TITLE:
Impact of Mutations on K-Ras-p120GAP Interaction
AUTHORS:
Chunxia Gao, Leif A. Eriksson
KEYWORDS:
Ras Protein; GTPase Activating Protein; Molecular Dynamics Simulations; In Silico Mutation Studies; Cancer
JOURNAL NAME:
Computational Molecular Bioscience,
Vol.3 No.2,
May
30,
2013
ABSTRACT: 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.