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Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome

While host miRNA usually plays an antiviral role, the relentless tides of viral evolution have carved out a mechanism to recruit host miRNA as a viral protector. By complementing miR-122 at the 5′ end of the genome, the hepatitis C virus (HCV) gene can form a complex with Argonaute 2 (Ago2) protein...

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Autores principales: Zhuang, Haiming, Ji, Dong, Fan, Jigang, Li, Mingyu, Tao, Ran, Du, Kui, Lu, Shaoyong, Chai, Zongtao, Fan, Xiaohua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687641/
https://www.ncbi.nlm.nih.gov/pubmed/36358979
http://dx.doi.org/10.3390/biom12111631
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author Zhuang, Haiming
Ji, Dong
Fan, Jigang
Li, Mingyu
Tao, Ran
Du, Kui
Lu, Shaoyong
Chai, Zongtao
Fan, Xiaohua
author_facet Zhuang, Haiming
Ji, Dong
Fan, Jigang
Li, Mingyu
Tao, Ran
Du, Kui
Lu, Shaoyong
Chai, Zongtao
Fan, Xiaohua
author_sort Zhuang, Haiming
collection PubMed
description While host miRNA usually plays an antiviral role, the relentless tides of viral evolution have carved out a mechanism to recruit host miRNA as a viral protector. By complementing miR-122 at the 5′ end of the genome, the hepatitis C virus (HCV) gene can form a complex with Argonaute 2 (Ago2) protein to protect the 5′ end of HCV RNA from exonucleolytic attacks. Experiments showed that the disruption of the stem-loop 1(SL1) structure and the 9th nucleotide (T9) of HCV site 1 RNA could enhance the affinity of the Ago2 protein to the HCV site 1 RNA (target RNA). However, the underlying mechanism of how the conformation and dynamics of the Ago2: miRNA: target RNA complex is affected by the SL1 and T9 remains unclear. To address this, we performed large-scale molecular dynamics simulations on the AGO2-miRNA complex binding with the WT target, T9-abasic target and SL1-disruption target, respectively. The results revealed that the T9 and SL1 structures could induce the departing motion of the PAZ, PIWI and N domains, propping up the mouth of the central groove which accommodates the target RNA, causing the instability of the target RNA and disrupting the Ago2 binding. The coordinated motion among the PAZ, PIWI and N domains were also weakened by the T9 and SL1 structures. Moreover, we proposed a new model wherein the Ago2 protein could adopt a more constraint conformation with the proximity and more correlated motions of the PAZ, N and PIWI domains to protect the target RNA from dissociation. These findings reveal the mechanism of the Ago2-miRNA complex’s protective effect on the HCV genome at the atomic level, which will offer guidance for the design of drugs to confront the protection effect and engineering of Ago2 as a gene-regulation tool.
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spelling pubmed-96876412022-11-25 Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome Zhuang, Haiming Ji, Dong Fan, Jigang Li, Mingyu Tao, Ran Du, Kui Lu, Shaoyong Chai, Zongtao Fan, Xiaohua Biomolecules Article While host miRNA usually plays an antiviral role, the relentless tides of viral evolution have carved out a mechanism to recruit host miRNA as a viral protector. By complementing miR-122 at the 5′ end of the genome, the hepatitis C virus (HCV) gene can form a complex with Argonaute 2 (Ago2) protein to protect the 5′ end of HCV RNA from exonucleolytic attacks. Experiments showed that the disruption of the stem-loop 1(SL1) structure and the 9th nucleotide (T9) of HCV site 1 RNA could enhance the affinity of the Ago2 protein to the HCV site 1 RNA (target RNA). However, the underlying mechanism of how the conformation and dynamics of the Ago2: miRNA: target RNA complex is affected by the SL1 and T9 remains unclear. To address this, we performed large-scale molecular dynamics simulations on the AGO2-miRNA complex binding with the WT target, T9-abasic target and SL1-disruption target, respectively. The results revealed that the T9 and SL1 structures could induce the departing motion of the PAZ, PIWI and N domains, propping up the mouth of the central groove which accommodates the target RNA, causing the instability of the target RNA and disrupting the Ago2 binding. The coordinated motion among the PAZ, PIWI and N domains were also weakened by the T9 and SL1 structures. Moreover, we proposed a new model wherein the Ago2 protein could adopt a more constraint conformation with the proximity and more correlated motions of the PAZ, N and PIWI domains to protect the target RNA from dissociation. These findings reveal the mechanism of the Ago2-miRNA complex’s protective effect on the HCV genome at the atomic level, which will offer guidance for the design of drugs to confront the protection effect and engineering of Ago2 as a gene-regulation tool. MDPI 2022-11-03 /pmc/articles/PMC9687641/ /pubmed/36358979 http://dx.doi.org/10.3390/biom12111631 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhuang, Haiming
Ji, Dong
Fan, Jigang
Li, Mingyu
Tao, Ran
Du, Kui
Lu, Shaoyong
Chai, Zongtao
Fan, Xiaohua
Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome
title Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome
title_full Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome
title_fullStr Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome
title_full_unstemmed Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome
title_short Mechanistic Insights into the Protection Effect of Argonaute–RNA Complex on the HCV Genome
title_sort mechanistic insights into the protection effect of argonaute–rna complex on the hcv genome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687641/
https://www.ncbi.nlm.nih.gov/pubmed/36358979
http://dx.doi.org/10.3390/biom12111631
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