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

Asim K. Bera, Jia Lu, Chunya Lu, Lianbo Li, Sudershan Gondi, Wei Yan, Andrew Nelson, Goujun Zhang, Kenneth D. Westover

Research output: Contribution to journalArticle

Abstract

RAS proteins are commonly mutated in cancerous tumors, but germline RAS mutations are also found in RASopathy syndromes such as Noonan syndrome (NS) and cardiofaciocutaneous (CFC) syndrome. Activating RAS mutations can be subclassified based on their activating mechanisms. Understanding the structural basis for these mechanisms may provide clues for how to manage associated health conditions. We determined high-resolution X-ray structures of the RASopathy mutant KRASP34R seen in NS and CFCS. GTP and GDP-bound KRASP34R crystallized in multiple forms, with each lattice consisting of multiple protein conformations. In all GTP-bound conformations, the switch regions are not compatible with GAP binding, suggesting a structural mechanism for the GAP insensitivity of this RAS mutant. However, GTP-bound conformations are compatible with intrinsic nucleotide hydrolysis, including one that places R34 in a position analogous to the GAP arginine finger or intrinsic arginine finger found in heterotrimeric G proteins, which may support intrinsic GTP hydrolysis. We also note that the affinity between KRASP34R and RAF-RBD is decreased, suggesting another possible mechanism for dampening of RAS signaling. These results may provide a foothold for development of new mutation-specific strategies to address KRASP34R-driven diseases.

Original languageEnglish (US)
Pages (from-to)708-717
Number of pages10
JournalBirth Defects Research
Volume112
Issue number10
DOIs
StatePublished - Jun 1 2020

Keywords

  • CFC syndrome
  • GAP-insensitive
  • GTPase
  • Noonan syndrome
  • RAS

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Toxicology
  • Developmental Biology
  • Health, Toxicology and Mutagenesis

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  • Cite this

    Bera, A. K., Lu, J., Lu, C., Li, L., Gondi, S., Yan, W., Nelson, A., Zhang, G., & Westover, K. D. (2020). GTP hydrolysis is modulated by Arg34 in the RASopathy-associated KRASP34R. Birth Defects Research, 112(10), 708-717. https://doi.org/10.1002/bdr2.1647