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dc.contributor.authorZhu, Lizhe
dc.contributor.authorJiang, Hanlun
dc.contributor.authorCao, Siqin
dc.contributor.authorUnarta, Ilona Christy
dc.contributor.authorGao, Xin
dc.contributor.authorHuang, Xuhui
dc.date.accessioned2021-12-01T12:19:28Z
dc.date.available2021-12-01T12:19:28Z
dc.date.issued2021-11-30
dc.date.submitted2021-05-17
dc.identifier.citationZhu, L., Jiang, H., Cao, S., Unarta, I. C., Gao, X., & Huang, X. (2021). Critical role of backbone coordination in the mRNA recognition by RNA induced silencing complex. Communications Biology, 4(1). doi:10.1038/s42003-021-02822-7
dc.identifier.issn2399-3642
dc.identifier.doi10.1038/s42003-021-02822-7
dc.identifier.urihttp://hdl.handle.net/10754/673870
dc.description.abstractAbstractDespite its functional importance, the molecular mechanism underlying target mRNA recognition by Argonaute (Ago) remains largely elusive. Based on extensive all-atom molecular dynamics simulations, we constructed quasi-Markov State Model (qMSM) to reveal the dynamics during recognition at position 6-7 in the seed region of human Argonaute 2 (hAgo2). Interestingly, we found that the slowest mode of motion therein is not the gRNA-target base-pairing, but the coordination of the target phosphate groups with a set of positively charged residues of hAgo2. Moreover, the ability of Helix-7 to approach the PIWI and MID domains was found to reduce the effective volume accessible to the target mRNA and therefore facilitate both the backbone coordination and base-pair formation. Further mutant simulations revealed that alanine mutation of the D358 residue on Helix-7 enhanced a trap state to slow down the loading of target mRNA. Similar trap state was also observed when wobble pairs were introduced in g6 and g7, indicating the role of Helix-7 in suppressing non-canonical base-paring. Our study pointed to a general mechanism for mRNA recognition by eukaryotic Agos and demonstrated the promise of qMSM in investigating complex conformational changes of biomolecular systems.
dc.description.sponsorshipWe thank Dr. Fu Kit Sheong for fruitful discussions about the Argonaute proteins. This work was supported by the Hong Kong Research Grant Council [16303919, 16307718, and 16318816] to X.H., Shenzhen Science and Technology Innovation Committee [JCYJ20200109150003938] to L.Z., the National Science Foundation of China General Fund [31971179] to L.Z., research fund from Warshel Institute for Computational Biology and Longgang District Shenzhen to L.Z., and King Abdullah University of Science and Technology (KAUST) under award number FCC/1/1976-04-01, URF/1/4098-01-01, URF/1/4352-01-01, and URF/1/4379-01-01 to X.G.. This research made use of the resources of the Supercomputing Laboratory at KAUST.
dc.publisherSpringer Science and Business Media LLC
dc.relation.urlhttps://www.nature.com/articles/s42003-021-02822-7
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleCritical role of backbone coordination in the mRNA recognition by RNA induced silencing complex
dc.typeArticle
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentComputer Science Program
dc.contributor.departmentComputer, Electrical and Mathematical Science and Engineering (CEMSE) Division
dc.contributor.departmentStructural and Functional Bioinformatics Group
dc.identifier.journalCommunications Biology
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionWarshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China.
dc.contributor.institutionDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
dc.contributor.institutionDepartment of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
dc.contributor.institutionDepartment of Biochemistry, Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
dc.contributor.institutionCenter of Systems Biology and Human Health, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
dc.identifier.volume4
dc.identifier.issue1
kaust.personGao, Xin
kaust.grant.numberFCC/1/1976-04
kaust.grant.numberURF/1/4098-01-01
kaust.grant.numberURF/1/4352-01-01
kaust.grant.numberURF/1/4379-01-0
dc.date.accepted2021-10-26
refterms.dateFOA2021-12-01T12:20:38Z
kaust.acknowledged.supportUnitFCC
kaust.acknowledged.supportUnitSupercomputing Laboratory at KAUST
dc.date.published-online2021-11-30
dc.date.published-print2021-12


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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.