Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets

摘要

Stretches of DNA known as genes provide the instructions to make the proteins and RNA molecules a cell needs to work. To make a protein, the gene is used as a template to make a type of RNA molecule called messenger RNA (mRNA), which is subsequently ‘translated’ into a protein. Most genes do not need to produce proteins all of the time, and so cells have several ways of stopping proteins from being made. For example, the Argonaute family of proteins prevents mRNA molecules from being translated into proteins. Argonautes are guided to their targets by short RNA molecules called microRNAs. RNA molecules are made up of a sequence of building blocks known as nucleotides, each of which can only bind to one other type of nucleotide. If part of the nucleotide sequence of a microRNA molecule corresponds with part of the nucleotide sequence of the mRNA, the two RNA molecules will bind to each other. This enables the microRNA and the Argonaute protein to prevent the mRNA being translated. If the mRNA has an adenine nucleotide in a particular position (called ‘t1’) near the binding region in the mRNA sequence, Argonaute proteins will prevent translation more effectively. An adenine nucleotide in the t1 position is also known as a t1A nucleotide. In 2014, researchers revealed the structure of a human Argonaute protein called Argonaute2 when it is bound to a microRNA-mRNA pair. This revealed that t1A nucleotides—but not other nucleotide types in the t1 position—interact with a ‘pocket’ in the Argonaute protein. However, it was not clear how the adenine nucleotide is recognized. Now, Schirle et al.—including several of the researchers involved in the 2014 work—use a technique called X-ray crystallography to examine how the t1A nucleotide interacts with Argonaute2 in more detail. This revealed that the Argonaute2 pocket contains many water molecules that form an organized network. This network interacts with part of the t1A nucleotide and helps to lock Argonaute2 onto its microRNA target sites. The discovery of the pocket and how t1A is recognized may now be used to design more effective ‘anti-miRs’—synthetic microRNA inhibitors that can treat diseases in which microRNAs work incorrectly, a feature common to many forms of cancer.