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

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 (Cys ) that lies ad...

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Bibliographic Details
Published in:Science signaling 2020-07, Vol.13 (639)
Main Authors: Byrne, Dominic P, Shrestha, Safal, Galler, Martin, Cao, Min, Daly, Leonard A, Campbell, Amy E, Eyers, Claire E, Veal, Elizabeth A, Kannan, Natarajan, Eyers, Patrick A
Format: Article
Language:English
Subjects:
Activation
Animals
Aurora Kinase A - chemistry
Aurora Kinase A - genetics
Aurora Kinase A - metabolism
Ca2+/calmodulin-dependent protein kinase
Catalytic activity
Cysteine
Cysteine - chemistry
Cysteine - genetics
Cysteine - metabolism
Diabetes mellitus
Drug development
Evolution, Molecular
HeLa Cells
Humans
Kinases
MAP kinase
Metabolism
Mice
Mitosis
Oligomerization
Oxidation
Oxidation-Reduction
Oxidative stress
Phosphorylation
Physiology
Protein kinase A
Protein-serine/threonine kinase
Proteins
Reactive oxygen species
Regulatory mechanisms (biology)
Residues
Yeast
Yeasts
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Summary: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 (Cys ) that lies adjacent to Thr , 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 Cys 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.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.aax2713