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J. Biol. Chem., Vol. 280, Issue 17, 17093-17100, April 29, 2005

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Structural Basis for the Unique Biological Function of Small GTPase RHEB^*

Yadong Yu, Sheng Li, Xiang Xu, Yong Li, Kunliang Guan, Eddy Arnold¶, and Jianping Ding||

From the Key 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, Life Science Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0606, and ^¶Center for Advanced Biotechnology and Medicine and Rutgers University Department of Chemistry and Chemical Biology, Piscataway, New Jersey 08854-5638

The small GTPase Rheb displays unique biological and biochemical properties different from other small GTPases and functions as an important mediator between the tumor suppressor proteins TSC1 and TSC2 and the mammalian target of rapamycin to stimulate cell growth. We report here the three-dimensional structures of human Rheb in complexes with GDP, GTP, and GppNHp (5'-(,-imide)triphosphate), which reveal novel structural features of Rheb and provide a molecular basis for its distinct properties. During GTP/GDP cycling, switch I of Rheb undergoes conformational change while switch II maintains a stable, unusually extended conformation, which is substantially different from the -helical conformation seen in other small GTPases. The unique switch II conformation results in a displacement of Gln⁶⁴ (equivalent to the catalytic Gln⁶¹ of Ras), making it incapable of participating in GTP hydrolysis and thus accounting for the low intrinsic GTPase activity of Rheb. This rearrangement also creates space to accommodate the side chain of Arg¹⁵, avoiding its steric hindrance with the catalytic residue and explaining its noninvolvement in GTP hydrolysis. Unlike Ras, the phosphate moiety of GTP in Rheb is shielded by the conserved Tyr³⁵ of switch I, leading to the closure of the GTP-binding site, which appears to prohibit the insertion of a potential arginine finger from its GTPase-activating protein. Taking the genetic, biochemical, biological, and structural data together, we propose that Rheb forms a new group of the Ras/Rap subfamily and uses a novel GTP hydrolysis mechanism that utilizes Asn¹⁶⁴³ of the tuberous sclerosis complex 2 GTPase-activating protein domain instead of Gln⁶⁴ of Rheb as the catalytic residue.

Received for publication, February 3, 2005 , and in revised form, February 22, 2005.

^* This work was supported by National Natural Science Foundation of China Grants 30125011, 30170223, and 30130080, Ministry of Science and Technology of China Grants 2002BA711A13, 2004AA235091, 2004CB720102, and 2004CB520801, and Chinese Academy of Sciences Grant KSCX1-SW-17. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (codes 1XTQ, 1XTR, and 1XTS) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^|| To whom correspondence should be addressed. Tel.: 86-21-54921619; Fax: 86-21-54921116; E-mail: jpding{at}sibs.ac.cn.

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