Characterization of Gain-of-Function Mutant Provides New Insights into ClpP Structure

doi:10.1021/acschembio.6b00390

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Characterization of Gain-of-Function Mutant Provides New Insights into ClpP Structure
	Ni, Tengfeng 2,3; Ye, Fei 4,5; Liu, Xing ; Zhang, Jie 2; Liu, Hongchuan 2; Li, Jiahui 2,3; Zhang, Yingyi 7; Sun, Yinqiang 1; Wang, Meining 6; Luo, Cheng5
刊名	ACS CHEMICAL BIOLOGY
	2016-07
卷号	11 期号:7 页码:1964-1972
ISSN号	1554-8929
DOI	10.1021/acschembio.6b00390
文献子类	Article
英文摘要	ATP-dependent Clp protease (ClpP), a highly conserved serine protease in vast bacteria, could be converted into a noncontrollable enzyme capable of degrading mature proteins in the presence of acyldepsipeptides (ADEPs). Here, we design such a gain-of-function mutant of Staphylococcus aureus ClpP (SaClpP) capable of triggering the same level of dysfunctional activity that occurs upon ADEPs treatment. The SaClpPY63A mutant degrades FtsZ in vivo and inhibits staphylococcal growth. The crystal structure of SaClpPY63A indicates that Asn42 would be an important domino to fall for further activation of ClpP. Indeed, the SaClpPN42AY63A mutant demonstrates promoted self-activated proteolysis, which is a result of an enlarged entrance pore as observed in cryo-electron microscopy images. In addition, the expression of the engineered clpP allele phenocopies treatment with ADEPs; inhibition of cell division occurs as does showing sterilizing with rifampicin antibiotics. Collectively, we show that the gain-of-function SaClpPN42AY63A mutant becomes a fairly nonspecific protease and kills persisters by degrading over 500 proteins, thus providing new insights into the structure of the ClpP protease.
资助项目	National Natural Science Foundation of China[21172234] ; Self deployment Project of Shanghai Institute of Materia Medica[CASIMM0120154016] ; Public Projects of Zhejiang Province[2015C33159]
WOS关键词	CASEINOLYTIC PROTEASE P ; AAA PLUS PROTEASE ; STAPHYLOCOCCUS-AUREUS ; CRYSTAL-STRUCTURE ; ANTIBACTERIAL ACTIVITY ; ACYLDEPSIPEPTIDES ACTIVATE ; DEPENDENT PROTEASES ; COMPLEX-FORMATION ; STRESS TOLERANCE ; CIPP PROTEASE
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000380181900024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275967]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Yang, Cai-Guang
作者单位	1.Shanghai Univ Tradit Chinese Med, Experirnent Ctr Sci & Technol, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Biol Chem Lab, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Design & Discovery Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai 201210, Peoples R China; 8.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式 GB/T 7714	Ni, Tengfeng,Ye, Fei,Liu, Xing,et al. Characterization of Gain-of-Function Mutant Provides New Insights into ClpP Structure[J]. ACS CHEMICAL BIOLOGY,2016,11(7):1964-1972.
APA	Ni, Tengfeng.,Ye, Fei.,Liu, Xing.,Zhang, Jie.,Liu, Hongchuan.,...&Yang, Cai-Guang.(2016).Characterization of Gain-of-Function Mutant Provides New Insights into ClpP Structure.ACS CHEMICAL BIOLOGY,11(7),1964-1972.
MLA	Ni, Tengfeng,et al."Characterization of Gain-of-Function Mutant Provides New Insights into ClpP Structure".ACS CHEMICAL BIOLOGY 11.7(2016):1964-1972.