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Protein argonaute-2

Known also as: Eukaryotic translation initiation factor 2C 2, PAZ Piwi domain protein, Protein slicer

Known abbreviations: Argonaute2, hAgo2, eIF-2C 2, eIF2C 2, PPD


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.

Catalytic activity

Endonucleolytic cleavage to 5'-phosphomonoester.

Enzyme regulation

Inhibited by EDTA.

Subunit structure

Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC). Together, DICER1, EIF2C2/AGO2 and TARBP2 constitute the trimeric RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Note however that the term RISC has also been used to describe the trimeric RLC/miRLC. The formation of RISC complexes containing siRNAs rather than miRNAs appears to occur independently of DICER1. Interacts with EIF2C1/AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, EIF6, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, MOV10, PABPC1, PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body components DCP1A and XRN1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is modulated under stress-induced conditions, occurs under both cell proliferation and differentiation conditions and in a RNA- and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71. Interacts with APOBEC3G in an RNA-dependent manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H.

Subcellular location

Cytoplasm › P-body. Nucleus.

Note: Translational repression of mRNAs results in their recruitment to P-bodies. Translocation to the nucleus requires IMP8.


The Piwi domain may perform RNA cleavage by a mechanism similar to that of RNase H. However, while RNase H utilizes a triad of Asp-Asp-Glu (DDE) for metal ion coordination, this protein appears to utilize a triad of Asp-Asp-His (DDH).

Post-translational modification

Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity.

Sequence caution

The sequence AAH07633.1 differs from that shown. Reason: Erroneous initiation.

The sequence AAL76093.1 differs from that shown. Reason: cDNA contains a duplication of an internal sequence at the 5' end.

The sequence BC125214 differs from that shown. Reason: Frameshift at position 450.


Activities in which Protein argonaute-2 is involved: Pathways in which Protein argonaute-2 is involved:

NCBI GI number(s): -
Species: Homo sapiens

Links to other databases:

Database ID Link
Uniprot Q9UKV8 Q9UKV8
KEGG hsa:27161 hsa:27161
PFAM: PF08699
InterPro: IPR014811
CATH: - -
SCOP: - -
Solved crystal structures: 3LUC
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Protein sequence:

Protein argonaute-2 (Homo sapiens) is product of expression of AGO2 gene.


Title Authors Journal Publication date (Issue) PubMed ID
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, K Genome Res 2004-10-01 (14) 15489334
TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R Nature 2005-08-04 (436) 15973356
Initial characterization of the human central proteome. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J BMC Syst Biol 2011-01-01 (5) 21269460
Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. Hock J, Weinmann L, Ender C, Rudel S, Kremmer E, Raabe M, Urlaub H, Meister G EMBO Rep 2007-11-01 (8) 17932509
LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for microRNA-mediated gene silencing. James V, Zhang Y, Foxler DE, de Moor CH, Kong YW, Webb TM, Self TJ, Feng Y, Lagos D, Chu CY, Rana TM, Morley SJ, Longmore GD, Bushell M, Sharp TV Proc Natl Acad Sci U S A 2010-07-13 (107) 20616046
DNA sequence and analysis of human chromosome 8. Nusbaum C, Mikkelsen TS, Zody MC, Asakawa S, Taudien S, Garber M, Kodira CD, Schueler MG, Shimizu A, Whittaker CA Nature 2006-02-19 (439) 16421571
Characterization of the interactions between mammalian PAZ PIWI domain proteins and Dicer. Tahbaz N, Kolb FA, Zhang H, Jaronczyk K, Filipowicz W, Hobman TC EMBO Rep 2004-01-01 (5) 14749716
Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R Cell 2005-11-18 (123) 16271387
Identification of novel argonaute-associated proteins. Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Luhrmann R, Tuschl T Curr Biol 2005-12-06 (15) 16289642
TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W EMBO Rep 2005-10-01 (6) 16142218
A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Maniataki E, Mourelatos Z Genes Dev 2005-12-15 (19) 16357216
RNA helicase A interacts with RISC in human cells and functions in RISC loading. Robb GB, Rana TM Mol Cell 2007-05-25 (26) 17531811
MicroRNA silencing through RISC recruitment of eIF6. Chendrimada TP, Finn KJ, Ji X, Baillat D, Gregory RI, Liebhaber SA, Pasquinelli AE, Shiekhattar R Nature 2007-06-14 (447) 17507929
Prolyl 4-hydroxylation regulates Argonaute 2 stability. Qi HH, Ongusaha PP, Myllyharju J, Cheng D, Pakkanen O, Shi Y, Lee SW, Peng J, Shi Y Nature 2008-09-18 (455) 18690212
In vitro reconstitution of the human RISC-loading complex. MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA Proc Natl Acad Sci U S A 2008-02-15 (105) 18178619
An mRNA m7G cap binding-like motif within human Ago2 represses translation. Kiriakidou M, Tan GS, Lamprinaki S, De Planell-Saguer M, Nelson PT, Mourelatos Z... Cell 2007-06-15 (129) 17524464
miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Mourelatos Z, Dostie J, Paushkin S, Sharma A, Charroux B, Abel L, Rappsilber J, Mann M, Dreyfuss G... Genes Dev 2002-03-15 (16) 11914277
Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence, genomic organization, localization to chromosomal bands 1p34-p35, and expression. Koesters R, Adams V, Betts D, Moos R, Schmid M, Siermann A, Hassam S, Weitz S, Lichter P, Heitz PU, von Knebel Doeberitz M, Briner J... Genomics 1999-10-15 (61) 10534406
RISC is a 5' phosphomonoester-producing RNA endonuclease. Martinez J, Tuschl T... Genes Dev 2004-05-01 (18) 15105377
Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T... Mol Cell 2004-07-23 (15) 15260970
Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. Pillai RS, Artus CG, Filipowicz W... RNA 2004-10-01 (10) 15337849
Argonaute2 is the catalytic engine of mammalian RNAi. Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ... Science 2004-09-03 (305) 15284456
Structural basis for 5'-end-specific recognition of guide RNA by the A. fulgidus Piwi protein. Ma JB, Yuan YR, Meister G, Pei Y, Tuschl T, Patel DJ... Nature 2005-03-31 (434) 15800629
Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies. Sen GL, Blau HM... Nat Cell Biol 2005-06-01 (7) 15908945
Purified Argonaute2 and an siRNA form recombinant human RISC. Rivas FV, Tolia NH, Song JJ, Aragon JP, Liu J, Hannon GJ, Joshua-Tor L... Nat Struct Mol Biol 2005-04-01 (12) 15800637
Inhibition of translational initiation by Let-7 MicroRNA in human cells. Pillai RS, Bhattacharyya SN, Artus CG, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W... Science 2005-09-02 (309) 16081698
Involvement of AGO1 and AGO2 in mammalian transcriptional silencing. Janowski BA, Huffman KE, Schwartz JC, Ram R, Nordsell R, Shames DS, Minna JD, Corey DR... Nat Struct Mol Biol 2006-09-01 (13) 16936728
Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. Chu CY, Rana TM... PLoS Biol 2006-07-01 (4) 16756390
Human retroviral host restriction factors APOBEC3G and APOBEC3F localize to mRNA processing bodies. Wichroski MJ, Robb GB, Rana TM... PLoS Pathog 2006-05-01 (2) 16699599
AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Vasudevan S, Steitz JA... Cell 2007-03-23 (128) 17382880
Switching from repression to activation: microRNAs can up-regulate translation. Vasudevan S, Tong Y, Steitz JA... Science 2007-12-21 (318) 18048652
Importance of translation and nonnucleolytic ago proteins for on-target RNA interference. Wu L, Fan J, Belasco JG... Curr Biol 2008-09-09 (18) 18771919
Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Weinmann L, Hock J, Ivacevic T, Ohrt T, Mutze J, Schwille P, Kremmer E, Benes V, Urlaub H, Meister G... Cell 2009-01-06 (136) 19167051
RNA-binding motif protein 4 translocates to cytoplasmic granules and suppresses translation via argonaute2 during muscle cell differentiation. Lin JC, Tarn WY... J Biol Chem 2009-12-11 (284) 19801630
APOBEC3G inhibits microRNA-mediated repression of translation by interfering with the interaction between Argonaute-2 and MOV10. Liu C, Zhang X, Huang F, Yang B, Li J, Liu B, Luo H, Zhang P, Zhang H... J Biol Chem 2012-08-24 (287) 22791714
HIV-1 replication and APOBEC3 antiviral activity are not regulated by P bodies. Phalora PK, Sherer NM, Wolinsky SM, Swanson CM, Malim MH... J Virol 2012-11-01 (86) 22915799

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Last modification of this entry: April 26, 2013.

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