1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets

  1. Nicole T Schirle
  2. Jessica Sheu-Gruttadauria
  3. Stanley D Chandradoss
  4. Chirlmin Joo
  5. Ian J MacRae  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. Delft University of Technology, Netherlands
Research Article
  • Cited 45
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Cite this article as: eLife 2015;4:e07646 doi: 10.7554/eLife.07646

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

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

Reviewing Editor

  1. Phillip D Zamore, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: March 21, 2015
  2. Accepted: September 10, 2015
  3. Accepted Manuscript published: September 11, 2015 (version 1)
  4. 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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