Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

How genes are silenced

Molecular snapshot reveals the mechanics of RNA interference.

It's the first time the argonaute protein has been seen bound to both target and guide strands. Credit: Tom Tuschl and Dinshaw Patel

A picture of a bacterial protein complex that selects and slices up RNA molecules, thereby silencing genes, provides fresh insight into the process of RNA interference (RNAi), researchers say. The structure is the first to capture the so-called argonaute protein when it is bound to both the genetic template that guides it to its RNA target, and the target strand of RNA itself.

Researchers use RNAi to block expression of selected genes, and some hope that it can be used to fight diseases. RNAi also occurs naturally to regulate gene expression and control viral infections, but researchers are still struggling to unravel exactly how the process works. Understanding those details, they say, could help them to improve therapeutic use of the procedure.

What is clear is that argonaute proteins are key components of the RNAi machinery. In mammals, Argonaute 2 binds to a template molecule of RNA called a 'guide'. The guide, in turn, binds to a 'target' RNA molecule with a complementary sequence, enabling Argonaute 2 to cleave the target RNA and thereby prevent the RNA from being used as a template to make a protein.

Unfortunately, mammalian argonaute proteins are difficult to produce in cell cultures, and they do not readily dissolve in solution: two common prerequisites for structural studies.

The same, but different

Biochemist Thomas Tuschl of the Rockefeller University in New York and his colleagues therefore decided to look at the argonaute protein in Thermus thermophilus, a bacterium found in thermal vents. The T. thermophilus argonaute protein is structurally similar to mammalian argonautes, but binds more efficiently to DNA guides than to RNA guides. So the researchers decided to work out the structure while the protein was bound to both a DNA guide and an RNA target. Their work is published in Nature1.

The team found that the three-molecule complex adopted a wider, more-open conformation than had been observed in structures of argonaute bound to DNA alone2. The researchers think that the protein and its DNA guide bind to RNA more easily when two regions of the protein spread apart, opening up an RNA-binding channel.

The researchers were surprised to find that in many cases, the guide DNA and argonaute protein bound and cleaved the target RNA even when there were mutations in the RNA strand.

"It was a bit unanticipated," says Tuschl. "Even in the region that is critical for recognition, [the process] could so easily accommodate mismatches in the target RNA." Tuschl says that researchers studying naturally occurring RNA molecules that regulate gene expression have also observed that the target sequence and the guide sequence did not always have to bind perfectly for silencing to occur.

Although, like T. thermophilus, a few bacteria produce argonaute proteins, they lack other proteins characteristic of the RNAi pathway. That has lead some to wonder just what the bacterial argonautes are actually doing.

"What we really need to understand is the extent to which this structure really reflects what's found in mammals," says biochemist Phillip Zamore of the University of Massachusetts Medical School in Worcester, who calls the new structure "an enormous step forward". However, Zamore adds that previous predictions based on data obtained from archaeal argonautes have held true in mammalian systems.

For now, Zamore says that researchers will be eager to use the system to explore ways to optimize RNAi. "They will want to know how we can use this structure to modify short interfering RNAs," he says, "and to take advantage of chemical features that aren't accessible to nature, but that we could incorporate into therapies."


  1. Wang, Y. et al. Nature 456, 921–926 (2008).

    PubMed Central  Google Scholar 

  2. Wang, Y., Sheng, G., Juranek, S., Tuschl, T., Patel, D. J. Nature 456, 209-213 (2008).

    ADS  CAS  Article  Google Scholar 

Download references


Related links

Related links

Related links in Nature Research

RNAi in Focus

RNA interference

Related external links

Thomas Tuschl

Phillip Zamore

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ledford, H. How genes are silenced. Nature (2008).

Download citation

  • Published:

  • DOI:


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing