Research Article

Structural basis for microRNA targeting

Science  31 Oct 2014:
Vol. 346, Issue 6209, pp. 608-613
DOI: 10.1126/science.1258040

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Repressing the right (and not the wrong) mRNA

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting a repressor complex to specific messenger RNAs (mRNAs). Schirle et al. determined structures of a miRNA bound to both the central component of the repressor complex, the protein Argonaute-2 (Ago2), and a target mRNA (see the Perspective by Patel). The miRNA in the complex first recognizes a short region of complementary sequence in the mRNA. This initial interaction promotes structural changes that allow the complex to bind additional target sequences. The authors suggest that in the absence of extensive miRNA-mRNA pairing, the repressor complex active site is rendered inactive, preventing repression of nontarget mRNAs.

Science, this issue p. 608; see also p. 542

Abstract

MicroRNAs (miRNAs) 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 a stepwise mechanism, in which Ago2 primarily exposes guide nucleotides (nt) 2 to 5 for initial target pairing. Pairing to nt 2 to 5 promotes conformational changes that expose nt 2 to 8 and 13 to 16 for further target recognition. Interactions with the guide-target minor groove allow Ago2 to interrogate target RNAs in a sequence-independent manner, whereas an adenosine binding-pocket opposite guide nt 1 further facilitates target recognition. Spurious slicing of miRNA targets is avoided through an inhibitory coordination of one catalytic magnesium ion. These results explain the conserved nucleotide-pairing patterns in animal miRNA target sites first observed over two decades ago.

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