Abstract
MicroRNAs (miRNAs) are small (~22 nt) regulatory RNAs that control expression of thousands of genes in plants and animals. miRNAs function by guiding Argonaute proteins to complementary sites in messenger RNAs (mRNAs) targeted for repression. We determined crystal structures of human Argonaute‐2 (Ago2) bound to a defined guide RNA with and without target RNAs representing miRNA recognition sites. These structures suggest Ago2 uses a stepwise mechanism for target recognition, in which Ago2 primarily exposes guide nucleotides 2–5 for initial target pairing. Pairing to nt 2–5 promotes conformational changes that expose guide nt 2–8 and 13–16 for further target recognition. Interactions with the guide‐target minor groove allow Ago2 to interrogate target RNAs in a sequence‐independent manner, while an adenosine binding‐pocket opposite guide nt 1 further facilitates target recognition. Three tandem tryptophan binding sites in the Ago2 PIWI domain mediate recruitment of silencing factors, ultimately leading to the repression of targeted mRNAs.
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