Mechanistic Insights into the Differential Catalysis by RheB and Its Mutants: Y35A and Y35A-D65A

ACS Omega
Chaithanya KotyadaMahavir Singh

Abstract

RheB GTPase is a Ras-related molecular switch, which regulates the mTOR signaling pathway by cycling between the active [guanosine triphosphate (GTP)] state and inactive [guanine diphosphate (GDP)] state. Impairment of GTPase activity because of mutations in several small GTPases is known to be associated with several cancers. The conventional GTPase mechanism such as in H-Ras requires a conserved glutamine (Q64) in the switch-II region of RheB to align the catalytic water molecule for efficient GTP hydrolysis. The conformation of this conserved glutamine is different in RheB, resulting in an altered conformation of the entire switch-II region. Studies on the atypical switch-II conformation in RheB revealed a distinct, noncanonical mode of GTP hydrolysis. An RheB mutant Y35A was previously shown to exclusively enhance the intrinsic GTPase activity of RheB, whereas the Y35A-D65A double mutant was shown to reduce the elevated GTPase activity. Here, we have used all-atom molecular dynamics (MD) simulations for comprehensive understanding of the conformational dynamics associated with the fast (Y35A) and slow (Y35A-D65A) hydrolyzing mutants of RheB. Using a combination of starting models from PDB structures and in-silico generated ...Continue Reading

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Citations

Dec 15, 2018·Chemistry & Biodiversity·Farideh Badichi AkherMahmoud E S Soliman

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Methods Mentioned

BETA
GTPases
GTPase
PCA

Software Mentioned

GROMACS
SASA
xtal
UCSF Chimera

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