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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
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A Mass Spectrometry-Based Approach to Identify Phosphoprotein Phosphatases and their Interactors
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Structural and functional basis of protein phosphatase 5 substrate specificity.

Jasmeen Oberoi1, Diana M Dunn2, Mark R Woodford2

  • 1Institute of Structural and Molecular Biology, Biological Sciences, University College London and Birkbeck College, London WC1E 7HX, United Kingdom;

Proceedings of the National Academy of Sciences of the United States of America
|July 29, 2016
PubMed
Summary

Protein Phosphatase 5 (PP5) dephosphorylates Cdc37, enabling heat shock protein 90 (Hsp90) chaperone complex release. PP5 activity influences Hsp90 inhibitor efficacy, suggesting therapeutic potential in tumors.

Keywords:
Cdc37Hsp90PP5chaperonephosphatase

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Area of Science:

  • Molecular biology
  • Biochemistry
  • Structural biology

Background:

  • Protein Phosphatase 5 (PP5) is a serine/threonine phosphatase that regulates cellular signaling pathways.
  • PP5 interacts with heat shock protein 90 (Hsp90) and dephosphorylates its cochaperone Cdc37.
  • This dephosphorylation is critical for activating Hsp90-dependent kinases, but the precise mechanism is unclear.

Purpose of the Study:

  • To elucidate the structural basis of PP5-Cdc37 interaction.
  • To understand how PP5 regulates Hsp90-dependent kinase activation and substrate release.
  • To explore the therapeutic implications of PP5 activity in cancer.

Main Methods:

  • Determined the crystal structure of PP5 catalytic domain bound to a Cdc37 phosphomimetic peptide.
  • Utilized structure-based mutations to assess PP5 function in vivo.
  • Investigated the effect of PP5 activity on Hsp90-inhibitor binding.

Main Results:

  • The crystal structure revealed PP5 employs conserved phosphoprotein phosphatase (PPP) structural elements for substrate binding.
  • Substrate specificity is determined by elements within the PP5 catalytic domain.
  • PP5-mediated dephosphorylation is essential for releasing kinases and steroid hormone receptors from the Hsp90 complex.
  • Altered PP5 activity modulated Hsp90 inhibitor binding, suggesting a role in therapeutic efficacy.

Conclusions:

  • PP5 plays a crucial role in Hsp90 chaperone complex dynamics through Cdc37 dephosphorylation.
  • The PP5 catalytic domain itself contributes to substrate specificity.
  • Modulating PP5 activity offers a potential strategy to enhance the effectiveness of Hsp90 inhibitors in cancer treatment.