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

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.

Related Concepts

Malignant Neoplasms
Chromosomes
Clinical Trials
Coenzymes
Cysteine
Laboratory mice
Microinjections
Protein KINASE
Research Activities
Oxidative Stress

Related Feeds

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.