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Impact of mutations on K-Ras-p120GAP interaction

Journal article
Authors Chunxia Gao
Leif A Eriksson
Published in Computational Molecular Biosciences
Volume 3
Issue 2
Pages 9-17
ISSN 2165-3445
Publication year 2013
Published at Department of Chemistry and Molecular Biology
Pages 9-17
Language en
Keywords Ras Protein; GTPase Activating Protein; Molecular Dynamics Simulations; In Silico Mutation Studies; Cancer
Subject categories Biophysical chemistry, Theoretical Chemistry, Biochemistry and Molecular Biology


The K-Ras protein plays a key role in the signal transduction cascade. Certain mutations in K-Ras lead to a permanent “on” state which results in tumorigenesis due to failed interaction with the GTPase activating protein (GAP). In this study, we examined the mutations E31N, D33N and D38N of K-Ras coupled and decoupled to wildtype GAP-334 and mutation K935N of GAP-334 coupled and decoupled to wildtype K-Ras, to illustrate the potential mechanism by which these mutants affect the interaction between the two proteins. We identify Tyr32 in the Ras Switch I region as a critical residue that acts as a gate to the GTP binding site and which needs to be “open” during Ras coupling with GAP to allow for insertion of GAP residue Arg789. This residue plays a vital role in stabilizing the transition state during GTP hydrolysis. The different mutations studied herein caused a reduced binding affinity, and the fluctuation of the Tyr32 side chain might hinder the insertion of Arg789. This may in turn be the cause of decreased GTP hydrolysis, and permanent “on” state of K-Ras, observed for these mutants.

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