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Published on: January 16, 2020

Mapping the nucleotide and isoform-dependent structural and dynamical features of Ras proteins

Alemayehu A Gorfe1, Barry J Grant, J Andrew McCammon

  • 1Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California-San Diego, La Jolla, CA 92093-0365, USA. abebe@mccammon.ucsd.edu

Structure (London, England : 1993)
|June 13, 2008
PubMed

Insights

Ras GTPases are key regulators of cell functions. This study reveals their inactive-to-active transition is a multiphase process, offering new insights into cancer mechanisms.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Ras GTPases are crucial signaling proteins regulating cell growth and differentiation.
  • Dysregulation of Ras GTPases is implicated in various cancers, yet their activation mechanism is not fully understood.

Purpose of the Study:

  • To elucidate the conformational transition mechanism of Ras GTPases between inactive and active states.
  • To quantitatively assess structural and dynamical features of Ras states and their interconversion.

Main Methods:

  • Analysis of experimental structures.
  • Molecular dynamics simulations.
  • Modeling of N-, K-, and H-ras isoforms.

Main Results:

  • The inactive-to-active transition of G12V H-ras is a multiphase process involving switch rearrangements and Tyr32 orientation.
  • K-ras exhibits greater flexibility compared to N- and H-ras.
  • Identified isoform-specific interactions mediating communication from the nucleotide-binding site to the C terminus.

Conclusions:

  • The study provides a quantitative understanding of Ras GTPase conformational dynamics.
  • Findings highlight isoform-specific differences in Ras flexibility and signaling pathways.
  • This research offers potential targets for cancer therapy by understanding Ras activation.

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