RBCC Red Blood Cell Collection

AGO2 (EIF2C2) [Confidence: high (present in two of the MS resources)]
Protein argonaute-2; Argonaute2; hAgo2; 3.1.26.n2 (Argonaute RISC catalytic component 2; Eukaryotic translation initiation factor 2C 2; eIF-2C 2; eIF2C 2; PAZ Piwi domain protein; PPD; Protein slicer)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00220349
IPI00220349 Eukaryotic translation initiation factor 2C 2 Eukaryotic translation initiation factor 2C 2 membrane n/a 1 14 7 14 1 12 6 1 n/a 5 4 3 4 1 2 4 7 11 7 membrane bound n/a expected molecular weight found in band > 188 kDa together with ubiquitin

UniProt Q9UKV8
ID AGO2_HUMAN Reviewed; 859 AA.
AC Q9UKV8; Q8TCZ5; Q8WV58; Q96ID1;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-MAY-2009, sequence version 3.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Protein argonaute-2;
DE Short=Argonaute2;
DE Short=hAgo2;
DE EC=3.1.26.n2;
DE AltName: Full=Argonaute RISC catalytic component 2;
DE AltName: Full=Eukaryotic translation initiation factor 2C 2;
DE Short=eIF-2C 2;
DE Short=eIF2C 2;
DE AltName: Full=PAZ Piwi domain protein;
DE Short=PPD;
DE AltName: Full=Protein slicer;
GN Name=AGO2; Synonyms=EIF2C2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 239-859 (ISOFORM 1).
RC TISSUE=Brain, and Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 47-859 (ISOFORM 1).
RX PubMed=11914277; DOI=10.1101/gad.974702;
RA Mourelatos Z., Dostie J., Paushkin S., Sharma A., Charroux B.,
RA Abel L., Rappsilber J., Mann M., Dreyfuss G.;
RT "miRNPs: a novel class of ribonucleoproteins containing numerous
RT microRNAs.";
RL Genes Dev. 16:720-728(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 275-859 (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 483-859 (ISOFORM 1).
RX PubMed=10534406; DOI=10.1006/geno.1999.5951;
RA Koesters R., Adams V., Betts D., Moos R., Schmid M., Siermann A.,
RA Hassam S., Weitz S., Lichter P., Heitz P.U., von Knebel Doeberitz M.,
RA Briner J.;
RT "Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence,
RT genomic organization, localization to chromosomal bands 1p34-p35, and
RT expression.";
RL Genomics 61:210-218(1999).
RN [6]
RP INTERACTION WITH DICER1.
RX PubMed=14749716; DOI=10.1038/sj.embor.7400070;
RA Tahbaz N., Kolb F.A., Zhang H., Jaronczyk K., Filipowicz W.,
RA Hobman T.C.;
RT "Characterization of the interactions between mammalian PAZ PIWI
RT domain proteins and Dicer.";
RL EMBO Rep. 5:189-194(2004).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15105377; DOI=10.1101/gad.1187904;
RA Martinez J., Tuschl T.;
RT "RISC is a 5' phosphomonoester-producing RNA endonuclease.";
RL Genes Dev. 18:975-980(2004).
RN [8]
RP FUNCTION.
RX PubMed=15260970; DOI=10.1016/j.molcel.2004.07.007;
RA Meister G., Landthaler M., Patkaniowska A., Dorsett Y., Teng G.,
RA Tuschl T.;
RT "Human Argonaute2 mediates RNA cleavage targeted by miRNAs and
RT siRNAs.";
RL Mol. Cell 15:185-197(2004).
RN [9]
RP FUNCTION, AND INTERACTION WITH GEMIN4.
RX PubMed=15337849; DOI=10.1261/rna.7131604;
RA Pillai R.S., Artus C.G., Filipowicz W.;
RT "Tethering of human Ago proteins to mRNA mimics the miRNA-mediated
RT repression of protein synthesis.";
RL RNA 10:1518-1525(2004).
RN [10]
RP FUNCTION, ENZYME REGULATION, AND MUTAGENESIS OF LEU-140; ASP-597;
RP GLN-633; HIS-634; ASP-669; HIS-682; PHE-704 AND THR-744.
RX PubMed=15284456; DOI=10.1126/science.1102513;
RA Liu J., Carmell M.A., Rivas F.V., Marsden C.G., Thomson J.M.,
RA Song J.-J., Hammond S.M., Joshua-Tor L., Hannon G.J.;
RT "Argonaute2 is the catalytic engine of mammalian RNAi.";
RL Science 305:1437-1441(2004).
RN [11]
RP FUNCTION, AND INTERACTION WITH DICER1 AND TARBP2.
RX PubMed=16271387; DOI=10.1016/j.cell.2005.10.022;
RA Gregory R.I., Chendrimada T.P., Cooch N., Shiekhattar R.;
RT "Human RISC couples microRNA biogenesis and posttranscriptional gene
RT silencing.";
RL Cell 123:631-640(2005).
RN [12]
RP FUNCTION, INTERACTION WITH DDX20; DICER1; GEMIN4; MOV10; PRMT5 AND
RP TNRC6B, AND SUBCELLULAR LOCATION.
RX PubMed=16289642; DOI=10.1016/j.cub.2005.10.048;
RA Meister G., Landthaler M., Peters L., Chen P.Y., Urlaub H.,
RA Luehrmann R., Tuschl T.;
RT "Identification of novel argonaute-associated proteins.";
RL Curr. Biol. 15:2149-2155(2005).
RN [13]
RP FUNCTION.
RX PubMed=16142218; DOI=10.1038/sj.embor.7400509;
RA Haase A.D., Jaskiewicz L., Zhang H., Laine S., Sack R., Gatignol A.,
RA Filipowicz W.;
RT "TRBP, a regulator of cellular PKR and HIV-1 virus expression,
RT interacts with Dicer and functions in RNA silencing.";
RL EMBO Rep. 6:961-967(2005).
RN [14]
RP FUNCTION, INTERACTION WITH DICER1 AND TARBP2, AND MUTAGENESIS OF
RP ASP-669.
RX PubMed=16357216; DOI=10.1101/gad.1384005;
RA Maniataki E., Mourelatos Z.;
RT "A human, ATP-independent, RISC assembly machine fueled by pre-
RT miRNA.";
RL Genes Dev. 19:2979-2990(2005).
RN [15]
RP MUTAGENESIS OF LYS-533; GLN-545 AND LYS-570.
RX PubMed=15800629; DOI=10.1038/nature03514;
RA Ma J.-B., Yuan Y.-R., Meister G., Pei Y., Tuschl T., Patel D.J.;
RT "Structural basis for 5'-end-specific recognition of guide RNA by the
RT A. fulgidus Piwi protein.";
RL Nature 434:666-670(2005).
RN [16]
RP INTERACTION WITH DICER1 AND TARBP2.
RX PubMed=15973356; DOI=10.1038/nature03868;
RA Chendrimada T.P., Gregory R.I., Kumaraswamy E., Norman J., Cooch N.,
RA Nishikura K., Shiekhattar R.;
RT "TRBP recruits the Dicer complex to Ago2 for microRNA processing and
RT gene silencing.";
RL Nature 436:740-744(2005).
RN [17]
RP SUBCELLULAR LOCATION.
RX PubMed=15908945; DOI=10.1038/ncb1265;
RA Sen G.L., Blau H.M.;
RT "Argonaute 2/RISC resides in sites of mammalian mRNA decay known as
RT cytoplasmic bodies.";
RL Nat. Cell Biol. 7:633-636(2005).
RN [18]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ASP-597;
RP ASP-669; GLU-673; GLU-683 AND HIS-807.
RX PubMed=15800637; DOI=10.1038/nsmb918;
RA Rivas F.V., Tolia N.H., Song J.-J., Aragon J.P., Liu J., Hannon G.J.,
RA Joshua-Tor L.;
RT "Purified Argonaute2 and an siRNA form recombinant human RISC.";
RL Nat. Struct. Mol. Biol. 12:340-349(2005).
RN [19]
RP FUNCTION, INTERACTION WITH DCP1A AND XRN1, AND SUBCELLULAR LOCATION.
RX PubMed=16081698; DOI=10.1126/science.1115079;
RA Pillai R.S., Bhattacharyya S.N., Artus C.G., Zoller T., Cougot N.,
RA Basyuk E., Bertrand E., Filipowicz W.;
RT "Inhibition of translational initiation by Let-7 MicroRNA in human
RT cells.";
RL Science 309:1573-1576(2005).
RN [20]
RP FUNCTION.
RX PubMed=16936728; DOI=10.1038/nsmb1140;
RA Janowski B.A., Huffman K.E., Schwartz J.C., Ram R., Nordsell R.,
RA Shames D.S., Minna J.D., Corey D.R.;
RT "Involvement of AGO1 and AGO2 in mammalian transcriptional
RT silencing.";
RL Nat. Struct. Mol. Biol. 13:787-792(2006).
RN [21]
RP FUNCTION, INTERACTION WITH DDX6 AND AGO1, AND SUBCELLULAR LOCATION.
RX PubMed=16756390; DOI=10.1371/journal.pbio.0040210;
RA Chu C.-Y., Rana T.M.;
RT "Translation repression in human cells by microRNA-induced gene
RT silencing requires RCK/p54.";
RL PLoS Biol. 4:E210-E210(2006).
RN [22]
RP INTERACTION WITH APOBEC3G.
RX PubMed=16699599; DOI=10.1371/journal.ppat.0020041;
RA Wichroski M.J., Robb G.B., Rana T.M.;
RT "Human retroviral host restriction factors APOBEC3G and APOBEC3F
RT localize to mRNA processing bodies.";
RL PLoS Pathog. 2:E41-E41(2006).
RN [23]
RP FUNCTION, INTERACTION WITH FXR1, AND SUBCELLULAR LOCATION.
RX PubMed=17382880; DOI=10.1016/j.cell.2007.01.038;
RA Vasudevan S., Steitz J.A.;
RT "AU-rich-element-mediated upregulation of translation by FXR1 and
RT Argonaute 2.";
RL Cell 128:1105-1118(2007).
RN [24]
RP FUNCTION, AND MUTAGENESIS OF PHE-470 AND PHE-505.
RX PubMed=17524464; DOI=10.1016/j.cell.2007.05.016;
RA Kiriakidou M., Tan G.S., Lamprinaki S., De Planell-Saguer M.,
RA Nelson P.T., Mourelatos Z.;
RT "An mRNA m7G cap binding-like motif within human Ago2 represses
RT translation.";
RL Cell 129:1141-1151(2007).
RN [25]
RP FUNCTION, ASSOCIATION WITH POLYSOMES AND MNRP, AND INTERACTION WITH
RP DDB1; DDX5; DHX30; DHX36; DDX47; ELAVL1; HNRNPF; IGF2BP1; ILF3; MATR3;
RP PABPC1; RBM4; SART3; UPF1 AND YBX1.
RX PubMed=17932509; DOI=10.1038/sj.embor.7401088;
RA Hoeck J., Weinmann L., Ender C., Ruedel S., Kremmer E., Raabe M.,
RA Urlaub H., Meister G.;
RT "Proteomic and functional analysis of Argonaute-containing mRNA-
RT protein complexes in human cells.";
RL EMBO Rep. 8:1052-1060(2007).
RN [26]
RP FUNCTION, AND INTERACTION WITH DHX9.
RX PubMed=17531811; DOI=10.1016/j.molcel.2007.04.016;
RA Robb G.B., Rana T.M.;
RT "RNA helicase A interacts with RISC in human cells and functions in
RT RISC loading.";
RL Mol. Cell 26:523-537(2007).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, INTERACTION WITH
RP DICER1; EIF6; MOV10 AND TARBP2, AND ASSOCIATION WITH THE 60S RIBOSOME.
RX PubMed=17507929; DOI=10.1038/nature05841;
RA Chendrimada T.P., Finn K.J., Ji X., Baillat D., Gregory R.I.,
RA Liebhaber S.A., Pasquinelli A.E., Shiekhattar R.;
RT "MicroRNA silencing through RISC recruitment of eIF6.";
RL Nature 447:823-828(2007).
RN [28]
RP FUNCTION.
RX PubMed=18048652; DOI=10.1126/science.1149460;
RA Vasudevan S., Tong Y., Steitz J.A.;
RT "Switching from repression to activation: microRNAs can up-regulate
RT translation.";
RL Science 318:1931-1934(2007).
RN [29]
RP FUNCTION, AND MUTAGENESIS OF ASP-597.
RX PubMed=18771919; DOI=10.1016/j.cub.2008.07.072;
RA Wu L., Fan J., Belasco J.G.;
RT "Importance of translation and nonnucleolytic ago proteins for on-
RT target RNA interference.";
RL Curr. Biol. 18:1327-1332(2008).
RN [30]
RP FUNCTION, INTERACTION WITH DICER1; P4HA1; P4HB; TNRC6A AND TNRC6B,
RP SUBCELLULAR LOCATION, HYDROXYLATION AT PRO-700, AND MUTAGENESIS OF
RP PRO-700.
RX PubMed=18690212; DOI=10.1038/nature07186;
RA Qi H.H., Ongusaha P.P., Myllyharju J., Cheng D., Pakkanen O., Shi Y.,
RA Lee S.W., Peng J., Shi Y.;
RT "Prolyl 4-hydroxylation regulates Argonaute 2 stability.";
RL Nature 455:421-424(2008).
RN [31]
RP FUNCTION, AND INTERACTION WITH DICER1 AND TARBP2.
RX PubMed=18178619; DOI=10.1073/pnas.0710869105;
RA MacRae I.J., Ma E., Zhou M., Robinson C.V., Doudna J.A.;
RT "In vitro reconstitution of the human RISC-loading complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:512-517(2008).
RN [32]
RP FUNCTION, INTERACTION WITH IMP8, AND SUBCELLULAR LOCATION.
RX PubMed=19167051; DOI=10.1016/j.cell.2008.12.023;
RA Weinmann L., Hoeck J., Ivacevic T., Ohrt T., Muetze J., Schwille P.,
RA Kremmer E., Benes V., Urlaub H., Meister G.;
RT "Importin 8 is a gene silencing factor that targets argonaute proteins
RT to distinct mRNAs.";
RL Cell 136:496-507(2009).
RN [33]
RP INTERACTION WITH RBM4.
RX PubMed=19801630; DOI=10.1074/jbc.M109.032946;
RA Lin J.C., Tarn W.Y.;
RT "RNA-binding motif protein 4 translocates to cytoplasmic granules and
RT suppresses translation via argonaute2 during muscle cell
RT differentiation.";
RL J. Biol. Chem. 284:34658-34665(2009).
RN [34]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH LIMD1; WTIP AND AJUBA.
RX PubMed=20616046; DOI=10.1073/pnas.0914987107;
RA James V., Zhang Y., Foxler D.E., de Moor C.H., Kong Y.W., Webb T.M.,
RA Self T.J., Feng Y., Lagos D., Chu C.Y., Rana T.M., Morley S.J.,
RA Longmore G.D., Bushell M., Sharp T.V.;
RT "LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
RT microRNA-mediated gene silencing.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:12499-12504(2010).
RN [35]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [36]
RP INTERACTION WITH TNRC6C, AND MUTAGENESIS OF PHE-470 AND PHE-505.
RX PubMed=21981923; DOI=10.1016/j.molcel.2011.09.007;
RA Braun J.E., Huntzinger E., Fauser M., Izaurralde E.;
RT "GW182 proteins directly recruit cytoplasmic deadenylase complexes to
RT miRNA targets.";
RL Mol. Cell 44:120-133(2011).
RN [37]
RP INTERACTION WITH MOV10.
RX PubMed=22791714; DOI=10.1074/jbc.M112.354001;
RA Liu C., Zhang X., Huang F., Yang B., Li J., Liu B., Luo H., Zhang P.,
RA Zhang H.;
RT "APOBEC3G inhibits microRNA-mediated repression of translation by
RT interfering with the interaction between Argonaute-2 and MOV10.";
RL J. Biol. Chem. 287:29373-29383(2012).
RN [38]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH APOBEC3A; APOBEC3C;
RP APOBEC3F; APOBEC3G AND APOBEC3H.
RX PubMed=22915799; DOI=10.1128/JVI.00595-12;
RA Phalora P.K., Sherer N.M., Wolinsky S.M., Swanson C.M., Malim M.H.;
RT "HIV-1 replication and APOBEC3 antiviral activity are not regulated by
RT P bodies.";
RL J. Virol. 86:11712-11724(2012).
CC -!- FUNCTION: Required for RNA-mediated gene silencing (RNAi) by the
CC RNA-induced silencing complex (RISC). The 'minimal RISC' appears
CC to include AGO2 bound to a short guide RNA such as a microRNA
CC (miRNA) or short interfering RNA (siRNA). These guide RNAs direct
CC RISC to complementary mRNAs that are targets for RISC-mediated
CC gene silencing. The precise mechanism of gene silencing depends on
CC the degree of complementarity between the miRNA or siRNA and its
CC target. Binding of RISC to a perfectly complementary mRNA
CC generally results in silencing due to endonucleolytic cleavage of
CC the mRNA specifically by AGO2. Binding of RISC to a partially
CC complementary mRNA results in silencing through inhibition of
CC translation, and this is independent of endonuclease activity. May
CC inhibit translation initiation by binding to the 7-methylguanosine
CC cap, thereby preventing the recruitment of the translation
CC initiation factor eIF4-E. May also inhibit translation initiation
CC via interaction with EIF6, which itself binds to the 60S ribosomal
CC subunit and prevents its association with the 40S ribosomal
CC subunit. The inhibition of translational initiation leads to the
CC accumulation of the affected mRNA in cytoplasmic processing bodies
CC (P-bodies), where mRNA degradation may subsequently occur. In some
CC cases RISC-mediated translational repression is also observed for
CC miRNAs that perfectly match the 3' untranslated region (3'-UTR).
CC Can also up-regulate the translation of specific mRNAs under
CC certain growth conditions. Binds to the AU element of the 3'-UTR
CC of the TNF (TNF-alpha) mRNA and up-regulates translation under
CC conditions of serum starvation. Also required for transcriptional
CC gene silencing (TGS), in which short RNAs known as antigene RNAs
CC or agRNAs direct the transcriptional repression of complementary
CC promoter regions.
CC -!- CATALYTIC ACTIVITY: Endonucleolytic cleavage to 5'-
CC phosphomonoester.
CC -!- ENZYME REGULATION: Inhibited by EDTA.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.1 nM for a synthetic 21-nucleotide single-stranded RNA;
CC -!- SUBUNIT: Interacts with DICER1 through its Piwi domain and with
CC TARBP2 during assembly of the RNA-induced silencing complex
CC (RISC). Together, DICER1, AGO2 and TARBP2 constitute the trimeric
CC RISC loading complex (RLC), or micro-RNA (miRNA) loading complex
CC (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to
CC process precursor miRNAs (pre-miRNAs) to mature miRNAs and then
CC load them onto AGO2. AGO2 bound to the mature miRNA constitutes
CC the minimal RISC and may subsequently dissociate from DICER1 and
CC TARBP2. Note however that the term RISC has also been used to
CC describe the trimeric RLC/miRLC. The formation of RISC complexes
CC containing siRNAs rather than miRNAs appears to occur
CC independently of DICER1. Interacts with AGO1. Also interacts with
CC DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, EIF6, ELAVL,
CC FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, MOV10, PABPC1,
CC PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1.
CC Interacts with the P-body components DCP1A and XRN1. Associates
CC with polysomes and messenger ribonucleoproteins (mNRPs). Interacts
CC with RBM4; the interaction is modulated under stress-induced
CC conditions, occurs under both cell proliferation and
CC differentiation conditions and in a RNA- and phosphorylation-
CC independent manner. Interacts with LIMD1, WTIP and AJUBA.
CC Interacts with TRIM71. Interacts with APOBEC3G in an RNA-dependent
CC manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H.
CC -!- INTERACTION:
CC Q9UIV1:CNOT7; NbExp=2; IntAct=EBI-528269, EBI-2105113;
CC Q96C10:DHX58; NbExp=2; IntAct=EBI-528269, EBI-744193;
CC Q9UPY3:DICER1; NbExp=12; IntAct=EBI-528269, EBI-395506;
CC Q13541:EIF4EBP1; NbExp=2; IntAct=EBI-528269, EBI-74090;
CC P63244:GNB2L1; NbExp=2; IntAct=EBI-528269, EBI-296739;
CC O15397:IPO8; NbExp=4; IntAct=EBI-528269, EBI-358808;
CC Q5S007:LRRK2; NbExp=3; IntAct=EBI-528269, EBI-5323863;
CC Q15633:TARBP2; NbExp=5; IntAct=EBI-528269, EBI-978581;
CC Q9UHD2:TBK1; NbExp=2; IntAct=EBI-528269, EBI-356402;
CC A7MCY6:TBKBP1; NbExp=2; IntAct=EBI-528269, EBI-359969;
CC Q8NDV7:TNRC6A; NbExp=10; IntAct=EBI-528269, EBI-2269715;
CC Q9UPQ9:TNRC6B; NbExp=3; IntAct=EBI-528269, EBI-947158;
CC Q9HCJ0:TNRC6C; NbExp=3; IntAct=EBI-528269, EBI-6507625;
CC Q9HA38:ZMAT3; NbExp=5; IntAct=EBI-528269, EBI-2548480;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, P-body. Nucleus.
CC Note=Translational repression of mRNAs results in their
CC recruitment to P-bodies. Translocation to the nucleus requires
CC IMP8.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UKV8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UKV8-2; Sequence=VSP_037001;
CC Note=No experimental confirmation available;
CC -!- DOMAIN: The Piwi domain may perform RNA cleavage by a mechanism
CC similar to that of RNase H. However, while RNase H utilizes a
CC triad of Asp-Asp-Glu (DDE) for metal ion coordination, this
CC protein appears to utilize a triad of Asp-Asp-His (DDH).
CC -!- PTM: Hydroxylated. 4-hydroxylation appears to enhance protein
CC stability but is not required for miRNA-binding or endonuclease
CC activity.
CC -!- SIMILARITY: Belongs to the argonaute family. Ago subfamily.
CC -!- SIMILARITY: Contains 1 PAZ domain.
CC -!- SIMILARITY: Contains 1 Piwi domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH07633.1; Type=Erroneous initiation;
CC Sequence=AAL76093.1; Type=Miscellaneous discrepancy; Note=cDNA contains a duplication of an internal sequence at the 5' end;
CC Sequence=BC125214; Type=Frameshift; Positions=450;
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DR EMBL; AC067931; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107375; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007633; AAH07633.1; ALT_INIT; mRNA.
DR EMBL; BC018727; AAH18727.2; -; mRNA.
DR EMBL; BC125214; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AY077717; AAL76093.1; ALT_SEQ; mRNA.
DR EMBL; BT007229; AAP35893.1; -; mRNA.
DR EMBL; AF121255; AAF13034.2; -; mRNA.
DR RefSeq; NP_001158095.1; NM_001164623.1.
DR RefSeq; NP_036286.2; NM_012154.3.
DR UniGene; Hs.743313; -.
DR PDB; 3LUC; X-ray; 1.69 A; A/B/C=439-575.
DR PDB; 3LUD; X-ray; 2.10 A; A/B/C=439-575.
DR PDB; 3LUG; X-ray; 1.85 A; A/B/C=439-575.
DR PDB; 3LUH; X-ray; 2.00 A; A/B/C=439-575.
DR PDB; 3LUJ; X-ray; 1.80 A; A/B/C=439-575.
DR PDB; 3LUK; X-ray; 1.70 A; A/B/C=439-575.
DR PDB; 3QX8; X-ray; 2.30 A; A/B/C=439-575.
DR PDB; 3QX9; X-ray; 2.00 A; A/B/C=439-575.
DR PDB; 4EI1; X-ray; 2.30 A; A=1-859.
DR PDB; 4EI3; X-ray; 2.89 A; A=1-859.
DR PDB; 4F3T; X-ray; 2.25 A; A=1-859.
DR PDBsum; 3LUC; -.
DR PDBsum; 3LUD; -.
DR PDBsum; 3LUG; -.
DR PDBsum; 3LUH; -.
DR PDBsum; 3LUJ; -.
DR PDBsum; 3LUK; -.
DR PDBsum; 3QX8; -.
DR PDBsum; 3QX9; -.
DR PDBsum; 4EI1; -.
DR PDBsum; 4EI3; -.
DR PDBsum; 4F3T; -.
DR DisProt; DP00736; -.
DR ProteinModelPortal; Q9UKV8; -.
DR SMR; Q9UKV8; 23-859.
DR DIP; DIP-29194N; -.
DR IntAct; Q9UKV8; 170.
DR MINT; MINT-1957975; -.
DR PhosphoSite; Q9UKV8; -.
DR DMDM; 229463006; -.
DR PaxDb; Q9UKV8; -.
DR PRIDE; Q9UKV8; -.
DR DNASU; 27161; -.
DR Ensembl; ENST00000220592; ENSP00000220592; ENSG00000123908.
DR Ensembl; ENST00000519980; ENSP00000430176; ENSG00000123908.
DR GeneID; 27161; -.
DR KEGG; hsa:27161; -.
DR UCSC; uc003yvn.3; human.
DR CTD; 27161; -.
DR GeneCards; GC08M141542; -.
DR HGNC; HGNC:3263; AGO2.
DR HPA; CAB019309; -.
DR MIM; 606229; gene.
DR neXtProt; NX_Q9UKV8; -.
DR PharmGKB; PA27694; -.
DR eggNOG; NOG279895; -.
DR HOGENOM; HOG000116043; -.
DR InParanoid; Q9UKV8; -.
DR KO; K11593; -.
DR OMA; VQGYAFK; -.
DR OrthoDB; EOG7HHWRC; -.
DR PhylomeDB; Q9UKV8; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; EIF2C2; human.
DR EvolutionaryTrace; Q9UKV8; -.
DR GeneWiki; EIF2C2; -.
DR GenomeRNAi; 27161; -.
DR NextBio; 49946; -.
DR PRO; PR:Q9UKV8; -.
DR ArrayExpress; Q9UKV8; -.
DR Bgee; Q9UKV8; -.
DR CleanEx; HS_EIF2C2; -.
DR Genevestigator; Q9UKV8; -.
DR GO; GO:0000932; C:cytoplasmic mRNA processing body; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0035068; C:micro-ribonucleoprotein complex; IDA:UniProtKB.
DR GO; GO:0005845; C:mRNA cap binding complex; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005844; C:polysome; IDA:UniProtKB.
DR GO; GO:0016442; C:RISC complex; IDA:UniProtKB.
DR GO; GO:0070551; F:endoribonuclease activity, cleaving siRNA-paired mRNA; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0003729; F:mRNA binding; IEA:Ensembl.
DR GO; GO:0000340; F:RNA 7-methylguanosine cap binding; IDA:UniProtKB.
DR GO; GO:0035197; F:siRNA binding; IDA:UniProtKB.
DR GO; GO:0003743; F:translation initiation factor activity; NAS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035279; P:mRNA cleavage involved in gene silencing by miRNA; IDA:UniProtKB.
DR GO; GO:0035278; P:negative regulation of translation involved in gene silencing by miRNA; IDA:UniProtKB.
DR GO; GO:0045947; P:negative regulation of translational initiation; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:1900153; P:positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay; ISS:UniProtKB.
DR GO; GO:0060213; P:positive regulation of nuclear-transcribed mRNA poly(A) tail shortening; ISS:UniProtKB.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0031054; P:pre-miRNA processing; IDA:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR HAMAP; MF_03031; AGO2; 1; -.
DR InterPro; IPR028602; AGO2.
DR InterPro; IPR014811; DUF1785.
DR InterPro; IPR003100; PAZ_dom.
DR InterPro; IPR003165; Piwi.
DR InterPro; IPR012337; RNaseH-like_dom.
DR Pfam; PF08699; DUF1785; 1.
DR Pfam; PF02170; PAZ; 1.
DR Pfam; PF02171; Piwi; 1.
DR SMART; SM00949; PAZ; 1.
DR SMART; SM00950; Piwi; 1.
DR SUPFAM; SSF101690; SSF101690; 1.
DR SUPFAM; SSF53098; SSF53098; 1.
DR PROSITE; PS50821; PAZ; 1.
DR PROSITE; PS50822; PIWI; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Endonuclease; Hydrolase; Hydroxylation; Metal-binding; Nitration;
KW Nuclease; Nucleus; Reference proteome; Repressor; Ribonucleoprotein;
KW RNA-binding; RNA-mediated gene silencing; Transcription;
KW Transcription regulation; Translation regulation.
FT CHAIN 1 859 Protein argonaute-2.
FT /FTId=PRO_0000194057.
FT DOMAIN 235 348 PAZ.
FT DOMAIN 517 818 Piwi.
FT METAL 597 597 Divalent metal cation (Probable).
FT METAL 669 669 Divalent metal cation (Probable).
FT METAL 807 807 Divalent metal cation (Probable).
FT MOD_RES 2 2 Nitrated tyrosine (By similarity).
FT MOD_RES 700 700 4-hydroxyproline.
FT VAR_SEQ 724 757 Missing (in isoform 2).
FT /FTId=VSP_037001.
FT MUTAGEN 140 140 L->W: No effect.
FT MUTAGEN 470 470 F->V: No effect on miRNA-binding or
FT target mRNA cleavage. Abrogates binding
FT to the 7-methylguanosine cap of mRNA and
FT prevents inhibition of translation.
FT Abolishes interaction with TNRC6C; when
FT associated with V-505.
FT MUTAGEN 470 470 F->W: No effect on binding to the 7-
FT methylguanosine cap of mRNA or inhibition
FT of translation.
FT MUTAGEN 505 505 F->V: No effect on miRNA-binding or
FT target mRNA cleavage. Abrogates binding
FT to the 7-methylguanosine cap of mRNA and
FT prevents inhibition of translation and
FT abolishes interaction with TNRC6C; when
FT associated with V-470.
FT MUTAGEN 505 505 F->W: No effect on binding to the 7-
FT methylguanosine cap of mRNA or inhibition
FT of translation.
FT MUTAGEN 533 533 K->A: Impairs RNA cleavage.
FT MUTAGEN 545 545 Q->A: Impairs RNA cleavage.
FT MUTAGEN 570 570 K->A: Impairs RNA cleavage.
FT MUTAGEN 597 597 D->A: Abrogates RNA cleavage but does not
FT affect binding to siRNA or translational
FT repression.
FT MUTAGEN 633 633 Q->A: No effect.
FT MUTAGEN 633 633 Q->R: Abrogates RNA cleavage. Binds
FT siRNA.
FT MUTAGEN 634 634 H->P,A: Abrogates RNA cleavage. Binds
FT siRNA.
FT MUTAGEN 669 669 D->A: Abrogates RNA cleavage but does not
FT affect binding to siRNA.
FT MUTAGEN 673 673 E->G: No effect on RNA cleavage.
FT MUTAGEN 682 682 H->Y: No effect.
FT MUTAGEN 683 683 E->G: No effect on RNA cleavage.
FT MUTAGEN 700 700 P->A: Reduced protein stability.
FT MUTAGEN 704 704 F->Y: No effect.
FT MUTAGEN 744 744 T->Y: No effect.
FT MUTAGEN 807 807 H->A,R: Abrogates RNA cleavage.
FT CONFLICT 564 564 C -> W (in Ref. 5; AAF13034).
FT CONFLICT 589 589 Q -> E (in Ref. 5; AAF13034).
FT CONFLICT 617 617 S -> R (in Ref. 5; AAF13034).
FT CONFLICT 637 637 E -> K (in Ref. 3; AAL76093).
FT STRAND 35 48
FT STRAND 53 63
FT HELIX 68 81
FT HELIX 83 87
FT STRAND 96 104
FT STRAND 112 116
FT STRAND 128 139
FT HELIX 140 148
FT STRAND 151 153
FT HELIX 156 173
FT STRAND 174 177
FT STRAND 180 182
FT STRAND 191 193
FT STRAND 196 208
FT STRAND 210 225
FT HELIX 230 238
FT HELIX 252 262
FT STRAND 266 270
FT STRAND 278 288
FT TURN 289 291
FT STRAND 293 297
FT STRAND 299 301
FT STRAND 303 307
FT HELIX 308 316
FT STRAND 325 331
FT TURN 333 336
FT STRAND 337 340
FT HELIX 341 343
FT STRAND 344 346
FT HELIX 358 368
FT HELIX 372 386
FT HELIX 388 390
FT HELIX 392 396
FT STRAND 406 412
FT STRAND 422 424
FT STRAND 450 455
FT TURN 459 461
FT HELIX 464 481
FT STRAND 490 494
FT HELIX 498 500
FT HELIX 501 511
FT STRAND 517 522
FT HELIX 528 537
FT TURN 538 540
FT STRAND 544 548
FT HELIX 549 553
FT HELIX 557 571
FT HELIX 585 588
FT STRAND 591 599
FT STRAND 610 617
FT STRAND 619 622
FT STRAND 625 633
FT HELIX 642 657
FT STRAND 662 670
FT HELIX 673 675
FT HELIX 676 694
FT STRAND 701 708
FT STRAND 715 719
FT HELIX 720 722
FT TURN 725 728
FT STRAND 734 736
FT STRAND 738 741
FT STRAND 743 745
FT STRAND 747 751
FT STRAND 763 770
FT HELIX 776 786
FT STRAND 793 795
FT HELIX 801 817
FT HELIX 842 845
FT HELIX 850 853
FT TURN 854 858
SQ SEQUENCE 859 AA; 97208 MW; 5C8552C43FC81345 CRC64;
MYSGAGPALA PPAPPPPIQG YAFKPPPRPD FGTSGRTIKL QANFFEMDIP KIDIYHYELD
IKPEKCPRRV NREIVEHMVQ HFKTQIFGDR KPVFDGRKNL YTAMPLPIGR DKVELEVTLP
GEGKDRIFKV SIKWVSCVSL QALHDALSGR LPSVPFETIQ ALDVVMRHLP SMRYTPVGRS
FFTASEGCSN PLGGGREVWF GFHQSVRPSL WKMMLNIDVS ATAFYKAQPV IEFVCEVLDF
KSIEEQQKPL TDSQRVKFTK EIKGLKVEIT HCGQMKRKYR VCNVTRRPAS HQTFPLQQES
GQTVECTVAQ YFKDRHKLVL RYPHLPCLQV GQEQKHTYLP LEVCNIVAGQ RCIKKLTDNQ
TSTMIRATAR SAPDRQEEIS KLMRSASFNT DPYVREFGIM VKDEMTDVTG RVLQPPSILY
GGRNKAIATP VQGVWDMRNK QFHTGIEIKV WAIACFAPQR QCTEVHLKSF TEQLRKISRD
AGMPIQGQPC FCKYAQGADS VEPMFRHLKN TYAGLQLVVV ILPGKTPVYA EVKRVGDTVL
GMATQCVQMK NVQRTTPQTL SNLCLKINVK LGGVNNILLP QGRPPVFQQP VIFLGADVTH
PPAGDGKKPS IAAVVGSMDA HPNRYCATVR VQQHRQEIIQ DLAAMVRELL IQFYKSTRFK
PTRIIFYRDG VSEGQFQQVL HHELLAIREA CIKLEKDYQP GITFIVVQKR HHTRLFCTDK
NERVGKSGNI PAGTTVDTKI THPTEFDFYL CSHAGIQGTS RPSHYHVLWD DNRFSSDELQ
ILTYQLCHTY VRCTRSVSIP APAYYAHLVA FRARYHLVDK EHDSAEGSHT SGQSNGRDHQ
ALAKAVQVHQ DTLRTMYFA
//

MIM 606229
*RECORD*
*FIELD* NO
606229
*FIELD* TI
*606229 EUKARYOTIC TRANSLATION INITIATION FACTOR 2C, SUBUNIT 2; EIF2C2
;;ARGONAUTE 2; AGO2
read more*FIELD* TX

DESCRIPTION

Binding of microRNA (miRNA) to mRNA within the RNA-induced silencing
complex (RISC) leads to either translational inhibition or destruction
of the target mRNA. EIF2C2, or Argonaute-2, is a core RISC component
that has both mRNA inhibition and degradation functions (summary by
O'Carroll et al., 2007).

CLONING

In the course of cloning EIF2C1 (606228), Koesters et al. (1999)
isolated a crosshybridizing cDNA that represented EIF2C2, a gene very
similar to EIF2C1. The EIF2C2 gene encodes a protein of 833 amino acids.
EIF2C2 and EIF2C1 share 85% amino acid identity. Northern blot analysis
detected an mRNA of 11 to 12 kb.

Kiriakidou et al. (2007) reported that human AGO2 contains 859 amino
acids and has an N-terminal PAZ domain, a middle (MID) domain, and a
large C-terminal PIWI domain. The PIWI domain is predicted to adopt an
RNase H fold and catalyze miRNA-directed mRNA degradation. Kiriakidou et
al. (2007) found that a portion of the MID domain, which they called the
MC domain, shares significant similarity with the 7-methylguanosine
(m7G) cap-binding domain of EIF4E (133440). The MC domain is conserved
in all mammalian Ago proteins and in some Agos from lower vertebrates
and invertebrates, including Drosophila Ago1 (EIF2C1), but not
Drosophila Ago2.

GENE FUNCTION

GEMIN3 (DDX20; 606168) is a DEAD box RNA helicase that binds to the SMN
(600354) protein and is a component of the SMN complex, which also
contains GEMIN2 (602595), GEMIN4 (606969), GEMIN5 (607005), and GEMIN6
(607006). Mourelatos et al. (2002) reported that GEMIN3 and GEMIN4 are
also in a separate complex that contains EIF2C2, a member of the
argonaute protein family. This novel complex is a large, approximately
15S RNP that contains numerous microRNAs, a class of small endogenous
RNAs.

Martinez et al. (2002) demonstrated that a single-stranded small
interfering RNA (siRNA) resides in human RISC together with the EIF2C1
and/or EIF2C2 proteins. RISC could be rapidly formed in HeLa cell
cytoplasmic extract supplemented with 21-nucleotide siRNA duplexes, but
also by adding single-stranded antisense RNAs, which range in size
between 19 and 29 nucleotides.

RISC-bound small RNA guides the RISC complex to identify and cleave
mRNAs with complementary sequences. Rand et al. (2004) showed that Ago2
was the only protein component in the purified functional Drosophila
RISC complex. They found an endonuclease V-like domain in Ago2 and
identified 3 residues within this domain as potential
magnesium-coordinating residues at the catalytic center of Ago2
nuclease.

AU-rich elements (AREs) in the 3-prime UTRs of unstable mRNAs dictate
their degradation. Using an RNA interference (RNAi)-based screen in
Drosophila S2 cells, Jing et al. (2005) found that Dicer-1 (606241),
Ago1 (606228), and Ago2, components involved in microRNA (miRNA)
processing and function, were required for rapid decay of mRNA
containing AREs of tumor necrosis factor-alpha (TNF; 191160). The
requirement for Dicer in the instability of ARE-containing mRNA
(ARE-RNA) was confirmed in HeLa cells. Jing et al. (2005) showed that
miRNA16 (miR16), a human miRNA containing an UAAAUAUU sequence that is
complementary to the ARE sequence, was required for ARE-RNA turnover.
The role of miR16 in ARE-RNA decay was sequence-specific and required
the ARE-binding protein tristetraprolin (TTP, or ZFP36; 190700). TTP did
not directly bind miR16, but interacted through association with
Ago/EIF2C family members to complex with miR16 and assist in the
targeting of ARE. Jing et al. (2005) concluded that miRNA targeting of
ARE appears to be an essential step in ARE-mediated mRNA degradation.

Chendrimada et al. (2005) demonstrated that TRBP (TARBP2; 605053), which
contains 3 double-stranded RNA-binding domains, is an integral component
of a Dicer-containing complex. Biochemical analysis of TRBP-containing
complexes revealed the association of Dicer-TRBP with AGO2, the
catalytic engine of RISC. The physical association of Dicer-TRBP and
AGO2 was confirmed after the isolation of the ternary complex using
Flag-tagged AGO2 cell lines. In vitro reconstitution assays demonstrated
that TRBP is required for the recruitment of AGO2 to the small
interfering RNA (siRNA) bound by Dicer. Knockdown of TRBP resulted in
destabilization of Dicer and a consequent loss of miRNA biogenesis.
Finally, depletion of the Dicer-TRBP complex via exogenously introduced
siRNAs diminished RISC-mediated reporter gene silencing. Chendrimada et
al. (2005) concluded that these results support a role of the Dicer-TRBP
complex not only in miRNA processing but also as a platform for RISC
assembly.

Maniataki and Mourelatos (2005) found that pre-miRNA-fueled assembly of
RISC in humans differed from the assembly of RISC by siRNA in Drosophila
in terms of the sequence of events, energy requirements, and the final
RISC product. In human cells, DICER was associated with AGO2 prior to
its encounter with pre-miRNA. The preformed AGO2/DICER-containing
complex assembled RISCs from pre-miRNAs but not from siRNA duplexes, and
the process was independent of added ATP or GTP. The final RISC product,
a ribonucleoprotein made up of AGO2 and miRNA, could be released from
DICER.

Gregory et al. (2005) immunoprecipitated approximately 500-kD RISC
complexes from human embryonic kidney cells and found that they
contained DICER, TRBP, and AGO2. The RISC complex cleaved target RNA
using pre-miRNA hairpin as well as duplex siRNA, but it displayed nearly
10-fold greater activity using the pre-miRNA DICER substrate. RISC
distinguished the guide strand of the siRNA from the passenger strand
and specifically incorporated the guide strand. ATP was not required for
miRNA processing, RISC assembly, or multiple rounds of AGO2-mediated
target RNA cleavage.

Using Drosophila and human HeLa cell lysates, Matranga et al. (2005)
showed that AGO2 directly received double-stranded siRNA from the RISC
loading complex. AGO2 then cleaved the siRNA passenger strand, thereby
liberating the single-stranded guide for inclusion in the RISC complex.

Liu et al. (2004) showed that the multiple Argonaute proteins present in
mammals are both biologically and biochemically distinct, with a single
mammalian family member, Argonaute2, being responsible for mRNA cleavage
activity. This protein is essential for mouse development, and cells
lacking Argonaute2 are unable to mount an experimental response to
siRNAs. Mutations within a cryptic ribonuclease H domain within
Argonaute2, as identified by comparison with the structure of an archeal
Argonaute protein, inactivate RISC. Thus, Liu et al. (2004) concluded
that their evidence supported a model in which Argonaute contributes
'slicer' activity to RISC, providing the catalytic engine for RNAi.

O'Carroll et al. (2007) found that Ago2 controlled early development of
mouse lymphoid and erythroid cells, although its Slicer endonuclease
activity was dispensable for hematopoiesis. Instead, they identified
Ago2 as a key regulator of miRNA homeostasis. Ago2 deficiency impaired
miRNA biogenesis from pre-miRNAs, followed by a reduction in miRNA
expression. O'Carroll et al. (2007) concluded that AGO2 is a specialized
member of the Argonaute family with an essential and Slicer-independent
function in the miRNA pathway.

The 5-prime end of eukaryotic mRNAs is modified by the addition of a
7-methylguanosine (m7G) cap, and binding of the m7G cap by the
translation initiation factor EIF4E (133440) is essential for mRNA
translation. Kiriakidou et al. (2007) showed that human AGO2 bound the
m7G cap of a reporter plasmid in transfected human cells and prevented
its translation. Substitution of the conserved phenylalanines in the MC
domain of AGO2 (F470 and F505) with valines prevented m7G cap binding by
AGO2 and permitted reporter translation. These mutations did not inhibit
assembly of AGO2 with miRNAs in HeLa cells or alter its endonucleolytic
activity. Kiriakidou et al. (2007) proposed that AGO2 represses
initiation of mRNA translation by binding to the m7G cap of target
mRNAs, thereby precluding recruitment of EIF4E. They hypothesized that
multiple miRNA recognition elements within the 3-prime end of the target
mRNA increases the number of AGO2 molecules bound to the mRNA, thus
increasing the probability that they will interact with the m7G cap and
augment miRNA-directed translational repression.

Kawamura et al. (2008) showed that in cultured Drosophila S2 cells, Ago2
associated with endogenous small RNAs of 20-22 nucleotides in length,
which they had collectively named endogenous short interfering RNAs
(esiRNAs). EsiRNAs can be divided into 2 groups: one that mainly
corresponds to a subset of retrotransposons, and the other that arises
from stem-loop structures. EsiRNAs are produced in a Dicer-2-dependent
manner from distinctive genomic loci, are modified at the 3-prime ends,
and can direct Ago2 to cleave target RNAs. Mutations in Dicer-2 caused
an increase in retrotransposon transcripts. Kawamura et al. (2008)
concluded that, together, their findings indicate that different types
of small RNAs and Argonautes are used to repress retrotransposons in
germline and somatic cells in Drosophila.

Czech et al. (2008) independently showed that Drosophila generated
endogenous small interfering RNAs in both gonadal and somatic tissues.
Production of esiRNAs required Dicer-2 but a subset depended
preferentially on Loquacious (TARBP2) rather than the canonical Dicer-2
partner, R2D2. EsiRNAs arose both from the convergent transcription
units and from structured genomic loci in a tissue-specific fashion.
They predominantly join Ago2 and have the capacity, as a class, to
target both protein-coding genes and mobile elements. Czech et al.
(2008) concluded that these observations expand the repertoire of small
RNAs in Drosophila, adding a class that blurs distinctions based on
known biogenesis mechanisms and functional roles.

Okamura et al. (2008) reported that siRNAs derived from long hairpin RNA
genes (hpRNA) program Slicer complexes that can repress endogenous
target transcripts. The Drosophila hpRNA pathway is a hybrid mechanism
that combines canonical RNA interference (RNAi) factors Dicer2, Hen1
(C1ORF59; 612178), and Ago2 with a canonical microRNA factor Loquacious
to generate approximately 21-nucleotide siRNAs. Okamura et al. (2008)
concluded that these novel regulatory RNAs reveal unexpected complexity
in the sorting of small RNAs, and open a window onto the biologic usage
of endogenous RNAi in Drosophila.

Qi et al. (2008) reported physical interactions between Ago2 and the
alpha (P4H-alpha-1) (P4HA1; 176710), and beta (P4H-beta) (P4HB; 176790)
subunits of the type I collagen prolyl-4-hydroxylase (C-P4H-I). Mass
spectrometric analysis identified hydroxylation of the endogenous Ago2
at proline-700. In vitro, both Ago2 and Ago4 (607356) seem to be more
efficiently hydroxylated than Ago1 (606228) and Ago3 (607355) by
recombinant human C-P4H-I. Human cells depleted of P4H-alpha-1 or
P4H-beta by short hairpin RNA, and C-P4H-alpha-I-null mouse embryonic
fibroblast cells, showed reduced stability of Ago2 and impaired short
interfering RNA-programmed RISC activity. Furthermore, mutation of
proline-700 to alanine also resulted in destabilization of Ago2, thus
linking Ago2 P700 and hydroxylation at this residue to its stability
regulation. Qi et al. (2008) concluded that their findings identified
hydroxylation as a posttranslational modification important for Ago2
stability and effective RNA interference.

Azuma-Mukai et al. (2008) found that most small RNAs immunopurified with
endogenous AGO2 and AGO3 from human Jurkat cell lysates were miRNAs, and
that the miRNAs associated with AGO2 and AGO3 largely overlapped.
Immunohistochemical analysis showed that both AGO2 and AGO3 localized in
processing (P) bodies, suggesting that both are involved in the miRNA
pathway. Endogenous AGO2 showed slicer activity, but AGO3 did not.
Azuma-Mukai et al. (2008) hypothesized that AGO3 may function as an
inhibitor of RNA interference activity.

In mice, Ago2 is uniquely required for viability, and only this
Argonaute family member retains catalytic competence. To investigate the
evolutionary pressure to conserve Argonaute enzymatic activity, Cheloufi
et al. (2010) engineered a mouse with catalytically inactive Ago2
alleles. Homozygous mutants died shortly after birth with an obvious
anemia. Examination of microRNAs and their potential targets revealed a
loss of miR451 (612071), a small RNA important for erythropoiesis.
Though this microRNA is processed by Drosha (608828), its maturation
does not require Dicer (606241). Instead, the pre-miRNA becomes loaded
into Ago and is cleaved by the Ago catalytic center to generate an
intermediate 3-prime end, which is then further trimmed. Cheloufi et al.
(2010) concluded that their findings linked the conservation of
Argonaute catalysis to a conserved mechanism of microRNA biogenesis that
is important for vertebrate development.

Unlike siRNAs, miRNAs rarely form extensive numbers of basepairs to the
mRNAs they regulate. Ameres et al. (2010) found that extensive
complementarity between a target RNA and an Argonaute-1-bound miRNA
triggers miRNA tailing and 3-prime-to 5-prime trimming. In flies,
Argonaute-2-bound small RNAs, but not those bound to Argonaute-1, bear a
2-prime-O-methyl group at their 3-prime ends. This modification blocks
target-directed small RNA remodeling: in flies lacking Hen1 (612178),
the enzyme that adds the 2-prime-O-methyl group, Argonaute-2-associated
siRNAs are tailed and trimmed. Target complementarity also affects small
RNA stability in human cells. Ameres et al. (2010) found that in
cultured HeLa cells transfection of antagomirs to miR16 (609704) or
miR21 (611020) triggered not only dose-dependent miRNA shortening, but
also tailing. As in Drosophila, target RNA-dependent trimming of small
RNAs in HeLa cells was nearly always 3-prime to 5-prime. Moreover,
Ameres et al. (2010) could recapitulate trimming of endogenous human
miRNAs in HeLa cell cytoplasmic extract: incubation of the extract with
in vitro transcribed, 7-methylguanosine-capped and polyadenylated target
mRNAs containing 6 sites fully complementary to miR16 and miR21
triggered shortening and loss of the corresponding miRNA. A control
target did not alter miRNA length or abundance. These results suggested
that target-dependent small RNA tailing and trimming is conserved
between flies and mammals.

Cifuentes et al. (2010) identified a Dicer-independent miRNA biogenesis
pathway that uses Ago2 slicer catalytic activity. In contrast to other
microRNAs, miR451 levels were refractory to Dicer loss of function but
were reduced in MZago2 (maternal-zygotic) mutants. Cifuentes et al.
(2010) found that pre-miR451 processing requires Ago2 catalytic activity
in vivo. MZago2 mutants showed delayed erythropoiesis that could be
rescued by wildtype Ago2 or miR451-duplex but not by catalytically dead
Ago2. Changing the secondary structure of Dicer-dependent miRNAs to
mimic that of pre-miR451 restored miRNA function and rescued
developmental defects in MZdicer mutants, indicating that the pre-miRNA
secondary structure determines the processing pathway in vivo. Cifuentes
et al. (2010) proposed that Ago2-mediated cleavage of pre-miRNAs,
followed by uridylation and trimming, generates functional miRNAs
independently of Dicer.

Gain-of-function mutations in LRRK2 (609007) cause Parkinson disease
(PARK8; 607060) characterized by age-dependent degeneration of
dopaminergic neurons. Gehrke et al. (2010) found that LRRK2 interacted
with the miRNA pathway to regulate protein synthesis. They showed that
mRNAs for Drosophila E2f1 (189971) and Dp (TFDP1; 189902), which had
previously been implicated in cell cycle and survival control (Girling
et al., 1993), were translationally repressed by the miRNAs Let7
(MIRLET7A1; 605386) and miR184* (613146), respectively. Pathogenic human
LRRK2 antagonized Let7 and miR184*, leading to overproduction of E2f1
and Dp, which was critical for LRRK2 pathogenesis. In Drosophila,
genetic deletion of Let7, antagomir-mediated blockage of Let7 and
miR184* action, transgenic expression of Dp target protector, or
replacement of endogenous Dp with a Dp transgene nonresponsive to Let7
each had toxic effects similar to those of pathogenic LRRK2. Conversely,
increasing the level of Let7 or miR184* attenuated pathogenic LRRK2
effects. Human LRRK2 associated with Drosophila Ago1 or human AGO2 of
RISC. In aged fly brain, Ago1 protein level was negatively regulated by
human LRRK2. Furthermore, pathogenic LRRK2 promoted the association of
phosphorylated 4EBP1 (EIF4EPB1; 602223) with human AGO2. Gehrke et al.
(2010) concluded that deregulated synthesis of E2F1 and DP caused by
miRNA pathway impairment is a key event in LRRK2 pathogenesis,
suggesting that novel miRNA-based therapeutic strategies may be useful
for Parkinson disease.

Shen et al. (2013) demonstrated that epidermal growth factor receptor
(EGFR; 131550), which is the product of a well-characterized oncogene in
human cancers, suppresses the maturation of specific tumor
suppressor-like microRNAs in response to hypoxic stress through
phosphorylation of AGO2 at tyr393 (Y393). The association between EGFR
and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393
phosphorylation, which in turn reduces the binding of Dicer (606241) to
Ago2 and inhibits miRNA processing from precursor to mature miRNA. Shen
et al. (2013) also identified a long-loop structure in precursor miRNAs
as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA
maturation. Furthermore, AGO2-Y393 phosphorylation mediates
EGFR-enhanced cell survival and invasiveness under hypoxia, and
correlates with poorer overall survival in breast cancer patients. Shen
et al. (2013) concluded that their study revealed a function of EGFR in
microRNA maturation and demonstrated how EGFR is likely to function as a
regulator of AGO2 through novel posttranslational modification.

Li et al. (2013) showed that infection of hamster cells and suckling
mice by Nodamura virus, a mosquito-transmissable RNA virus, requires RNA
interference (RNAi) suppression by its B2 protein. Loss of B2 expression
or its suppressor activity leads to abundant production of viral siRNAs
and rapid clearance of the mutant viruses in mice. However, viral small
RNAs detected during virulent infection by Nodamura virus do not have
the properties of canonical siRNAs. Maillard et al. (2013) demonstrated
that undifferentiated mouse cells infected with encephalomyocarditis
virus or Nodamura virus accumulate approximately 22-nucleotide RNAs with
all the signature features of siRNAs. These derive from viral
double-strand RNA (dsRNA) replication intermediates, incorporate into
Ago2, are eliminated in Dicer knockout cells, and decrease in abundance
upon cell differentiation. Furthermore, genetically ablating a Nodamura
virus-encoded suppressor of RNAi that antagonizes Dicer during authentic
infections reduces Nodamura virus accumulation, which is rescued in
RNAi-deficient mouse cells. Maillard et al. (2013) concluded that
antiviral RNAi operates in mammalian cells. Li et al. (2013) concluded
that their findings and those of Maillard et al. (2013) illustrated that
Dicer-dependent processing of dsRNA viral replication intermediates into
successive siRNAs is a conserved mammalian immune response to infection
by 2 distinct positive-strand RNA viruses.

BIOCHEMICAL FEATURES

- Crystal Structure

Lingel et al. (2003) presented the 3-dimensional nuclear magnetic
resonance structure of the Drosophila Ago2 PAZ domain. This domain
adopts a nucleic acid-binding fold that is stabilized by conserved
hydrophobic residues. The nucleic acid-binding patch is located in a
cleft between the surface of a central beta-barrel and a conserved
module comprising strands beta-3, beta-4, and helix alpha-3. Because
critical structural residues and the binding surface are conserved,
Lingel et al. (2003) suggested that PAZ domains in all members of the
Argonaute and Dicer families adopt a similar fold with nucleic
acid-binding function, and that this plays an important part in gene
silencing.

Frank et al. (2010) reported the crystal structure of a MID domain from
a eukaryotic AGO protein, human AGO2. The structure, in complex with
nucleoside monophosphates (AMP, CMP, GMP, and UMP) mimicking the 5-prime
end of miRNAs, showed that there are specific contacts made between the
base of UMP or AMP and a rigid loop in the MID domain. Notably, the
structure of the loop discriminates between CMP and GMP, and
dissociation constants calculated from NMR titration experiments
confirmed these results, showing that AMP (0.26 mM) and UMP (0.12 mM)
bind with up to 30-fold higher affinity than either CMP (3.6 mM) or GMP
(3.3 mM). Frank et al. (2010) concluded that their study provides
structural evidence for nucleotide-specific interactions in the MID
domain of eukaryotic AGO proteins and explains the observed preference
for U or A at the 5-prime end of miRNAs.

Schirle and MacRae (2012) determined the 2.3-angstrom resolution crystal
structure of human AGO2, which revealed a bilobed 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 target mRNAs. Between nucleotides 6
and 7, there is a kink that may function in microRNA target recognition
or release of sliced RNA products. Tandem tryptophan-binding pockets in
the PIWI domain define a likely interaction surface for recruitment of
glycine-tryptophan-182 (GW182) or other tryptophan-rich cofactors.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the EIF2C2
gene to chromosome 8 (TMAP STS-T95471).

MOLECULAR GENETICS

By examining DNA copy number in 283 known miRNA genes, Zhang et al.
(2006) found a high proportion of copy number abnormalities in 227 human
ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA
copy number correlated with miRNA expression. They also found a high
frequency of copy number abnormalities of DICER1, AGO2, and other
miRNA-associated genes in these cancers. Zhang et al. (2006) concluded
that copy number alterations of miRNAs and their regulatory genes are
highly prevalent in cancer and may account partly for the frequent miRNA
gene deregulation reported in several tumor types.

ANIMAL MODEL

Wang et al. (2006) demonstrated that an RNA interference pathway
protects adult flies from infection by 2 evolutionarily diverse viruses.
Their work also described a molecular framework for the viral immunity,
in which viral double-stranded RNA produced during infection acts as the
pathogen trigger whereas Drosophila Dicer-2 (see 606241) and Argonaute-2
act as host sensor and effector, respectively. Wang et al. (2006)
concluded that their findings established a Drosophila model for
studying the innate immunity against viruses in animals.

Morita et al. (2007) found that Eif2c2-null mouse embryos stopped
growing around embryonic day 5.5, suggesting that Eif2c2 is required for
postimplantation development. Mutant embryos where slightly
morphologically misshapen compared with wildtype and heterozygous
embryos, and the size of each of the cells was irregular. There were no
apparent morphologic differences in blastocysts. Eif2c2 was not required
for maintenance of DNA methylation in imprinted genes, centromeric
repeats, or Xist (314670).

Schaefer et al. (2010) generated mice lacking Ago2 in dopamine receptor
D2 (DRD2; 126450)-expressing striatum neurons. These mice had normal
neuron and brain morphology. Ablation of Ago2 in Drd2-expressing
striatum neurons alleviated cocaine addiction, as manifested by reduced
motivation to self-administer the drug. Reduced drug dependence was
associated with selective downregulation of a set of miRNAs in
Ago2-deficient striatum. Comparison of these Ago2-dependent miRNAs with
miRNAs enriched and/or upregulated in Drd2-expressing neurons revealed
23 miRNAs likely to play a role in cocaine addiction. Reporter assays
showed that these 23 miRNAs regulated genes important for the
development of cocaine addiction, including Cdk5r1 (603460) and the
transcription factors Fosb (164772) and Mef2d (600663).

*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 1/31/2014
Ada Hamosh - updated: 8/27/2013
Ada Hamosh - updated: 6/21/2012
Paul J. Converse - updated: 2/11/2011
Patricia A. Hartz - updated: 10/13/2010
Ada Hamosh - updated: 8/30/2010
Ada Hamosh - updated: 8/20/2010
Ada Hamosh - updated: 7/30/2010
Ada Hamosh - updated: 7/12/2010
Ada Hamosh - updated: 6/14/2010
Patricia A. Hartz - updated: 7/10/2009
Patricia A. Hartz - updated: 5/5/2009
Ada Hamosh - updated: 10/2/2008
Ada Hamosh - updated: 7/9/2008
Patricia A. Hartz - updated: 9/20/2007
Patricia A. Hartz - updated: 6/22/2007
Patricia A. Hartz - updated: 7/28/2006
Ada Hamosh - updated: 5/23/2006
Ada Hamosh - updated: 2/15/2006
Patricia A. Hartz - updated: 1/24/2006
Ada Hamosh - updated: 9/7/2005
Stylianos E. Antonarakis - updated: 3/28/2005
Patricia A. Hartz - updated: 10/15/2004
Ada Hamosh - updated: 12/3/2003
Ada Hamosh - updated: 7/8/2003
Stylianos E. Antonarakis - updated: 9/13/2002

*FIELD* CD
Ada Hamosh: 8/28/2001

*FIELD* ED
alopez: 01/31/2014
alopez: 1/31/2014
alopez: 8/27/2013
alopez: 6/28/2012
terry: 6/21/2012
terry: 5/24/2012
mgross: 2/11/2011
terry: 2/11/2011
mgross: 10/14/2010
mgross: 10/13/2010
terry: 10/13/2010
mgross: 8/30/2010
alopez: 8/30/2010
terry: 8/20/2010
alopez: 7/30/2010
terry: 7/30/2010
alopez: 7/13/2010
terry: 7/12/2010
alopez: 6/21/2010
terry: 6/14/2010
mgross: 7/10/2009
terry: 7/10/2009
mgross: 5/5/2009
terry: 5/5/2009
alopez: 10/6/2008
terry: 10/2/2008
wwang: 7/15/2008
terry: 7/9/2008
mgross: 10/4/2007
terry: 9/20/2007
mgross: 7/11/2007
terry: 6/22/2007
wwang: 8/7/2006
terry: 7/28/2006
alopez: 5/23/2006
mgross: 3/1/2006
alopez: 2/15/2006
wwang: 2/10/2006
terry: 1/24/2006
alopez: 9/14/2005
terry: 9/7/2005
mgross: 3/28/2005
mgross: 10/15/2004
alopez: 12/4/2003
terry: 12/3/2003
mgross: 7/14/2003
terry: 7/8/2003
mgross: 11/15/2002
mgross: 9/13/2002
alopez: 9/6/2001
alopez: 8/28/2001