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Structural basis for the unique biological function of small GTPase RHEB
Yadong Yu1, Sheng Li, Xiang Xu
1Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
The Journal of Biological Chemistry
|February 25, 2005
Summary
Rheb, a small GTPase, has unique structural features that explain its low GTPase activity. These findings reveal a novel GTP hydrolysis mechanism involving tuberous sclerosis complex 2.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Rheb is a small GTPase mediating between TSC1/TSC2 tumor suppressors and mTOR to regulate cell growth.
- Its unique properties distinguish it from other small GTPases.
Purpose of the Study:
- To elucidate the three-dimensional structures of human Rheb in complex with GDP, GTP, and GppNHp.
- To provide a molecular basis for Rheb's distinct biological and biochemical properties.
Main Methods:
- X-ray crystallography to determine the 3D structures of Rheb-GDP, Rheb-GTP, and Rheb-GppNHp complexes.
- Comparative structural analysis with other small GTPases.
Main Results:
- Rheb exhibits a unique extended conformation in switch II, unlike the alpha-helical switch II in other GTPases.
- This conformation displaces Gln64, rendering Rheb incapable of intrinsic GTP hydrolysis.
- The GTP-binding site is shielded by Tyr35, potentially hindering GTPase-activating protein (GAP) interaction.
Conclusions:
- Rheb represents a new group within the Ras/Rap subfamily.
- A novel GTP hydrolysis mechanism is proposed, utilizing Asn1643 from the tuberous sclerosis complex 2 GAP domain as the catalytic residue.