| Structural highlights
Function
AGO2_HUMAN Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include EIF2C2/AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by EIF2C2/AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
Publication Abstract from PubMed
Argonaute proteins form the functional core of the RNA-induced silencing complexes (RISCs) that mediate RNA silencing in eukaryotes. The 2.3-angstrom-resolution crystal structure of human Argonaute2 (Ago2) reveals a bi-lobed molecule with a central cleft for binding guide and target RNAs. Nucleotides 2 to 6 of a heterogeneous mixture of guide RNAs are positioned in an A-form conformation for base pairing with mRNA targets. Between nucleotides 6 and 7 there is a kink, which may function in miRNA target recognition or release of sliced RNA products. Tandem tryptophan binding pockets in the PIWI domain define a likely interaction surface for recruitment of GW182 or other tryptophan-rich cofactors. These results will enable structure-based approaches for harnessing the untapped therapeutic potential of RNA silencing in humans.
The Crystal Structure of Human Argonaute2.,Schirle NT, Macrae IJ Science. 2012 Apr 26. PMID:22539551[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinez J, Tuschl T. RISC is a 5' phosphomonoester-producing RNA endonuclease. Genes Dev. 2004 May 1;18(9):975-80. Epub 2004 Apr 22. PMID:15105377 doi:http://dx.doi.org/10.1101/gad.1187904
- ↑ Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell. 2004 Jul 23;15(2):185-97. PMID:15260970 doi:http://dx.doi.org/10.1016/j.molcel.2004.07.007
- ↑ Pillai RS, Artus CG, Filipowicz W. Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA. 2004 Oct;10(10):1518-25. Epub 2004 Aug 30. PMID:15337849 doi:http://dx.doi.org/10.1261/rna.7131604
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- ↑ Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Luhrmann R, Tuschl T. Identification of novel argonaute-associated proteins. Curr Biol. 2005 Dec 6;15(23):2149-55. Epub 2005 Nov 10. PMID:16289642 doi:10.1016/j.cub.2005.10.048
- ↑ Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 2005 Oct;6(10):961-7. PMID:16142218 doi:10.1038/sj.embor.7400509
- ↑ Maniataki E, Mourelatos Z. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005 Dec 15;19(24):2979-90. PMID:16357216 doi:10.1101/gad.1384005
- ↑ Rivas FV, Tolia NH, Song JJ, Aragon JP, Liu J, Hannon GJ, Joshua-Tor L. Purified Argonaute2 and an siRNA form recombinant human RISC. Nat Struct Mol Biol. 2005 Apr;12(4):340-9. Epub 2005 Mar 30. PMID:15800637 doi:10.1038/nsmb918
- ↑ Pillai RS, Bhattacharyya SN, Artus CG, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W. Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science. 2005 Sep 2;309(5740):1573-6. Epub 2005 Aug 4. PMID:16081698 doi:http://dx.doi.org/10.1126/science.1115079
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- ↑ Chu CY, Rana TM. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 2006 Jul;4(7):e210. PMID:16756390 doi:http://dx.doi.org/06-PLBI-RA-0036R3
- ↑ Vasudevan S, Steitz JA. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell. 2007 Mar 23;128(6):1105-18. PMID:17382880 doi:http://dx.doi.org/10.1016/j.cell.2007.01.038
- ↑ Kiriakidou M, Tan GS, Lamprinaki S, De Planell-Saguer M, Nelson PT, Mourelatos Z. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell. 2007 Jun 15;129(6):1141-51. Epub 2007 May 24. PMID:17524464 doi:http://dx.doi.org/10.1016/j.cell.2007.05.016
- ↑ Hock J, Weinmann L, Ender C, Rudel S, Kremmer E, Raabe M, Urlaub H, Meister G. Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO Rep. 2007 Nov;8(11):1052-60. Epub 2007 Oct 12. PMID:17932509 doi:http://dx.doi.org/7401088
- ↑ Robb GB, Rana TM. RNA helicase A interacts with RISC in human cells and functions in RISC loading. Mol Cell. 2007 May 25;26(4):523-37. PMID:17531811 doi:http://dx.doi.org/10.1016/j.molcel.2007.04.016
- ↑ Chendrimada TP, Finn KJ, Ji X, Baillat D, Gregory RI, Liebhaber SA, Pasquinelli AE, Shiekhattar R. MicroRNA silencing through RISC recruitment of eIF6. Nature. 2007 Jun 14;447(7146):823-8. Epub 2007 May 16. PMID:17507929 doi:http://dx.doi.org/10.1038/nature05841
- ↑ Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007 Dec 21;318(5858):1931-4. Epub 2007 Nov 29. PMID:18048652 doi:http://dx.doi.org/10.1126/science.1149460
- ↑ Wu L, Fan J, Belasco JG. Importance of translation and nonnucleolytic ago proteins for on-target RNA interference. Curr Biol. 2008 Sep 9;18(17):1327-32. doi: 10.1016/j.cub.2008.07.072. PMID:18771919 doi:10.1016/j.cub.2008.07.072
- ↑ Qi HH, Ongusaha PP, Myllyharju J, Cheng D, Pakkanen O, Shi Y, Lee SW, Peng J, Shi Y. Prolyl 4-hydroxylation regulates Argonaute 2 stability. Nature. 2008 Sep 18;455(7211):421-4. doi: 10.1038/nature07186. Epub 2008 Aug 6. PMID:18690212 doi:http://dx.doi.org/10.1038/nature07186
- ↑ MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):512-7. doi: 10.1073/pnas.0710869105., Epub 2008 Jan 4. PMID:18178619 doi:10.1073/pnas.0710869105
- ↑ Weinmann L, Hock J, Ivacevic T, Ohrt T, Mutze J, Schwille P, Kremmer E, Benes V, Urlaub H, Meister G. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell. 2009 Feb 6;136(3):496-507. doi: 10.1016/j.cell.2008.12.023. Epub 2009 Jan, 22. PMID:19167051 doi:http://dx.doi.org/10.1016/j.cell.2008.12.023
- ↑ Schirle NT, Macrae IJ. The Crystal Structure of Human Argonaute2. Science. 2012 Apr 26. PMID:22539551 doi:10.1126/science.1221551
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