A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus

Handle URI:
http://hdl.handle.net/10754/621481
Title:
A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus
Authors:
Zhu, Lizhe; Jiang, Hanlun; Sheong, Fu Kit; Cui, Xuefeng; Gao, Xin ( 0000-0002-7108-3574 ) ; Wang, Yanli; Huang, Xuhui
Abstract:
Argonaute proteins (Ago) are core components of the RNA Induced Silencing Complex (RISC) that load and utilize small guide nucleic acids to silence mRNAs or cleave foreign DNAs. Despite the essential role of Ago in gene regulation and defense against virus, the molecular mechanism of guide-strand loading into Ago remains unclear. We explore such a mechanism in the bacterium Thermus thermophilus Ago (TtAgo), via a computational approach combining molecular dynamics, bias-exchange metadynamics, and protein-DNA docking. We show that apo TtAgo adopts multiple closed states that are unable to accommodate guide-DNA. Conformations able to accommodate the guide are beyond the reach of thermal fluctuations from the closed states. These results suggest an induced-fit dominant mechanism for guide-strand loading in TtAgo, drastically different from the two-step mechanism for human Ago 2 (hAgo2) identified in our previous study. Such a difference between TtAgo and hAgo2 is found to mainly originate from the distinct rigidity of their L1-PAZ hinge. Further comparison among known Ago structures from various species indicates that the L1-PAZ hinge may be flexible in general for prokaryotic Agos but rigid for eukaryotic Agos. © 2016 American Chemical Society.
KAUST Department:
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Citation:
Zhu L, Jiang H, Sheong FK, Cui X, Gao X, et al. (2016) A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus . J Phys Chem B 120: 2709–2720. Available: http://dx.doi.org/10.1021/acs.jpcb.5b12426.
Publisher:
American Chemical Society (ACS)
Journal:
The Journal of Physical Chemistry B
Issue Date:
24-Feb-2016
DOI:
10.1021/acs.jpcb.5b12426
Type:
Article
ISSN:
1520-6106; 1520-5207
Sponsors:
X.H. acknowledges National Basic Research Program of China (973 program 2013CB834703), National Science Foundation of China (No. 21273188), and Hong Kong Research Grants Council (609813, 16304215, 16302214, and AoE/M 09/12). This research made use of the resources of the Supercomputing Laboratory at King Abdullah University of Science & Technology. X.C. and X.G. were supported by grants from King Abdullah University of Science & Technology.
Appears in Collections:
Articles; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorZhu, Lizheen
dc.contributor.authorJiang, Hanlunen
dc.contributor.authorSheong, Fu Kiten
dc.contributor.authorCui, Xuefengen
dc.contributor.authorGao, Xinen
dc.contributor.authorWang, Yanlien
dc.contributor.authorHuang, Xuhuien
dc.date.accessioned2016-11-03T08:30:25Z-
dc.date.available2016-11-03T08:30:25Z-
dc.date.issued2016-02-24en
dc.identifier.citationZhu L, Jiang H, Sheong FK, Cui X, Gao X, et al. (2016) A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus . J Phys Chem B 120: 2709–2720. Available: http://dx.doi.org/10.1021/acs.jpcb.5b12426.en
dc.identifier.issn1520-6106en
dc.identifier.issn1520-5207en
dc.identifier.doi10.1021/acs.jpcb.5b12426en
dc.identifier.urihttp://hdl.handle.net/10754/621481-
dc.description.abstractArgonaute proteins (Ago) are core components of the RNA Induced Silencing Complex (RISC) that load and utilize small guide nucleic acids to silence mRNAs or cleave foreign DNAs. Despite the essential role of Ago in gene regulation and defense against virus, the molecular mechanism of guide-strand loading into Ago remains unclear. We explore such a mechanism in the bacterium Thermus thermophilus Ago (TtAgo), via a computational approach combining molecular dynamics, bias-exchange metadynamics, and protein-DNA docking. We show that apo TtAgo adopts multiple closed states that are unable to accommodate guide-DNA. Conformations able to accommodate the guide are beyond the reach of thermal fluctuations from the closed states. These results suggest an induced-fit dominant mechanism for guide-strand loading in TtAgo, drastically different from the two-step mechanism for human Ago 2 (hAgo2) identified in our previous study. Such a difference between TtAgo and hAgo2 is found to mainly originate from the distinct rigidity of their L1-PAZ hinge. Further comparison among known Ago structures from various species indicates that the L1-PAZ hinge may be flexible in general for prokaryotic Agos but rigid for eukaryotic Agos. © 2016 American Chemical Society.en
dc.description.sponsorshipX.H. acknowledges National Basic Research Program of China (973 program 2013CB834703), National Science Foundation of China (No. 21273188), and Hong Kong Research Grants Council (609813, 16304215, 16302214, and AoE/M 09/12). This research made use of the resources of the Supercomputing Laboratory at King Abdullah University of Science & Technology. X.C. and X.G. were supported by grants from King Abdullah University of Science & Technology.en
dc.publisherAmerican Chemical Society (ACS)en
dc.titleA Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilusen
dc.typeArticleen
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.identifier.journalThe Journal of Physical Chemistry Ben
dc.contributor.institutionDepartment of Chemistry, School of Science, Institute for Advance Study, Clear Water Bay, Kowloon, Hong Kongen
dc.contributor.institutionCenter of Systems Biology and Human Health, School of Science, Institute for Advance Study, Clear Water Bay, Kowloon, Hong Kongen
dc.contributor.institutionBioengineering Graduate Program, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kongen
dc.contributor.institutionLaboratory of Non-Coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, Chinaen
kaust.authorCui, Xuefengen
kaust.authorGao, Xinen
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