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Int. J. Mol. Sci. 2016, 17(1), 22; doi:10.3390/ijms17010022

Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2

1
Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
2
Institute for Neuro- and Bioinformatics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
3
Computational Structural Biology, Bijvoet Center for Biomolecular Research, Faculty of Science—Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
*
Authors to whom correspondence should be addressed.
Academic Editor: Martin Pichler
Received: 3 November 2015 / Revised: 14 December 2015 / Accepted: 16 December 2015 / Published: 24 December 2015
(This article belongs to the Collection Regulation by Non-Coding RNAs)
View Full-Text   |   Download PDF [3405 KB, uploaded 24 December 2015]   |  

Abstract

The human Argonaute 2 (hAgo2) protein is a key player of RNA interference (RNAi). Upon complex formation with small non-coding RNAs, the protein initially interacts with the 5′-end of a given guide RNA through multiple interactions within the MID domain. This interaction has been reported to show a strong bias for U and A over C and G at the 5′-position. Performing molecular dynamics simulations of binary hAgo2/OH–guide–RNA complexes, we show that hAgo2 is a highly flexible protein capable of binding to guide strands with all four possible 5′-bases. Especially, in the case of C and G this is associated with rather large individual conformational rearrangements affecting the MID, PAZ and even the N-terminal domains to different degrees. Moreover, a 5′-G induces domain motions in the protein, which trigger a previously unreported interaction between the 5′-base and the L2 linker domain. Combining our in silico analyses with biochemical studies of recombinant hAgo2, we find that, contrary to previous observations, hAgo2 is capable of functionally accommodating guide strands regardless of the 5′-base. View Full-Text
Keywords: RNAi; MD; enzyme kinetics; pre-steady-state kinetics; fluorescence spectroscopy RNAi; MD; enzyme kinetics; pre-steady-state kinetics; fluorescence spectroscopy
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Kalia, M.; Willkomm, S.; Claussen, J.C.; Restle, T.; Bonvin, A.M.J.J. Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2. Int. J. Mol. Sci. 2016, 17, 22.

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