Research ArticleBiochemistry

Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity

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Science Signaling  07 Jul 2020:
Vol. 13, Issue 639, eaax2713
DOI: 10.1126/scisignal.aax2713

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Kinase regulation conserved under stress

Oxidative stress is necessary for normal cellular function and tissue physiology but can also be pathological, and its effects are mediated in part through functional modification of various proteins. Shrestha et al. and Byrne et al. found that the oxidation of kinases at active site-adjacent cysteine residues, which were conserved across the eukaryotic kinome, regulated cell metabolism and mitosis. Shrestha et al. found that conserved cysteine residues within the diabetes-associated metabolic kinase FN3K acted as a toggle switch upon oxidation, promoting its functional oligomerization and consequently altering cellular redox status. Byrne et al. found that oxidation of mitotic kinases in human cells and yeast suppressed kinase catalytic activity and, in yeast, impaired cellular division. Exploring the effect of chronic oxidative stress on kinase function and how that may be spatiotemporally regulated may enable the development of new targeted therapeutics.


Reactive oxygen species (ROS) are physiological mediators of cellular signaling and play potentially damaging roles in human diseases. In this study, we found that the catalytic activity of the Ser/Thr kinase Aurora A was inhibited by the oxidation of a conserved cysteine residue (Cys290) that lies adjacent to Thr288, a critical phosphorylation site in the activation segment. Cys is present at the equivalent position in ~100 human Ser/Thr kinases, a residue that we found was important not only for the activity of human Aurora A but also for that of fission yeast MAPK-activated kinase (Srk1) and PKA (Pka1). Moreover, the presence of this conserved Cys predicted biochemical redox sensitivity among a cohort of human CAMK, AGC, and AGC-like kinases. Thus, we predict that redox modulation of the conserved Cys290 of Aurora A may be an underappreciated regulatory mechanism that is widespread in eukaryotic Ser/Thr kinases. Given the key biological roles of these enzymes, these findings have implications for understanding physiological and pathological responses to ROS and highlight the importance of protein kinase regulation through multivalent modification of the activation segment.

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