Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets

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Abstract

MicroRNAs (miRNA) 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. Here, 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.

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Nicole T Schirle

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Jessica Sheu-Gruttadauria

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Stanley D Chandradoss

Kavli Institute of NanoScience, Department of BioNanoScience, Delft University of Technology, Delft, Netherlands

Competing interests
The authors declare that no competing interests exist.
Chirlmin Joo

Kavli Institute of NanoScience, Department of BioNanoScience, Delft University of Technology, Delft, Netherlands

Competing interests
The authors declare that no competing interests exist.
Ian J MacRae

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States

For correspondence
macrae@scripps.edu

Competing interests
The authors declare that no competing interests exist.

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