mRNA structural dynamics shape Argonaute-target interactions

Suzan Ruijtenberg, Stijn Sonneveld, Tao Ju Cui, Ive Logister, Dion de Steenwinkel, Yao Xiao, Ian J MacRae, Chirlmin Joo, Marvin E Tanenbaum

Research output: Contribution to journal/periodicalArticleScientificpeer-review

26 Citations (Scopus)


Small interfering RNAs (siRNAs) promote RNA degradation in a variety of processes and have important clinical applications. siRNAs direct cleavage of target RNAs by guiding Argonaute2 (AGO2) to its target site. Target site accessibility is critical for AGO2-target interactions, but how target site accessibility is controlled in vivo is poorly understood. Here, we use live-cell single-molecule imaging in human cells to determine rate constants of the AGO2 cleavage cycle in vivo. We find that the rate-limiting step in mRNA cleavage frequently involves unmasking of target sites by translating ribosomes. Target site masking is caused by heterogeneous intramolecular RNA-RNA interactions, which can conceal target sites for many minutes in the absence of translation. Our results uncover how dynamic changes in mRNA structure shape AGO2-target recognition, provide estimates of mRNA folding and unfolding rates in vivo, and provide experimental evidence for the role of mRNA structural dynamics in control of mRNA-protein interactions.

Original languageEnglish
Pages (from-to)790-801
Number of pages12
JournalNature Structural & Molecular Biology
Issue number9
Publication statusPublished - Sept 2020


  • Argonaute Proteins/metabolism
  • Cell Line
  • HEK293 Cells
  • Humans
  • Nucleic Acid Conformation
  • RNA Cleavage
  • RNA Folding
  • RNA, Messenger/chemistry
  • Ribosomes/metabolism


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