Tracing Argonaute binding

Argonaute proteins inhibit gene expression by binding to messenger RNA via a small nucleic-acid guide. Structures of the Argonaute complex bound to target RNA reveal snapshots of a silencing machine at work. One of the means by which RNA silencing downregulates gene expression is through small RNA-directed cleavage of a complementary mRNA. Argonaute family proteins are essential regulators of gene expression in plants and animals. They act by binding to single-stranded guide RNA molecules to form RISC complexes that catalyse splitting of the mRNA just where the sequence is complementary to the Argonaute-bound RNA. The crystal structure of several Thermus thermophilus Argonaute proteins mutated to inhibit cleavage activity have now been determined, in complex with a guide RNA and target RNAs of different lengths. Comparison of the various structures reveals conformational changes as the guide and target RNAs pair and suggests a mechanism for cleavage involving three aspartates and two Mg2+ ions.