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A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation

文献类型：期刊论文

作者Lu, Junyan1,3; Jiang, Chenxiao1; Li, Xiaojing1; Jiang, Lizhi1; Li, Zengxia1; Schneider-Poetsch, Tilman4; Liu, Jianwei5,6; Yu, Kunqian3; Liu, Jun O.2,7; Jiang, Hualiang3
刊名NUCLEIC ACIDS RESEARCH
出版日期2015-12-02
卷号43期号:21页码:10157-10167
ISSN号0305-1048
DOI10.1093/nar/gkv1033
文献子类Article
英文摘要Eukaryotic translation initiation factor eIF4AI, the founding member of DEAD-box helicases, undergoes ATP hydrolysis-coupled conformational changes to unwind mRNA secondary structures during translation initiation. However, the mechanism of its coupled enzymatic activities remains unclear. Here we report that a gating mechanism for Pi release controlled by the inter-domain linker of eIF4AI regulates the coupling between ATP hydrolysis and RNA unwinding. Molecular dynamic simulations and experimental results revealed that, through forming a hydrophobic core with the conserved SAT motif of the N-terminal domain and I357 from the C-terminal domain, the linker gated the release of Pi from the hydrolysis site, which avoided futile hydrolysis cycles of eIF4AI. Further mutagenesis studies suggested this linker also plays an auto-inhibitory role in the enzymatic activity of eIF4AI, which may be essential for its function during translation initiation. Overall, our results reveal a novel regulatory mechanism that controls eIF4AI-mediated mRNA unwinding and can guide further mechanistic studies on other DEAD-box helicases.
WOS关键词DEAD-BOX PROTEINS ; MARINE NATURAL-PRODUCT ; PATEAMINE-A ; CONFORMATIONAL-CHANGES ; PHOSPHATE RELEASE ; HIGH-THROUGHPUT ; ATP UTILIZATION ; HELICASES ; NUCLEOTIDE ; MYOSIN
资助项目Ministry of Science and Technology of China[2015CB910304] ; Hi-Tech Research and Development Program of China[2012AA020301] ; Hi-Tech Research and Development Program of China[2012AA01A305] ; Hi-Tech Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[31270830] ; National Natural Science Foundation of China[21572038] ; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences[00000000] ; Fudan University[00000000] ; State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505]
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000366410900017
出版者OXFORD UNIV PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/276292]  
专题药物发现与设计中心
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Dang, Yongjun
作者单位1.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai 200032, Peoples R China;
2.Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
4.RIKEN, Chem Genet Lab, Wako, Saitama 3510198, Japan;
5.Fudan Univ, Dept Chem, Shanghai Key Lab Chem Biol Prot Res, Shanghai 200433, Peoples R China;
6.Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China;
7.Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA;
推荐引用方式
GB/T 7714		 Lu, Junyan,Jiang, Chenxiao,Li, Xiaojing,et al. A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation[J]. NUCLEIC ACIDS RESEARCH,2015,43(21):10157-10167.
APA Lu, Junyan.,Jiang, Chenxiao.,Li, Xiaojing.,Jiang, Lizhi.,Li, Zengxia.,...&Dang, Yongjun.(2015).A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation.NUCLEIC ACIDS RESEARCH,43(21),10157-10167.
MLA Lu, Junyan,et al."A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation".NUCLEIC ACIDS RESEARCH 43.21(2015):10157-10167.

入库方式： OAI收割

来源：上海药物研究所

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