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

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...

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Autores principales: Kalia, Munishikha, Willkomm, Sarah, Claussen, Jens Christian, Restle, Tobias, Bonvin, Alexandre M. J. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730269/
https://www.ncbi.nlm.nih.gov/pubmed/26712743
http://dx.doi.org/10.3390/ijms17010022
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author Kalia, Munishikha
Willkomm, Sarah
Claussen, Jens Christian
Restle, Tobias
Bonvin, Alexandre M. J. J.
author_facet Kalia, Munishikha
Willkomm, Sarah
Claussen, Jens Christian
Restle, Tobias
Bonvin, Alexandre M. J. J.
author_sort Kalia, Munishikha
collection PubMed
description 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.
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spelling pubmed-47302692016-02-11 Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2 Kalia, Munishikha Willkomm, Sarah Claussen, Jens Christian Restle, Tobias Bonvin, Alexandre M. J. J. Int J Mol Sci Article 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. MDPI 2015-12-24 /pmc/articles/PMC4730269/ /pubmed/26712743 http://dx.doi.org/10.3390/ijms17010022 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kalia, Munishikha
Willkomm, Sarah
Claussen, Jens Christian
Restle, Tobias
Bonvin, Alexandre M. J. J.
Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
title Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
title_full Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
title_fullStr Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
title_full_unstemmed Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
title_short Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
title_sort novel insights into guide rna 5′-nucleoside/tide binding by human argonaute 2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730269/
https://www.ncbi.nlm.nih.gov/pubmed/26712743
http://dx.doi.org/10.3390/ijms17010022
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