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Interaction mechanism of endogenous PP2A inhibitor protein ENSA with PP2A

Chandan Thapa1,2,3, Pekka Roivas2,3, Tatu Haataja1

  • 1Department of Biological and Environmental Science and Nanoscience Center, University of Jyvaskyla, Finland.

The FEBS Journal
|August 4, 2021
PubMed

Insights

α-endosulfine (ENSA) is a protein inhibitor of protein phosphatase 2A (PP2A). This study reveals ENSA

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Protein phosphatase 2A (PP2A) holoenzyme composition is diverse, regulating cellular growth and signal transduction.
  • PP2A is inhibited by endogenous proteins, including α-endosulfan (ENSA), in pathological conditions like cancer.
  • ENSA inhibits PP2A activity upon phosphorylation by Greatwall (Gwl) kinase, but its inhibition mechanism is poorly understood.

Purpose of the Study:

  • To structurally characterize ENSA and its interaction with PP2A A- and B56-subunit isoforms.
  • To elucidate the molecular mechanism of ENSA-mediated PP2A inhibition.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Small-angle X-ray scattering (SAXS)
  • Protein interaction assays

Main Results:

  • ENSA is an intrinsically disordered protein with three transient α-helical structures.
  • ENSA interacts primarily with the PP2A A-subunit, showing significantly higher affinity than with B56 subunits.
  • The interaction between ENSA and the PP2A A-subunit appears to follow a dock-and-coalesce mechanism.

Conclusions:

  • This study provides a structural and molecular framework for understanding ENSA-mediated PP2A inhibition.
  • The findings are crucial for developing novel therapies targeting PP2A inhibition in diseases.
  • Elucidating the ENSA-PP2A interaction mechanism opens new avenues for therapeutic intervention.
Keywords:
ENSAIDPsNMRPP2APP2A inhibitor proteinSAXS

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