Related Experiment Video

Updated: Dec 26, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

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GTP hydrolysis is modulated by Arg34 in the RASopathy-associated KRASP34R

Asim K Bera1, Jia Lu1, Chunya Lu1,2

  • 1Department of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

Birth Defects Research
|March 19, 2020
PubMed

Insights

Structural insights into the KRASP34R mutation, common in RASopathies like Noonan syndrome, reveal mechanisms for altered RAS signaling. This may guide the development of targeted therapies for KRASP34R-driven diseases.

Area of Science:

  • Molecular biology
  • Structural biology
  • Genetics

Background:

  • RAS proteins are frequently mutated in cancer, and germline mutations cause RASopathy syndromes.
  • RASopathies such as Noonan syndrome (NS) and cardiofaciocutaneous (CFC) syndrome are linked to specific RAS mutations.
  • Understanding the structural basis of RAS mutations is crucial for managing associated diseases.

Purpose of the Study:

  • To determine the high-resolution X-ray structures of the KRASP34R mutant.
  • To elucidate the structural mechanisms underlying the altered signaling of KRASP34R.
  • To provide a foundation for developing mutation-specific therapeutic strategies.

Main Methods:

  • High-resolution X-ray crystallography of GTP- and GDP-bound KRASP34R.
  • Analysis of protein conformations and interactions in different crystalline forms.

Main Results:

  • KRASP34R structures revealed conformations incompatible with GTPase-activating protein (GAP) binding, explaining GAP insensitivity.
  • GTP-bound conformations support intrinsic GTP hydrolysis, potentially through R34 mimicking arginine finger roles.
  • Decreased affinity between KRASP34R and RAF-RBD suggests another mechanism for dampened RAS signaling.

Conclusions:

  • The structural findings offer insights into the molecular mechanisms of KRASP34R-associated RASopathies.
  • These results may facilitate the design of novel, mutation-specific treatments for diseases driven by KRASP34R.
  • The study provides a structural basis for understanding RASopathy pathogenesis and therapeutic targeting.
Keywords:
CFC syndromeGAP-insensitiveGTPaseNoonan syndromeRAS

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