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. We determined crystal structures of human Argonaute-2 (Ago2) bound to a defined guide RNA with an...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2014-10, Vol.346 (6209), p.608-613
Main Authors: Schirle, Nicole T., Sheu-Gruttadauria, Jessica, MacRae, Ian J.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Adenosines
Animals
Argon
Argonaute Proteins - chemistry
Argonaute Proteins - genetics
Base Sequence
BASIC BIOLOGICAL SCIENCES
Catalytic Domain
Conserved Sequence
Crystallography, X-Ray
Exposure
Gene expression
Gene Expression Regulation
Humans
Magnesium - chemistry
MicroRNAs - chemistry
MicroRNAs - genetics
Models, Molecular
Nucleic Acid Conformation
Protein Structure, Secondary
Proteins
Ribonucleic acid
Ribonucleic acids
RNA
RNA, Guide - chemistry
RNA, Guide - genetics
Target recognition
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1258040