RNAi: finding the elusive endonuclease - PubMed (original) (raw)

Review

RNAi: finding the elusive endonuclease

Andreas Lingel et al. RNA. 2004 Nov.

Abstract

RNA interference involves endonucleolytic cleavage of mRNAs at a site determined by complementary siRNAs. Initial cleavage leads to rapid degradation of the message, resulting in a corresponding reduction in the level of the encoded protein. Despite intensive study, the identity of the endonucleolytic activity (designated slicer) has remained obscure. Now, a combination of structural and biochemical analyses provide compelling evidence that human Argonaute2 (Ago2), a protein already known to be a key player in the RNAi pathway, is in fact the missing endonuclease.

PubMed Disclaimer

Figures

FIGURE 1.

FIGURE 1.

Comparison of the Drosophila melanogaster Argonaute2 PAZ domain (DmAgo2, left) and the PAZ domain of the Argonaute protein from Pyrococcus furiosus (PfAgo, right). Structures are shown as ribbon diagrams, with helices colored green and β-strands shown in blue. The β-hairpin/α-helix module is shown in orange. This module contains two β-helices in the PAZ domain of PfAgo. Side chains of residues shown to contact nucleic acids in structures of the DmAgo2 PAZ domain in complex with nucleic acids are shown in gray and are labeled (Lingel et al. 2004). Residues in equivalent positions in the PfAgo protein are indicated.

FIGURE 2.

FIGURE 2.

The Piwi domain of the PfAgo protein comprises an RNase H fold. The structure of RNase HI from E. coli is shown on the left (RCSB protein data bank accession no. 1RDD) (Katayanagi et al. 1993), the Piwi domain of the PfAgo protein on the right. Secondary structure elements that constitute the RNase H fold are colored as in Figure 1 ▶; additional structural elements are shown in gray. Catalytic side chains of RNase HI and the corresponding side chains in the PfAgo protein are indicated and labeled. Figures 1 ▶ and 2 ▶ were prepared with the programm MOLMOL (Koradi et al. 1996).

Similar articles

Cited by

References

    1. Bartel, D.P. 2004. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116: 281–297. - PubMed
    1. Bernstein, E., Caudy, A.A., Hammond, S.M., and Hannon, G.J. 2001. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409: 363–366. - PubMed
    1. Carmell, M.A., Xuan, Z., Zhang, M.Q., and Hannon, G.J. 2002. The Argonaute family: Tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes & Dev. 16: 2733–2742. - PubMed
    1. Caudy, A.A., Ketting, R.F., Hammond, S.M., Denli, A.M., Bathoorn, A.M., Tops, B.B., Silva, J.M., Myers, M.M., Hannon, G.J., and Plasterk, R.H. 2003. A micrococcal nuclease homologue in RNAi effector complexes. Nature 425: 411–414. - PubMed
    1. Cerutti, L., Mian, N., and Bateman, A. 2000. Domains in gene silencing and cell differentiation proteins: The novel PAZ domain and redefinition of the Piwi domain. Trends Biochem. Sci. 25: 481–482. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources