciences, Warsaw 02-776, Poland.
7
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
10
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Electronic address: vincent.tagliabracci@utsouthwestern.edu.

Abstract

Approximately 10% of human protein kinases are believed to be inactive and named pseudokinases because they lack residues required for catalysis. Here, we show that the highly conserved pseudokinase selenoprotein-O (SelO) transfers AMP from ATP to Ser, Thr, and Tyr residues on protein substrates (AMPylation), uncovering a previously unrecognized activity for a member of the protein kinase superfamily. The crystal structure of a SelO homolog reveals a protein kinase-like fold with ATP flipped in the active site, thus providing a structural basis for catalysis. SelO pseudokinases localize to the mitochondria and AMPylate proteins involved in redox homeostasis. Consequently, SelO activity is necessary for the proper cellular response to oxidative stress. Our results suggest that AMPylation may be a more widespread post-translational modification than previously appreciated and that pseudokinases should be analyzed for alternative transferase activities.

KEYWORDS:

SELENOO; adenylylation; glutaredoxin; glutathionylation; kinase structure; oxidative stress; selenocysteine

PMID:
30270044
PMCID:
PMC6524645
DOI:
10.1016/j.cell.2018.08.046
[Indexed for MEDLINE]
Free PMC Article

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