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Wavelet coherence phase analysis decodes the universal switching mechanism of Ras GTPase superfamily

Zenia Motiwala1,2, Anand S Sandholu1,2, Durba Sengupta2,3

  • 1Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune 411008, India.

Iscience
|July 14, 2023
PubMed

Insights

Researchers developed a novel wavelet coherence phase coupling (WPC) analysis to define Ras GTPase functional states. This method reveals how structural changes in switch regions dictate protein function and identifies aberrant mechanisms in oncogenic GTPases.

Area of Science:

  • Molecular Biology
  • Biophysics
  • Computational Biology

Background:

  • Ras GTPases are crucial regulators of cellular processes.
  • Their function relies on switching between GTP-bound (ON) and GDP-bound (OFF) states.
  • Conformational changes in switch regions (SWI/SWII) drive this mechanism, but vary across the Ras superfamily, lacking a universal descriptor.

Purpose of the Study:

  • To develop a universal parameter for defining Ras GTPase functional states.
  • To investigate the role of structural allostery in Ras protein function and dysfunction.
  • To decode the universal switching mechanism of Ras proteins.

Main Methods:

  • Development of a unique wavelet coherence (WC) analysis-based approach.
  • Mapping structural changes in Ras switch regions onto wavelet coherence phase couplings (WPCs).
  • Analysis of WPCs in oncogenic GTPases and simulated switch region conformers.

Main Results:

  • Wavelet coherence phase couplings (WPCs) can serve as unique parameters to define Ras GTPase functional states.
  • Disentanglement of WPCs reveals the breakdown of structural allostery in oncogenic GTPases, leading to aberrant function.
  • The observed phenomena are consistent even with simulated ensembles of switch region conformers.

Conclusions:

  • Wavelet coherence phase couplings (WPCs) offer a novel method to characterize Ras protein structural dynamics.
  • This approach can unravel latent structural deviations and decode the universal switching mechanism of Ras proteins.
  • Understanding these mechanisms provides insights into oncogenic GTPase function.
Keywords:
BiomoleculesProtein structure aspectsStructural biology

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