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SLAC National Accelerator Laboratory

Structure of Human Argonaute2: A Programmable Ribonuclease

July 2013 SSRL Science Summary by Manuel Gnida, SLAC Office of Communications


RNA degradation is an important process in all organisms with functions including cellular clean-up of unwanted RNA, defense against RNA viruses, and a variety of other cellular strategies involving RNA modifications. RNA degradation is mediated by ribonucleases (RNases), which are for the most part relatively non-specific. However, Argonaute proteins are a class of RNases that degrade target RNAs in a sequence-specific manner. Argonaute proteins acquire their specificity by binding small RNA molecules, called guide RNAs, which are then used to locate target RNAs with a complementary nucleotide sequence. Subsequently, Argonaute either hydrolyzes the target RNA or it recruits additional molecules known as silencing factors that accelerate the decay of the RNA target. By choosing an appropriate guide RNA, Argonaute proteins can be programmed to target any desired RNA sequence and, hence, are of great interest for potential therapeutic interventions.

Nicole Schirle and Ian MacRae, two researchers from The Scripps Research Institute, have now shed light on the mechanism of Argonaute proteins. Using SSRL’s Beam Line 11-1, the scientists determined the crystal structure of human Argonaute2 (Ago2, 2.3 Å resolution), which was reported in the journal Science. The structure revealed the binding of the guide RNA in a hydrophilic channel between two protein lobes, leaving the base edges solvent exposed and amenable to specific base-pairing with target RNA. Moreover, the researchers found nucleotides 2–7 of the guide to be in a helical conformation – a pre-organization that reduces the entropy of target-RNA binding and enables Argonaute to locate and bind target RNA ten times faster than complementary RNAs of similar length. Furthermore, the researchers modeled the interaction of Argonaute with silencing factors such as TNRC6, a protein with a tryptophan-rich N-terminal region. Based on the structure of Ago2 in complex with L-tryptophan, the researchers proposed a novel Argonaute-binding mode, in which two tryptophans are bound in tandem.

Argonaute proteins play an important role in the biological process of RNA interference (RNAi), i.e. the knockdown of target genes through degradation of the corresponding messenger RNA (mRNA). RNAi-based therapeutics may provide new treatments for human diseases, particularly in cases where conventional drugs cannot be applied. Therefore, a detailed understanding of Ago2 interactions with target RNA may benefit the design of novel RNAi therapeutics. 


Primary Citation

N. T. Schirle and I. J. MacRae, "The Crystal Structure of Human Argonaute2", Science 336, 1037 (2012); doi: 10.1126/science.1221551.

Related Links


Nicole T. Schirle, The Scripps Research Institute
Ian J. MacRae, The Scripps Research Institute

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