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Sci. Signal., 27 January 2009
Vol. 2, Issue 55, p. ra3
[DOI: 10.1126/scisignal.2000029]

RESEARCH

Editor's Summary

Caught in the Act
The small guanosine triphosphatase (GTPase) Rheb, a member of the Ras superfamily of small GTPases, activates the protein kinase mammalian target of rapamycin (mTOR) when in its GTP-bound, active conformation. The intrinsic rate of GTP hydrolysis by Rheb is slow, but it is substantially accelerated when Rheb interacts with the GTPase-activating protein (GAP) domain of tuberous sclerosis complex 2 (TSC2); when GTP is hydrolyzed to GDP, Rheb is inactivated. TSC2 exists in a heterodimer with TSC1, and the stability of this complex is affected by cytokines, growth factors, and the energy status of the cell. Mutations in the gene encoding TSC2 are associated with tuberous sclerosis. Marshall et al. developed a real-time, nuclear magnetic resonance (NMR)–based assay to monitor the intrinsic GTPase activity of Rheb. They also investigated how the GAP domain of TSC2 accelerated the rate of GTP hydrolysis by Rheb and studied the effects of tuberous sclerosis–associated and engineered mutants of TSC2 on its GAP activity. This method can now be used to gain further understanding of the mechanisms of action of other GTPases and their GAP partners.

Citation: C. B. Marshall, J. Ho, C. Buerger, M. J. Plevin, G.-Y. Li, Z. Li, M. Ikura, V. Stambolic, Characterization of the Intrinsic and TSC2-GAP–Regulated GTPase Activity of Rheb by Real-Time NMR. Sci. Signal. 2, ra3 (2009).

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