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Updated: Sep 4, 2025

Monitoring On-Target Signaling Responses in Larval Zebrafish - Z-REX Unmasks Precise Mechanisms of Electrophilic Drugs and Metabolites
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Monitoring On-Target Signaling Responses in Larval Zebrafish - Z-REX Unmasks Precise Mechanisms of Electrophilic Drugs and Metabolites

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Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism

Yong-Gang Chang1, Christopher J Lupton2, Charles Bayly-Jones2

  • 1Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. tyler.chang@monash.edu.

Nature Structural & Molecular Biology
|July 21, 2022
PubMed

Insights

P-Rex1, a key regulator of Rho GTPases, is autoinhibited by its domain arrangement. Structural studies reveal how Gβγ and PI(3,4,5)P3 binding triggers a conformational change to activate P-Rex1 signaling.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • P-Rex (PI(3,4,5)P3-dependent Rac exchanger) proteins are guanine nucleotide exchange factors that activate Rho GTPases.
  • P-Rex proteins are subject to autoinhibition and are synergistically activated by Gβγ and PI(3,4,5)P3.
  • Dysregulation of P-Rex proteins is implicated in cancer.

Purpose of the Study:

  • To determine the structural basis of human P-Rex1 autoinhibition.
  • To elucidate the mechanism of P-Rex1 activation by Gβγ and PI(3,4,5)P3.

Main Methods:

  • X-ray crystallography
  • Cryogenic electron microscopy (cryo-EM)
  • Crosslinking mass spectrometry

Main Results:

  • P-Rex1 exhibits a bipartite structure with N- and C-terminal modules linked by a four-helix bundle.
  • Autoinhibition involves occlusion of the Dbl homology (DH) domain catalytic surface by the DH-PH-DEP1 domain arrangement.
  • Activation requires a conformational transition involving a 126° opening of the DH domain hinge helix and a 90° counter-rotation of P-Rex1 halves.
  • Gβγ and PI(3,4,5)P3 binding sites are positioned off-axis, facilitating PH domain uncoupling and DH domain release.

Conclusions:

  • The study reveals the structural mechanism underlying P-Rex1 autoinhibition and activation.
  • Understanding P-Rex1 regulation provides insights into Rho GTPase signaling pathways.
  • The findings may inform therapeutic strategies targeting cancers with dysregulated P-Rex signaling.

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