@article{46d510274fe2441f856b8a3373ba2ce4,
title = "Protein AMPylation by an Evolutionarily Conserved Pseudokinase",
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. The structure of SelO, a conserved pseudokinase, reveals ATP flipped in the substrate binding pocket, leading to the discovery that SelO is actually an AMPylating enzyme.",
keywords = "SELENOO, adenylylation, glutaredoxin, glutathionylation, kinase structure, oxidative stress, selenocysteine",
author = "Anju Sreelatha and Yee, {Samantha S.} and Lopez, {Victor A.} and Park, {Brenden C.} and Kinch, {Lisa N.} and Sylwia Pilch and Servage, {Kelly A.} and Junmei Zhang and Jenny Jiou and Monika Karasiewicz-Urba{\'n}ska and Ma{\l}gorzata {\L}obocka and Grishin, {Nick V} and Orth, {Kim A} and Roza Kucharczyk and Krzysztof Paw{\l}owski and Tomchick, {Diana R} and Tagliabracci, {Vincent S}",
note = "Funding Information: We thank Drs. Joseph Goldstein, Eric Olson, Peter Roach, Greg Taylor, Amanda Casey, Benjamin Tu, and members of the Tagliabracci laboratory for insightful discussions. We also thank Christine Nolan and Greg Urquhart for technical assistance. Results shown in this report are derived from work performed at the Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. This work was supported by NIH grants R00DK099254 (V.S.T.), GM094575 and GM127390 (N.V.G.), GM115188 (K.O.), T32DK007257-37 (A.S.), and T32GM008203-29 (V.A.L.); Welch Foundation grants I-1911 (V.S.T.), I-1505 (N.V.G.), and I-1561 (K.O.); the Once upon a Time…Foundation (K.O.); a CPRIT grant RP170674 (V.S.T.); and the Polish National Science Centre grant 2014/15/B/NZ1/03359 (K.P.). V.S.T. is the Michael L. Rosenberg Scholar in Medical Research, a Cancer Prevention Research Institute of Texas Scholar (RR150033), and a Searle Scholar (SSP-2018-2745). Funding Information: We thank Drs. Joseph Goldstein, Eric Olson, Peter Roach, Greg Taylor, Amanda Casey, Benjamin Tu, and members of the Tagliabracci laboratory for insightful discussions. We also thank Christine Nolan and Greg Urquhart for technical assistance. Results shown in this report are derived from work performed at the Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. This work was supported by NIH grants R00DK099254 (V.S.T.), GM094575 and GM127390 (N.V.G.), GM115188 (K.O.), T32DK007257-37 (A.S.), and T32GM008203-29 (V.A.L.); Welch Foundation grants I-1911 (V.S.T.), I-1505 (N.V.G.), and I-1561 (K.O.); the Once upon a Time…Foundation (K.O.); a CPRIT grant RP170674 (V.S.T.); and the Polish National Science Centre grant 2014/15/B/NZ1/03359 (K.P.). V.S.T. is the Michael L. Rosenberg Scholar in Medical Research, a Cancer Prevention Research Institute of Texas Scholar (RR150033), and a Searle Scholar (SSP-2018-2745). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = oct,
day = "18",
doi = "10.1016/j.cell.2018.08.046",
language = "English (US)",
volume = "175",
pages = "809--821.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}