Researching the Interactions Between Argonaute Proteins and RNA

Human Argonaute 1 protein (cyan) bound to let-7 microRNA (magenta). Ago protein family plays a role in RNA silencing processes. Cartoon model with semi-transparent surface.

Human Argonaute 1 protein (cyan) bound to let-7 microRNA (magenta). Ago protein family plays a role in RNA silencing processes. Cartoon model with semi-transparent surface. Shutterstock | petarg

Argonaute proteins play essential roles in RNA interference methods and also as a central component of the RNAi silencing complex (RISC). In mammals, the RISC is loaded with either micro RNAs (miRNAs) or small interfering RNAs (siRNAs) to regulate mRNA translation silencing or degradation, depending on the target.

The family of Argonaute proteins are highly conversed and form a key part of the RISC complex. Due to this, they play key roles as RNAi ‘effectors’ and other related phenomena in organisms, which includes mammals, Drosophila and Saccharomyces spp.

The roles of Argonaute proteins 1 and 2 (which, in Drosophila are named Ago1 and Ago2) have been researched the most. In Drosophila, Ago2 was identified by Okamura et al. (2004) as part of RISC and important for the siRNA-directed RNAi response. Ago2 is needed to unwind the siRNA duplex and therefore to assemble siRNA into RISC in Drosophila embryos.

It has also been realized that Drosophila embryos defective in siRNA-directed RNAi can still achieve miRNA-directed RNA cleavage. This research suggests that several different proteins may carry out the Ago2 nuclease role.

Ago1, which is used for RNA cleavage directed by siRNA, is needed to produce the mature RNA needed for miRNA-directed RNA cleavage (Okamura et al. 2004). Associations between Ago1 with pre-miRNA and Dicer-1 indicate that Ago1 may take part in miRNA biogenesis.

Argonaute proteins play roles beyond RNAi-like mechanisms as they also influence cell development, and a subset of Argonaute proteins play roles in the determination of stem cells. Research by Cerutti et al. (2000) showed they are highly basic and formed from two domains, PAZ and PIWI, with a total weight of around 100 kD.

PAZ is made of 130 amino acids and has been found by Bernstein et al. (2001a) in both Argonaute proteins and in Dicer. PAZ is not known to have any specific function but is believed to interact with other proteins to regulate dimerization processes.

Other research suggested that the highly basic nature of Argonaute proteins facilitates binding to RNA. Research that supports this showed that when in vivo Miwi (a murine-based homolog of Piwi) is surrounded by a target mRNA complex (Deng & Lin, 2002) whereas in vivo Drosophila Ago1 is known to bind to ribonucleotide based polymers (Kataoka et al. 2001).

In addition to the above, the fact alone that Argonaute proteins are part of RISC suggests they would interact with RNA. To determine how exactly these interactions occur, and the proteins precise function, more research must be undertaken.

Key Research on Argonaute Proteins

  • Sen GL. & Blau HM. (2005) Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies. Nat Cell Biol. 7(6):633-6. Pubmed: 15908945
  • Yan KS. et al (2005) Structure and conserved RNA binding of the PAZ domain. Nature. 27;426(6965):468-74. Pubmed: 14615802
  • Rivas FV. et al (2005) Purified Argonaute2 and an siRNA form recombinant human RISC. Nat Struct Mol Biol. 12(4):340-9. Pubmed: 15800637
  • Lingel A. & Izaurralde E. (2004) RNAi: finding the elusive endonuclease. RNA. 10(11):1675-9. Review. Pubmed: 15496518
  • Okamura K. et al (2004) Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes Dev. 18(14):1655-66. Pubmed: 15231716
  • Liu J. et al (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science. 305(5689):1437-41. Pubmed: 15284456
  • Shi H. et al (2004) Function of the Trypanosome Argonaute 1 protein in RNA interference requires the N-terminal RGG domain and arginine 735 in the Piwidomain. J Biol Chem. 279(48):49889-93. Pubmed: 15383544
  • Pillai RS. et al (2004) Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA. 10(10):1518-25. Pubmed: 15337849
  • Zilberman D. et al (2004) Role of Arabidopsis ARGONAUTE4 in RNA-directed DNA methylation triggered by inverted repeats. Curr Biol. 13;14(13):1214-20. Pubmed: 15242620
  • Zilberman D. et al (2003) ARGONAUTE4 control of locus-specific siRNAaccumulation and DNA and histone methylation. Science. 31;299(5607):716-9. Pubmed: 12522258
  • Martinez J. et al (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell. 110(5):563-74. Pubmed: 12230974

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Last updated: Apr 1, 2019 at 6:36 AM

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