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Covalent Aurora A regulation by the metabolic integrator coenzyme A

DOI: 10.1016/j.redox.2019.101318 DOI Help

Authors: Yugo Tsuchiya (University College London) , Dominic P. Byrne (University of Liverpool) , Selena G. Burgess (University of Leeds) , Jenny Bormann (University College London) , Jovana Baković (University College London) , Yueyang Huang (University College London) , Alexander Zhyvoloup (University College London) , Bess Yi Kun Yu (University College London) , Sew Peak-chew (MRC Laboratory of Molecular Biology) , Trang Tran (University College London) , Fiona Bellany (University College London) , Alethea B. Tabor (University College London) , A. W. Edith Chan (University College London) , Lalitha Guruprasad (University of Hyderabad) , Oleg Garifulin (Institute of Molecular Biology and Genetics, Kyiv) , Valeriy Filonenko (Institute of Molecular Biology and Genetics, Kyiv) , Matthias Vonderach (University of Liverpool) , Samantha Ferries (University of Liverpool) , Claire E. Eyers (University of Liverpool) , John Carroll (University College London) , Mark Skehel (MRC Laboratory of Molecular Biology) , Richard Bayliss (University of Leeds) , Patrick A. Eyers (University of Liverpool) , Ivan Gout (University College London; Institute of Molecular Biology and Genetics, Kyiv)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Redox Biology

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 15378

Open Access Open Access

Abstract: Aurora A kinase is a master mitotic regulator whose functions are controlled by several regulatory interactions and post-translational modifications. It is frequently dysregulated in cancer, making Aurora A inhibition a very attractive antitumor target. However, recently uncovered links between Aurora A, cellular metabolism and redox regulation are not well understood. In this study, we report a novel mechanism of Aurora A regulation in the cellular response to oxidative stress through CoAlation. A combination of biochemical, biophysical, crystallographic and cell biology approaches revealed a new and, to our knowledge, unique mode of Aurora A inhibition by CoA, involving selective binding of the ADP moiety of CoA to the ATP binding pocket and covalent modification of Cys290 in the activation loop by the thiol group of the pantetheine tail. We provide evidence that covalent CoA modification (CoAlation) of Aurora A is specific, and that it can be induced by oxidative stress in human cells. Oxidising agnets, such as diamide, hydrogen peroxide and menadione were found to induce Thr 288 phosphorylation and DTT-dependent dimerization of Aurora A. Moreover, microinjection of CoA into fertilized mouse embryos disrupts bipolar spindle formation and the alignment of chromosomes, consistent with Aurora A inhibition. Altogether, our data reveal CoA as a new, rather selective, inhibitor of Aurora A, which locks this kinase in an inactive state via a “dual anchor” mechanism of inhibition that might also operate in the cellular response to oxidative stress. Finally, and perhaps most importantly, we believe that these novel findings provide a new rationale for developing effective and irreversible inhibitors of Aurora A, and perhaps other protein kinases containing appropriately conserved Cys residues.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Documents:
redox334.pdf