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
Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA.
Sci Signal. 2020 Jul 7;13(639):eaax2713. doi: 10.1126/scisignal.aax2713.
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.
活性氧（ROS）是细胞信号传导的生理介质，在人类疾病中发挥潜在的破坏作用。在本研究中，我们发现，位于苏氨酸（Thr）（激活结构域中的一个关键磷酸化位点）旁边的一个保守半胱氨酸残基（Cys）发生氧化时，丝氨酸/苏氨酸激酶Aurora A的催化活性受到抑制。半胱氨酸存在于约100种人类丝氨酸/苏氨酸激酶的等效位置，我们发现该残基不仅对人类Aurora A的活性很重要，对裂殖酵母丝裂原活化蛋白激酶激活的激酶（Srk1）和蛋白激酶A（Pka1）的活性也很重要。此外，这一保守半胱氨酸的存在预示着一组人类钙/钙调蛋白依赖性蛋白激酶（CAMK）、蛋白激酶A（AGC）和AGC样激酶在生化上对氧化还原敏感。因此，我们预测，Aurora A保守半胱氨酸的氧化还原调节可能是一种未被充分认识的调节机制，在真核生物丝氨酸/苏氨酸激酶中广泛存在。鉴于这些酶的关键生物学作用，这些发现对于理解对ROS的生理和病理反应具有重要意义，并突出了通过激活结构域的多价修饰来调节蛋白激酶的重要性。
