The Structure of Human Argonaute-2 in Complex with miR-20a

By E. Elkayam, Claus-D. Kuhn, A. Tocilj, A. Haase, E. Greene, Gregory J. Hannon, L. Joshua-Tor. Cell, 2012

617 citations recorded by the source corpus.

SUMMARY Argonaute proteins lie at the heart of the RNA-induced silencing complex (RISC), wherein they use small RNA guides to recognize targets. Initial insight into the architecture of Argonautes came from studies of prokaryotic proteins, revealing a crescent-shaped base made up of the amino-terminal, PAZ, middle, and PIWI domains. The recently reported crystal structure of human Argonaute-2 (hAgo2), the “slicer” in RNA interference, in complex with a mixed population of RNAs derived from insect cells provides insight into the architecture of a eukaryotic Argonaute protein with defined biochemical and biological functions. Here, we report the structure of human Ago2 bound to a physiologically relevant microRNA, microRNA-20a, at 2.2 Å resolution. The miRNA is anchored at both ends by the Mid and PAZ domains and makes several kinks and turns along the binding groove. Interestingly, miRNA binding confers remarkable stability on hAgo2, locking this otherwise flexible enzyme into a stable conformation.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ec17cbdeca9cdd159178fd3074168275f2824705

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Citations in the corpus

Metazoan MicroRNAs (2018, background): “Structural results have revised this idea, revealing that a guide-RNA kink and steric barrier imposed by Ago α–helix 7 leaves only miRNA nucleotides 2–5 suitably preorganized and accessible for the target search (Elkayam et al., 2012; Nakanishi et al., 2012; Schirle and MacRae, 2012) (Figure 6A, ste”
Chemistry, structure and function of approved oligonucleotide therapeutics (2023, background): “The latter idea was inspired by a kink between nucleotides AS6 and AS7 in the siRNA seed region in the structures of Ago2 complexes bound either to miRNA (303) or guide/passenger strand seed duplexes (217) (Figure 15A).”
Mapping the Human miRNA Interactome by CLASH Reveals Frequent Noncanonical Binding (2013, neutral): “The recently published human AGO2 crystal structure (Elkayam et al., 2012) does not exclude the possibility of noncanonical seed interactions.”
microRNAs in action: biogenesis, function and regulation (2023, background): “However, as the miRNA 5′ base is bound by the specificity loop in the Ago MID domain 55,56 , it is not actually available for pairing 19,20 .”
Molecular mechanisms of RNA interference (2013, neutral): “The seed portion (positions 2–6) is typically well-ordered, while electron density has not been observed for nucleotides past position 10, with the exception of a PAZ-bound terminal nucleotide (19, 65, 77, 95).”