Structural basis for the unique biological function of small GTPase RHEB

	Structural basis for the unique biological function of small GTPase RHEB
	Yu, YD; Li, S; Xu, X; Li, Y; Guan, KL; Arnold, E; Ding, JP
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2005
卷号	280 期号:17 页码:17093-17100
通讯作者	Ding, JP (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Key Lab Proteom, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,jpding@sibs.ac.cn
英文摘要	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'-(beta, gamma-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 alpha-helical conformation seen in other small GTPases. The unique switch II conformation results in a displacement of Gln(64) ( equivalent to the catalytic Gln(61) 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 Arg(15), 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 Tyr(35) 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 Asn(1643) of the tuberous sclerosis complex 2 GTPase-activating protein domain instead of Gln(64) of Rheb as the catalytic residue.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	TUBEROUS SCLEROSIS COMPLEX ; TUMOR-SUPPRESSOR PROTEINS ; RAS-RELATED PROTEIN ; TSC2 GAP ACTIVITY ; CELL-GROWTH ; GENE-PRODUCTS ; DIRECT TARGET ; ACTIVATION ; DROSOPHILA ; MUTANTS
收录类别	SCI
语种	英语
WOS记录号	WOS:000228615500068
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1980]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Yu, YD,Li, S,Xu, X,et al. Structural basis for the unique biological function of small GTPase RHEB[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2005,280(17):17093-17100.
APA	Yu, YD.,Li, S.,Xu, X.,Li, Y.,Guan, KL.,...&Ding, JP.(2005).Structural basis for the unique biological function of small GTPase RHEB.JOURNAL OF BIOLOGICAL CHEMISTRY,280(17),17093-17100.
MLA	Yu, YD,et al."Structural basis for the unique biological function of small GTPase RHEB".JOURNAL OF BIOLOGICAL CHEMISTRY 280.17(2005):17093-17100.