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Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase

文献类型：期刊论文

作者Law, Yee-Song4,5; Utt, Age6; Tan, Yaw Bia4,5; Zheng, Jie1,2; Wang, Sainan6; Chen, Ming Wei3,5; Griffin, Patrick R.1; Merits, Andres6; Luo, Dahai4,5
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2019-05-07
卷号116期号:19页码:9558-9567
关键词Chikungunya virus nonstructural protein 2 superfamily 1 helicase ATP hydrolysis Alphavirus
ISSN号0027-8424
DOI10.1073/pnas.1900656116
通讯作者Merits, Andres(andres.merits@ut.ee) ; Luo, Dahai(luodahai@ntu.edu.sg)
英文摘要Chikungunya virus (CHIKV) is transmitted to humans through mosquitoes and causes Chikungunya fever. Nonstructural protein 2 (nsP2) exhibits the protease and RNA helicase activities that are required for viral RNA replication and transcription. Unlike for the C-terminal protease, the structure of the N-terminal RNA helicase (nsP2h) has not been determined. Here, we report the crystal structure of the nsP2h bound to the conserved 3'-end 14 nucleotides of the CHIKV genome and the nonhydrolyzable transitionstate nucleotide analog ADP-AlF4. Overall, the structural analysis revealed that nsP2h adopts a uniquely folded N-terminal domain followed by a superfamily 1 RNA helicase fold. The conserved helicase motifs establish polar contacts with the RNA backbone. There are three hydrophobic residues (Y161, F164, and F287) which form stacking interactions with RNA bases and thereby bend the RNA backbone. An F287A substitution that disrupted these stacking interactions increased the basal ATPase activity but decreased the RNA binding affinity. Furthermore, the F287A substitution reduced viral infectivity by attenuating subgenomic RNA synthesis. Replication of the mutant virus was restored by pseudoreversion (A287V) or adaptive mutations in the RecA2 helicase domain (T358S or V410I). Y161A and/or F164A substitutions, which were designed to disrupt the interactions with the RNA molecule, did not affect the ATPase activity but completely abolished the replication and transcription of viral RNA and the infectivity of CHIKV. Our study sheds light on the roles of the RNA helicase region in viral replication and provides insights that might be applicable to alphaviruses and other RNA viruses in general.
WOS关键词FUNCTIONAL INSIGHTS ; CRYSTAL-STRUCTURE ; SINDBIS VIRUS ; OLD-WORLD ; PROTEINS ; ALPHAVIRUSES ; REPLICATION ; COMPLEXES ; MECHANISM ; EXCHANGE
资助项目Ministry of Education of Singapore[MOE2016T22097] ; Ministry of Health of Singapore[NMRC OFIRG17nov084] ; Estonian Research Council[IUT 20-27]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000467226400058
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/289876]  
专题中国科学院上海药物研究所
通讯作者Merits, Andres; Luo, Dahai
作者单位1.Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore
4.Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 636921, Singapore
5.Nanyang Technol Univ, NTU Inst Struct Biol, Singapore 636921, Singapore
6.Univ Tartu, Inst Technol, EE-50411 Tartu, Estonia
推荐引用方式
GB/T 7714		 Law, Yee-Song,Utt, Age,Tan, Yaw Bia,et al. Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(19):9558-9567.
APA Law, Yee-Song.,Utt, Age.,Tan, Yaw Bia.,Zheng, Jie.,Wang, Sainan.,...&Luo, Dahai.(2019).Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(19),9558-9567.
MLA Law, Yee-Song,et al."Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.19(2019):9558-9567.

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来源：上海药物研究所

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