Related Experiment Video

Updated: Jul 13, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Structural insights into the complex of oncogenic KRas4BG12V and Rgl2, a RalA/B activator

Mishal Tariq1, Teppei Ikeya2, Naoyuki Togashi2

  • 1Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.

Life Science Alliance
|October 13, 2023
PubMed

Insights

Mutations in Ras isoforms are common in human cancers. This study reveals how oncogenic KRas4B interacts with RalGEFs, offering insights into cancer signaling pathways.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • Ras isoforms are frequently mutated in human cancers.
  • Ral guanine nucleotide exchange factors (RalGEFs) are key activators of RalA and RalB small GTPases.
  • RalGEFs play a crucial role in oncogenic Ras-induced signaling pathways.

Purpose of the Study:

  • To investigate the interaction between human KRas4B and the Ras association (RA) domain of Rgl2 (Rgl2RA).
  • To elucidate the structural basis of the interaction between oncogenic KRas4BG12V and Rgl2RA.
  • To understand the mechanism by which KRas4BG12V hyperactivates the RalA/B pathway.

Main Methods:

  • Studied the interaction kinetics between human KRas4B and Rgl2RA.
  • Determined the crystal structure of the KRas4BG12V: Rgl2RA complex.
  • Compared the structural arrangement with known Ras:effector complexes.

Main Results:

  • The G12V oncogenic KRas4B mutation alters interaction kinetics with Rgl2RA.
  • The crystal structure revealed a 2:2 heterotetramer of KRas4BG12V: Rgl2RA.
  • The G12V mutation was located at the dimer interface of KRas4BG12V, suggesting a distinct binding mode compared to Ras:Raf complexes.

Conclusions:

  • RalGEFs may form Ras:effector complexes via a distinct mechanism.
  • The structural findings provide a mechanistic explanation for oncogenic KRas4BG12V-mediated hyperactivation of the RalA/B pathway.
  • This study sheds light on the molecular basis of oncogenic Ras signaling in cancer.

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