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Human Argonaute proteins: To slice or not to slice?

Posted June 7, 2013

What makes one Argonaute a slicer and another one not? Human Argonaute proteins are key players in the gene regulation process known as RNA interference, RNAi. Professor Joshua-Tor’s group of Cold Spring Harbor Laboratory present the structure of human Argonaute-1 and determine key mutations and other features that distinguish it from human Argonaute-2, which is also known as “slicer” for its unique ability among the human Argonautes to cut messenger RNA.

Human Argonautes (hAgo), are key proteins involved in a process known as RNA interference. RNAi, as it is often called, is a mechanism that cells use to regulate gene expression. Human Argonaute-2 (hAgo2) is known as “slicer” for its unique ability among the 4 human Argonaute proteins to directly cut messenger RNA—which carries the information coded in genomic DNA to make a protein—and thus disable “messages” generated from genes.

The atomic resolution structure of hAgo2 solved previously, revealed the active site, a region of the enzyme that is key to its slicing activity. The other human Argonaute proteins, hAgo1, 3 and 4, while very similar to hAgo2, lack slicing activity. So an important question left unanswered was: what features in these proteins explain why none of them are able to act as “slicers”?

A team at Cold Spring Harbor Laboratory (CSHL) led by Professor and HHMI Investigator Leemor Joshua-Tor of the W. M. Keck structural biology laboratory today publishes a paper in the journal Cell Reports that defines the critical differences between the human Argonautes that lead to their differences in activity.

Here, the group determined the structure of the non-slicer hAgo1 in complex with a microRNA (miRNA) called let-7. This RNA does not code for a protein but is highly conserved by evolution, occurring in many species, and is involved in regulating gene expression during human development and cancer. “This is the highest-resolution structure of a eukaryotic Argonaute to date, which allows for more in-depth analysis of important features like its active site,” says Joshua-Tor.

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