Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif

	Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif
	Ding, JP; Wang, JC; Zhong, C; Wang, F
刊名	FASEB JOURNAL
	2013
卷号	27 期号:1 页码:42006
关键词	activation loop hydrophobic motif mammalian target of rapamycin (mTOR) signalling phosphorylation ribosomal protein subunit 6 kinase 1 (S6K1) zinc finger
通讯作者	,
英文摘要	The activity of S6K1 (p70 ribosomal protein subunit 6 kinase 1) is stimulated by phosphorylation of Thr(389) in the hydrophobic motif by mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of Thr(229) in the activation loop by PDK1 (phosphoinositide-dependent kinase 1); however, the order of the two events is still ambiguous. In the present paper we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data, together with the biochemical data, reveal in vivo phosphorylation of Thr(389) in the absence of Thr(229) phosphorylation and demonstrate the importance of two conserved residues, Gln(140) and Arg(121), in the establishment of a hydrogen-bonding network between the N-lobe (N-terminal lobe) and the hydrophobic motif. Phosphorylation of Thr(389) or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix alpha C. Furthermore, comparisons of S6K1 with other AGC (protein kinase A/protein kinase G/protein kinase C) family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix aC account for their divergence in PDK1 dependency. Taken together, the results of the present study indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of, and probably precedes and promotes, phosphorylation of the activation loop.
学科主题	Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology
类目[WOS]	Biochemistry & Molecular Biology ; Biology ; Cell Biology
关键词[WOS]	ACTIVATION LOOP PHOSPHORYLATION ; CELL-GROWTH CONTROL ; PROTEIN-KINASES ; CATALYTIC DOMAIN ; IN-VIVO ; BINDING POCKET ; DOCKING SITE ; PDK1 ; TARGET ; MTOR
收录类别	SCI
语种	英语
WOS记录号	WOS:000319883504298
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/509]
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	Ding, JP,Wang, JC,Zhong, C,et al. Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif[J]. FASEB JOURNAL,2013,27(1):42006.
APA	Ding, JP,Wang, JC,Zhong, C,&Wang, F.(2013).Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif.FASEB JOURNAL,27(1),42006.
MLA	Ding, JP,et al."Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif".FASEB JOURNAL 27.1(2013):42006.