Related Experiment Video

Updated: Jun 27, 2026

PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions
10:58

PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions

Published on: July 27, 2017

Structures of the PI3Kα/KRas complex on lipid bilayers reveal molecular mechanisms of PI3Kα activation

Hayarpi Torosyan1, Michael D Paul1, Brigitte G Meyer2

  • 1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.

Molecular Cell
|June 25, 2026
PubMed

Insights

This study reveals the molecular mechanism of PI3Kα activation using cryo-electron microscopy. The findings uncover new therapeutic targets for PI3Kα-driven cancers by mapping its conformational changes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Phosphoinositide 3-kinase alpha (PI3Kα) is a key oncogene.
  • It converts PIP2 to PIP3 at the plasma membrane, crucial for cell signaling.
  • Dysregulation of PI3Kα is implicated in various cancers.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing PI3Kα activation.
  • To visualize the conformational states of PI3Kα during its transition to an active signaling complex.
  • To identify potential therapeutic targets for PI3Kα-driven oncogenesis.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures.
  • PI3Kα/KRas complexes were reconstituted and studied within lipid nanodiscs.
  • Cellular assays were performed to validate findings in a biological context.

Main Results:

  • Structures revealed a spectrum of PI3Kα conformations, illustrating the release of inhibitory domains.
  • PIP2 binding induced significant restructuring of active site regulatory elements.
  • An activating phosphopeptide promoted PI3Kα/KRas complex dimerization via a novel interface.
  • Dimeric PI3Kα was shown to amplify Akt signaling in response to growth factors in cells.

Conclusions:

  • The study provides a comprehensive map of PI3Kα conformational dynamics during activation.
  • Novel interfaces involved in PI3Kα activation and dimerization were identified.
  • These findings offer new avenues for developing targeted therapies against PI3Kα-.
Keywords:
PI3KPIP2Rascryo-EMnanodiscp110p85phosphotyrosinesignalingsignalosome

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