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The structural basis of PTEN regulation by multi-site phosphorylation

Daniel R Dempsey1,2, Thibault Viennet2,3, Reina Iwase1,2

  • 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Nature Structural & Molecular Biology
|October 9, 2021
PubMed

Insights

Phosphatase and tensin homolog (PTEN) regulation by C-terminal phosphorylation was elucidated. This phosphorylation event forms a belt, impacting PTEN

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Biology

Background:

  • Phosphatase and tensin homolog (PTEN) is a tumor suppressor.
  • PTEN regulates cell growth and survival by dephosphorylating PIP3.
  • PTEN's function is modulated by C-terminal phosphorylation (phospho-C-tail).

Purpose of the Study:

  • To elucidate the molecular mechanisms of PTEN regulation by phospho-C-tail.
  • To determine the structural basis for PTEN's catalytic activity and cellular localization.

Main Methods:

  • Protein semisynthesis
  • Biochemical assays
  • Nuclear Magnetic Resonance (NMR)
  • X-ray crystallography
  • Computational simulations

Main Results:

  • The phospho-C-tail forms a regulatory belt around PTEN's C2 and phosphatase domains.
  • A dynamic N-terminal α-helix is crucial for PTEN catalysis but becomes disordered upon phospho-C-tail interaction.
  • A detailed structural model of PTEN regulation was established.

Conclusions:

  • C-terminal phosphorylation is a key regulator of PTEN's structure and function.
  • Understanding PTEN regulation provides insights into cancer development.
  • This study offers a framework for targeting PTEN in cancer therapy.

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