Helix-7 in Argonaute2 shapes the microRNA seed region for rapid target recognition

Shannon M. Klum, Stanley D. Chandradoss, Nicole T. Schirle, Chirlmin Joo, Ian J. MacRae

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Argonaute proteins use microRNAs (miRNAs) to identify mRNAs targeted for post-transcriptional repression. Biochemical assays have demonstrated that Argonaute functions by modulating the binding properties of its miRNA guide so that pairing to the seed region is exquisitely fast and accurate. However, the mechanisms used by Argonaute to reshape the binding properties of its small RNA guide remain poorly understood. Here, we identify a structural element, α-helix-7, in human Argonaute2 (Ago2) that is required for speed and fidelity in binding target RNAs. Biochemical, structural, and single-molecule data indicate that helix-7 acts as a molecular wedge that pivots to enforce rapid making and breaking of miRNA:target base pairs in the 3′ half of the seed region. These activities allow Ago2 to rapidly dismiss off-targets and dynamically search for seed-matched sites at a rate approaching the limit of diffusion.

Original languageEnglish
Pages (from-to)75-88
Number of pages14
JournalEMBO Journal
Volume37
Issue number1
DOIs
StatePublished - 4 Jan 2018

Keywords

  • Argonaute
  • microRNA
  • RNA silencing
  • seed
  • target search

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