Research ArticleBiochemistry

Redox priming promotes Aurora A activation during mitosis

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Science Signaling  21 Jul 2020:
Vol. 13, Issue 641, eabb6707
DOI: 10.1126/scisignal.abb6707

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Structurally primed by CoA

The mitotic kinase Aurora A promotes tumor growth. Redox modification of an evolutionarily conserved cysteine residue in the activation loop of Aurora A may be exploitable therapeutically. Lim et al. identified Cys-binding redox compounds and elucidated how such adducts may conformationally affect Aurora A activation. One such compound, coenzyme A, resulted in two types of dimers—one that was Cys290-coAlated in which the active site was in an open conformation that showed how covalent modification of the activation loop can promote dimerization and the other one that lacked CoAlation but showed how dimerization can lead to a catalytically active conformation that promotes autophosphorylation. The findings suggest that CoAlation may promote Aurora A activation through an intermediate conformation. Hence, compounds that block CoAlation may suppress Aurora A activation in tumors.


Cell cycle–dependent redox changes can mediate transient covalent modifications of cysteine thiols to modulate the activities of regulatory kinases and phosphatases. Our previously reported finding that protein cysteine oxidation is increased during mitosis relative to other cell cycle phases suggests that redox modifications could play prominent roles in regulating mitotic processes. The Aurora family of kinases and their downstream targets are key components of the cellular machinery that ensures the proper execution of mitosis and the accurate segregation of chromosomes to daughter cells. In this study, x-ray crystal structures of the Aurora A kinase domain delineate redox-sensitive cysteine residues that, upon covalent modification, can allosterically regulate kinase activity and oligomerization state. We showed in both Xenopus laevis egg extracts and mammalian cells that a conserved cysteine residue within the Aurora A activation loop is crucial for Aurora A activation by autophosphorylation. We further showed that covalent disulfide adducts of this residue promote autophosphorylation of the Aurora A kinase domain. These findings reveal a potential mechanistic link between Aurora A activation and changes in the intracellular redox state during mitosis and provide insights into how novel small-molecule inhibitors may be developed to target specific subpopulations of Aurora A.

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