The crystal structure of human Argonaute2

Schirle, N.T. & MacRae, I.J. Science 336, 1037–1040 (2012)

Speaker: Hsin-Pei Hsieh (謝欣倍)                                Time: 13:10~14:00, Oct. 3, 2012

Commentator: Dr. Wen-Yih Jeng (鄭文義博士)          Place: Room 601

Abstract

Argonaute (Ago) proteins play an important role in sequence-specific gene silencing and form RNA-induced silencing complex (RISC) with additional silencing factors. They guide mRNA degradation and translational repression through associating with small RNAs. Ago proteins are multidomain proteins typically composed of four conserved domains (N, PAZ, MID and PIWI) and two long linkers (L1 and L2)¹.  The structures of the isolated MID, PAZ, and MID-PIWI domains from several eukaryotic Ago proteins have been reported previously², but the overall domain organization and mode of small RNAs of eukaryotic Ago proteins is still unclear. The authors solved the crystal structure of full-length human Ago2 at 2.3 Å resolution, and reveal the two lobes consist of the walls of central cleft for guide and target RNAs. The I365 residue of Ago2 is inserted to nucleotides 6 and 7 of RNA that results in guide RNA conformational change from B-form to A-form which reduce energy cost to maintain stability of duplex with target RNAs³. They successfully identify two tandem tryptophan-binding pockets in the PIWI domain, which are interaction site for binding to silencing factor, glycine-tryptophan-182 (GW182) protein. These finding establish a structural basis aspect of RISC and leads to better understanding of RNA-silencing related diseases and provides basis of drug development.

References

1.      Hutvagner, G. & Simard, M. J. Argonaute proteins: key players in RNA silencing. Nat. Rev. Mol. Cell Biol. 9, 22-32 (2008).

2.      Hock, J. & Meister, G. The Argonaute protein family. Genome Biol. 9, 210 (2008).

3.      Sasaki, H. M. & Tomari, Y. The true core of RNA silencing revealed. Nat. Struct. Mol. Biol. 19, 657-660 (2012).