气候变化领域集成服务门户(CCPortal): Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation

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DOI	10.1073/pnas.2017715118
	Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation
	Lapointe C.P.; Grosely R.; Johnson A.G.; Wang J.; Fernández I.S.; Puglisi J.D.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-CoV that recently emerged as a human pathogen and is the causative agent of the COVID-19 pandemic. A molecular framework of how the virus manipulates host cellular machinery to facilitate infection remains unclear. Here, we focus on SARS-CoV-2 NSP1, which is proposed to be a virulence factor that inhibits protein synthesis by directly binding the human ribosome. We demonstrate biochemically that NSP1 inhibits translation of model human and SARS-CoV-2 messenger RNAs (mRNAs). NSP1 specifically binds to the small (40S) ribosomal subunit, which is required for translation inhibition. Using single-molecule fluorescence assays to monitor NSP1-40S subunit binding in real time, we determine that eukaryotic translation initiation factors (eIFs) allosterically modulate the interaction of NSP1 with ribosomal preinitiation complexes in the absence of mRNA. We further elucidate that NSP1 competes with RNA segments downstream of the start codon to bind the 40S subunit and that the protein is unable to associate rapidly with 80S ribosomes assembled on an mRNA. Collectively, our findings support a model where NSP1 proteins from viruses in at least two subgenera of beta-CoVs associate with the open head conformation of the 40S subunit to inhibit an early step of translation, by preventing accommodation of mRNA within the entry channel. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Eukaryotic translation initiation; Human ribosome; NSP1; SARS-CoV-2; Single-molecule fluorescence
语种	英语
scopus关键词	initiation factor; messenger RNA; NSP1 protein, SARS-CoV-2; ribosomal protein S20; ribosome protein; viral protein; virus RNA; 40S ribosomal subunit; genetics; human; metabolism; pandemic; pathogenicity; protein processing; protein synthesis; ribosome; translation initiation; virology; COVID-19; Eukaryotic Initiation Factors; Humans; Pandemics; Peptide Chain Initiation, Translational; Protein Biosynthesis; Protein Processing, Post-Translational; Ribosomal Proteins; Ribosome Subunits, Small, Eukaryotic; Ribosomes; RNA, Messenger; RNA, Viral; SARS-CoV-2; Viral Nonstructural Proteins
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180778
作者单位	Department of Structural Biology, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York City, NY 10032, United States; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, United States
推荐引用方式 GB/T 7714	Lapointe C.P.,Grosely R.,Johnson A.G.,et al. Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation[J],2021,118(6).
APA	Lapointe C.P.,Grosely R.,Johnson A.G.,Wang J.,Fernández I.S.,&Puglisi J.D..(2021).Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	Lapointe C.P.,et al."Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).