Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets
MicroRNAs (miRNAs) direct post-transcriptional regulation of human genes by guiding Argonaute proteins to complementary sites in messenger RNAs (mRNAs) targeted for repression. An enigmatic feature of many conserved mammalian miRNA target sites is that an adenosine (A) nucleotide opposite miRNA nucl...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/07646 |
| _version_ | 1811180493329137664 |
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| author | Nicole T Schirle Jessica Sheu-Gruttadauria Stanley D Chandradoss Chirlmin Joo Ian J MacRae |
| author_facet | Nicole T Schirle Jessica Sheu-Gruttadauria Stanley D Chandradoss Chirlmin Joo Ian J MacRae |
| author_sort | Nicole T Schirle |
| collection | DOAJ |
| description | MicroRNAs (miRNAs) direct post-transcriptional regulation of human genes by guiding Argonaute proteins to complementary sites in messenger RNAs (mRNAs) targeted for repression. An enigmatic feature of many conserved mammalian miRNA target sites is that an adenosine (A) nucleotide opposite miRNA nucleotide-1 confers enhanced target repression independently of base pairing potential to the miRNA. In this study, we show that human Argonaute2 (Ago2) possesses a solvated surface pocket that specifically binds adenine nucleobases in the 1 position (t1) of target RNAs. t1A nucleotides are recognized indirectly through a hydrogen-bonding network of water molecules that preferentially interacts with the N6 amine on adenine. t1A nucleotides are not utilized during the initial binding of Ago2 to its target, but instead function by increasing the dwell time on target RNA. We also show that N6 adenosine methylation blocks t1A recognition, revealing a possible mechanism for modulation of miRNA target site potency. |
| first_indexed | 2024-04-11T09:04:03Z |
| format | Article |
| id | doaj.art-b488e6ba7de44b14ac4ed2010e91cec2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:04:03Z |
| publishDate | 2015-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b488e6ba7de44b14ac4ed2010e91cec22022-12-22T04:32:42ZengeLife Sciences Publications LtdeLife2050-084X2015-09-01410.7554/eLife.07646Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targetsNicole T Schirle0Jessica Sheu-Gruttadauria1Stanley D Chandradoss2Chirlmin Joo3Ian J MacRae4Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United StatesDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United StatesKavli Institute of NanoScience, Department of BioNanoScience, Delft University of Technology, Delft, NetherlandsKavli Institute of NanoScience, Department of BioNanoScience, Delft University of Technology, Delft, NetherlandsDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United StatesMicroRNAs (miRNAs) direct post-transcriptional regulation of human genes by guiding Argonaute proteins to complementary sites in messenger RNAs (mRNAs) targeted for repression. An enigmatic feature of many conserved mammalian miRNA target sites is that an adenosine (A) nucleotide opposite miRNA nucleotide-1 confers enhanced target repression independently of base pairing potential to the miRNA. In this study, we show that human Argonaute2 (Ago2) possesses a solvated surface pocket that specifically binds adenine nucleobases in the 1 position (t1) of target RNAs. t1A nucleotides are recognized indirectly through a hydrogen-bonding network of water molecules that preferentially interacts with the N6 amine on adenine. t1A nucleotides are not utilized during the initial binding of Ago2 to its target, but instead function by increasing the dwell time on target RNA. We also show that N6 adenosine methylation blocks t1A recognition, revealing a possible mechanism for modulation of miRNA target site potency.https://elifesciences.org/articles/07646microRNAArgonauteRNA silencing |
| spellingShingle | Nicole T Schirle Jessica Sheu-Gruttadauria Stanley D Chandradoss Chirlmin Joo Ian J MacRae Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets eLife microRNA Argonaute RNA silencing |
| title | Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets |
| title_full | Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets |
| title_fullStr | Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets |
| title_full_unstemmed | Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets |
| title_short | Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets |
| title_sort | water mediated recognition of t1 adenosine anchors argonaute2 to microrna targets |
| topic | microRNA Argonaute RNA silencing |
| url | https://elifesciences.org/articles/07646 |
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