Inhibitory Mechanism of Caspase-6 Phosphorylation Revealed by Crystal   Structures, Molecular Dynamics Simulations, and Biochemical Assays

doi:10.1074/jbc.M112.351213

CORC > 北京大学 > 化学与分子工程学院

	Inhibitory Mechanism of Caspase-6 Phosphorylation Revealed by Crystal Structures, Molecular Dynamics Simulations, and Biochemical Assays
	Cao, Qin ; Wang, Xiao-Jun ; Liu, Cheng-Wen ; Liu, Dai-Fei ; Li, Lan-Fen ; Gao, Yi-Qin ; Su, Xiao-Dong
刊名	journal of biological chemistry
	2012
关键词	MICHAEL ACCEPTORS MUTANT HUNTINGTIN SELF-ACTIVATION IN-VITRO CLEAVAGE DEATH CONFORMATION DISEASE SYSTEM MODE
DOI	10.1074/jbc.M112.351213
英文摘要	The apoptotic effector caspase-6 (CASP6) has been clearly identified as a drug target due to its strong association with neurodegeneration and axonal pruning events as well as its crucial roles in Huntington disease and Alzheimer disease. CASP6 activity is suppressed by ARK5-mediated phosphorylation at Ser(257) with an unclear mechanism. In this work, we solved crystal structures of Delta proCASP6S257E and p20/p10S257E, which mimicked the phosphorylated CASP6 zymogen and activated CASP6, respectively. The structural investigation combined with extensive biochemical assay and molecular dynamics simulation studies revealed that phosphorylation on Ser(257) inhibited self-activation of CASP6 zymogen by "locking" the enzyme in the TEVD193-bound "inhibited state." The structural and biochemical results also showed that phosphorylation on Ser(257) inhibited the CASP6 activity by steric hindrance. These results disclosed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design.; http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000304006300019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701 ; Biochemistry & Molecular Biology; SCI(E); EI; PubMed; 12; ARTICLE; 19; 15371-15379; 287
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/343443]
专题	化学与分子工程学院生命科学学院
推荐引用方式 GB/T 7714	Cao, Qin,Wang, Xiao-Jun,Liu, Cheng-Wen,et al. Inhibitory Mechanism of Caspase-6 Phosphorylation Revealed by Crystal Structures, Molecular Dynamics Simulations, and Biochemical Assays[J]. journal of biological chemistry,2012.
APA	Cao, Qin.,Wang, Xiao-Jun.,Liu, Cheng-Wen.,Liu, Dai-Fei.,Li, Lan-Fen.,...&Su, Xiao-Dong.(2012).Inhibitory Mechanism of Caspase-6 Phosphorylation Revealed by Crystal Structures, Molecular Dynamics Simulations, and Biochemical Assays.journal of biological chemistry.
MLA	Cao, Qin,et al."Inhibitory Mechanism of Caspase-6 Phosphorylation Revealed by Crystal Structures, Molecular Dynamics Simulations, and Biochemical Assays".journal of biological chemistry (2012).