Structure of yeast Argonaute with guide RNA

Kotaro Nakanishi, David E. Weinberg, David P. Bartel () and Dinshaw J. Patel ()
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Kotaro Nakanishi: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
David E. Weinberg: Whitehead Institute for Biomedical Research, 9 Cambridge Center
David P. Bartel: Whitehead Institute for Biomedical Research, 9 Cambridge Center
Dinshaw J. Patel: Structural Biology Program, Memorial Sloan-Kettering Cancer Center

Nature, 2012, vol. 486, issue 7403, 368-374

Abstract: Abstract The RNA-induced silencing complex, comprising Argonaute and guide RNA, mediates RNA interference. Here we report the 3.2 Å crystal structure of Kluyveromyces polysporus Argonaute (KpAGO) fortuitously complexed with guide RNA originating from small-RNA duplexes autonomously loaded and processed by recombinant KpAGO. Despite their diverse sequences, guide-RNA nucleotides 1–8 are positioned similarly, with sequence-independent contacts to bases, phosphates and 2′-hydroxyl groups pre-organizing the backbone of nucleotides 2–8 in a near-A-form conformation. Compared with prokaryotic Argonautes, KpAGO has numerous surface-exposed insertion segments, with a cluster of conserved insertions repositioning the N domain to enable full propagation of guide–target pairing. Compared with Argonautes in inactive conformations, KpAGO has a hydrogen-bond network that stabilizes an expanded and repositioned loop, which inserts an invariant glutamate into the catalytic pocket. Mutation analyses and analogies to ribonuclease H indicate that insertion of this glutamate finger completes a universally conserved catalytic tetrad, thereby activating Argonaute for RNA cleavage.

Date: 2012
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DOI: 10.1038/nature11211

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