DOI: 10.1101/469585Nov 14, 2018Paper

Covalent Aurora A regulation by the metabolic integrator coenzyme A

BioRxiv : the Preprint Server for Biology
Yugo TsuchiyaIvan Gout


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.

Related Concepts

Malignant Neoplasms
Clinical Trials
Laboratory mice
Protein KINASE
Research Activities
Oxidative Stress

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