Covalent Aurora A regulation by the metabolic integrator coenzyme A

Tsuchiya, Y.; Byrne, D.; Burgess, S.; Bormann, J.; Bakovic, J.; Huang, Y.; Zhyvoloup, A.; Peak-Chew, S.; Tran, T.; Bellany, F.; Tabor, A.; Chan, E.; Guruprasad, L.; Garifulin, O.; Filonenko, V.; Ferries, S.; Eyers, C.; Carroll, J.; Skehel, M.; Bayliss, R.; Eyers, P.; Gout, I.

doi:10.1101/469585

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bioRxiv · 10.1101/469585

Covalent Aurora A regulation by the metabolic integrator coenzyme A

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Abstract

Aurora A is a cell cycle protein kinase implicated in multiple human cancers, and several Aurora A-specific kinase inhibitors have progressed into clinical trials. In this study, we report structural and cellular analysis of a novel biochemical mode of Aurora A inhibition, which occurs through reversible covalent interaction with the universal metabolic integrator coenzyme A (CoA). Mechanistically, the CoA 3-phospho ADP moiety interacts with Thr 217, an Aurora A selectivity filter, which permits the formation of an unprecedented covalent bond with Cys 290 in the kinase activation segment, lying some 15 [A] away. CoA modification (CoAlation) of endogenous Aurora A is rapidly induced by oxidative stresses at Cys 290 in human cells, and microinjection of CoA into mouse embryos perturbs meitoic spindle formation and chromosome alignment. Aurora A regulation by CoA reveals how targeting of Aurora A might be accomplished in the future by development of a double-anchored covalent inhibitor.

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Tsuchiya, Y., Byrne, D., Burgess, S., Bormann, J., Bakovic, J., Huang, Y., Zhyvoloup, A., Peak-Chew, S., Tran, T., Bellany, F., Tabor, A., Chan, E., Guruprasad, L., Garifulin, O., Filonenko, V., Ferries, S., Eyers, C., Carroll, J., Skehel, M., Bayliss, R., Eyers, P., Gout, I.. 2018-11-14. Covalent Aurora A regulation by the metabolic integrator coenzyme A. https://doi.org/10.1101/469585

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