Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets
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.
Article and author information
Author details
Reviewing Editor
- Phillip D Zamore, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
Version history
- Received: March 21, 2015
- Accepted: September 10, 2015
- Accepted Manuscript published: September 11, 2015 (version 1)
- Version of Record published: October 15, 2015 (version 2)
Copyright
© 2015, Schirle et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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