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Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations

Hari Leontiadou1, Ioannis Galdadas1, Christina Athanasiou1

  • 1Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527, Athens, Greece.

Scientific Reports
|October 21, 2018
PubMed

Insights

The E545K mutation in phosphoinositide 3-kinase alpha (PI3Kα) disrupts subunit interactions, leading to uncontrolled PI3Kα activity and potential oncogenesis. Molecular dynamics simulations reveal the atomic-level mechanism behind this activating mutation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Phosphoinositide 3-kinase alpha (PI3Kα) regulates critical cellular functions like proliferation and differentiation.
  • Aberrant PI3Kα activity, often due to mutations such as E545K, is implicated in human cancers.
  • The E545K mutation involves a charge-reversal substitution, hypothesized to abrogate inter-subunit interactions.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the PI3Kα E545K mutation leads to constitutive activity.
  • To investigate the conformational dynamics and allosteric signaling changes in PI3Kα upon E545K mutation.

Main Methods:

  • Extensive microsecond Molecular Dynamics (MD) simulations were employed.
  • Comparative analysis of wild-type (WT) and E545K mutant PI3Kα conformational changes.
  • Examination of the allosteric network and communication pathways between regulatory (p85α) and catalytic (p110α) subunits.

Main Results:

  • The E545K mutation induced a spontaneous detachment of the nSH2 domain of the regulatory subunit (p85α) from the helical domain of the catalytic subunit (p110α).
  • A significant loss of communication between the regulatory and catalytic subunits was observed in the mutant.
  • A specific cluster of residues around the E545K mutation site was identified as crucial for signal transmission.

Conclusions:

  • The PI3Kα E545K mutation causes significant dynamical and structural alterations at the atomic level.
  • The observed detachment and disrupted communication provide a mechanistic explanation for the loss of regulation and constitutive activity conferred by the E545K mutation.
  • These findings offer insights into oncogenesis driven by PI3Kα mutations.

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