Redox priming promotes Aurora A activation during mitosis.

Autor:	Lim DC; MIT Center for Precision Cancer Medicine, Koch Institute for Integrative Cancer Research, and Departments of Biological Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. danlim@mit.edu myaffe@mit.edu., Joukov V; N. N. Petrov National Medical Research Center of Oncology, Saint Petersburg 197758, Russian Federation., Rettenmaier TJ; Jnana Therapeutics, Boston, MA 02210, USA.; Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA., Kumagai A; The Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Dunphy WG; The Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Wells JA; Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA., Yaffe MB; MIT Center for Precision Cancer Medicine, Koch Institute for Integrative Cancer Research, and Departments of Biological Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. danlim@mit.edu myaffe@mit.edu.; Divisions of Acute Care Surgery, Trauma, and Surgical Critical Care, and Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2020 Jul 21; Vol. 13 (641). Date of Electronic Publication: 2020 Jul 21.
DOI:	10.1126/scisignal.abb6707
Abstrakt:	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. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu