skip to main content

Title: Structural basis for microRNA targeting

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. In this paper, 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. Finally, these results explain the conserved nucleotide-pairing patterns in animal miRNA target sites first observed over two decades ago.
Authors:
 [1] ;  [1] ;  [1]
  1. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
Publication Date:
OSTI Identifier:
1163773
Grant/Contract Number:
AC02-06CH11357; P41 GM103403; R01 GM104475
Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 346; Journal Issue: 6209; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
The Scripps Research Inst., La Jolla, CA (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH) (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES