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Dissociation mechanism of GDP from Cdc42 via DOCK9 revealed by molecular dynamics simulations

Ning Kang1, Jiansheng Liu2, Yaxue Zhao1

  • 1School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.

Proteins
|February 5, 2019
PubMed

Insights

The guanine nucleotide exchange factor DOCK9 facilitates cancer metastasis by activating Cdc42. This study reveals how DOCK9 helps Cdc42 release GDP, a crucial step in its activation mechanism.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Computational biology

Background:

  • Cell division control protein 42 homolog (Cdc42) regulates cell migration and polarity.
  • Deregulation of Cdc42 is linked to human diseases and cancer metastasis.
  • DOCK family guanine nucleotide exchange factors (GEFs) activate Cdc42, but the mechanism remains unclear.

Purpose of the Study:

  • To elucidate the GDP dissociation mechanism of Cdc42 mediated by DOCK9.
  • To identify key residues in Cdc42 involved in GDP release during activation.

Main Methods:

  • Molecular dynamics (MD) simulations.
  • Molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations.

Main Results:

  • Mg2+ ion influences Cdc42's switch I conformation via Pro34, facilitating GDP dissociation.
  • DOCK9 binding alters Cdc42 residue orientations (Lys16, Thr17, Cys18, Phe28), weakening Cdc42-GDP interactions.
  • The study identifies specific Cdc42 residues essential for GDP release.

Conclusions:

  • This research provides the first detailed mechanism of GDP dissociation from Cdc42 by DOCK9.
  • Findings align with experimental data and offer insights for developing targeted cancer metastasis therapies.
Keywords:
GDP dissociation processMD simulationsMM-PBSAMgbinding free energy

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