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Investigating the Regulation of Ribosomal Protein S6 Kinase 1 by CoAlation.

Oksana Malanchuk1,2, Anna Bdzhola2, Sergii Palchevskyi2

  • 1Department of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.

International Journal of Molecular Sciences
|August 29, 2024
PubMed
Summary
This summary is machine-generated.

Oxidative stress triggers coenzyme A (CoA) to covalently modify ribosomal protein S6 kinase 1 (p70S6K1) at Cys217, inhibiting its activity. This discovery reveals a new regulatory mechanism for p70S6K1 and protein kinase inhibition.

Keywords:
cell signallingcoenzyme Akinase regulationoxidative stressp70S6K1post-translational modificationsprotein CoAlation

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Signaling

Background:

  • Ribosomal protein S6 kinases (p70S6Ks) are crucial eukaryotic enzymes regulating cell growth, proliferation, survival, and stress responses.
  • p70S6K1 activation involves multiple phosphorylation events mediated by key regulators of cell growth and metabolism.

Purpose of the Study:

  • To investigate the novel covalent modification of p70S6K1 by coenzyme A (CoA) under oxidative stress.
  • To elucidate the mechanism and functional consequences of CoA binding to p70S6K1.

Main Methods:

  • Mass spectrometry to map the CoA binding site.
  • In vitro assays to assess the impact of CoAlation on p70S6K1 kinase activity.
  • Molecular docking and dynamics simulations to determine the binding mode.

Main Results:

  • Coenzyme A (CoA) covalently modifies p70S6K1 at Cysteine 217 (Cys217) in response to oxidative stress.
  • This modification, termed CoAlation, inhibits p70S6K1 kinase activity.
  • Molecular modeling revealed a 'dual anchor' mechanism involving non-covalent and covalent interactions for CoA binding.

Conclusions:

  • CoAlation represents a novel regulatory mechanism for p70S6K1 activity, particularly under oxidative stress conditions.
  • The findings suggest a new paradigm for protein kinase inhibition via CoAlation.
  • This research may pave the way for developing novel p70S6K1 inhibitors.