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Protein

Protein argonaute-2

Gene

AGO2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include 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 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.UniRule annotationBy similarity23 Publications

Catalytic activityi

Endonucleolytic cleavage to 5'-phosphomonoester.UniRule annotation2 Publications

Cofactori

Mg2+1 Publication, Mn2+1 Publication

Activity regulationi

Inhibited by EDTA.1 Publication

Kineticsi

  1. KM=1.1 nM for a synthetic 21-nucleotide single-stranded RNA2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi597Divalent metal cationCurated1
    Metal bindingi669Divalent metal cationCurated1
    Metal bindingi807Divalent metal cationCurated1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionEndonuclease, Hydrolase, Nuclease, Repressor, Ribonucleoprotein, RNA-binding
    Biological processRNA-mediated gene silencing, Transcription, Transcription regulation, Translation regulation
    LigandMagnesium, Manganese, Metal-binding

    Enzyme and pathway databases

    ReactomeiR-HSA-1912408 Pre-NOTCH Transcription and Translation
    R-HSA-203927 MicroRNA (miRNA) biogenesis
    R-HSA-4086398 Ca2+ pathway
    R-HSA-426486 Small interfering RNA (siRNA) biogenesis
    R-HSA-426496 Post-transcriptional silencing by small RNAs
    R-HSA-5578749 Transcriptional regulation by small RNAs
    R-HSA-5628897 TP53 Regulates Metabolic Genes
    R-HSA-5687128 MAPK6/MAPK4 signaling
    R-HSA-8934593 Regulation of RUNX1 Expression and Activity
    R-HSA-8943723 Regulation of PTEN mRNA translation
    R-HSA-8948700 Competing endogenous RNAs (ceRNAs) regulate PTEN translation
    R-HSA-9018519 Estrogen-dependent gene expression
    SIGNORiQ9UKV8

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Protein argonaute-2UniRule annotation (EC:3.1.26.n2UniRule annotation)
    Short name:
    Argonaute2UniRule annotation
    Short name:
    hAgo2
    Alternative name(s):
    Argonaute RISC catalytic component 2
    Eukaryotic translation initiation factor 2C 2UniRule annotation
    Short name:
    eIF-2C 2UniRule annotation
    Short name:
    eIF2C 2UniRule annotation
    PAZ Piwi domain protein
    Short name:
    PPD
    Protein slicerUniRule annotation
    Gene namesi
    Name:AGO2
    Synonyms:EIF2C2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 8

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000123908.11
    HGNCiHGNC:3263 AGO2
    MIMi606229 gene
    neXtProtiNX_Q9UKV8

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi140L → W: No effect. 1 Publication1
    Mutagenesisi470F → V: No effect on miRNA-binding or target mRNA cleavage. Abrogates binding to the 7-methylguanosine cap of mRNA and prevents inhibition of translation. Abolishes interaction with TNRC6C; when associated with V-505. 2 Publications1
    Mutagenesisi470F → W: No effect on binding to the 7-methylguanosine cap of mRNA or inhibition of translation. 2 Publications1
    Mutagenesisi505F → V: No effect on miRNA-binding or target mRNA cleavage. Abrogates binding to the 7-methylguanosine cap of mRNA and prevents inhibition of translation and abolishes interaction with TNRC6C; when associated with V-470. 2 Publications1
    Mutagenesisi505F → W: No effect on binding to the 7-methylguanosine cap of mRNA or inhibition of translation. 2 Publications1
    Mutagenesisi533K → A: Impairs RNA cleavage. 1 Publication1
    Mutagenesisi545Q → A: Impairs RNA cleavage. 1 Publication1
    Mutagenesisi570K → A: Impairs RNA cleavage. 1 Publication1
    Mutagenesisi597D → A: Abrogates RNA cleavage but does not affect binding to siRNA or translational repression. 3 Publications1
    Mutagenesisi633Q → A: No effect. 1 Publication1
    Mutagenesisi633Q → R: Abrogates RNA cleavage. Binds siRNA. 1 Publication1
    Mutagenesisi634H → P or A: Abrogates RNA cleavage. Binds siRNA. 1 Publication1
    Mutagenesisi669D → A: Abrogates RNA cleavage but does not affect binding to siRNA. 3 Publications1
    Mutagenesisi673E → A: Impairs RNA cleavage. 2 Publications1
    Mutagenesisi673E → G: No effect on RNA cleavage. 2 Publications1
    Mutagenesisi676F → A, I, M, R or Y: Impairs RNA cleavage. 1 Publication1
    Mutagenesisi676F → V: Abrogates RNA cleavage. 1 Publication1
    Mutagenesisi682H → Y: No effect. 1 Publication1
    Mutagenesisi683E → G: No effect on RNA cleavage. 1 Publication1
    Mutagenesisi700P → A: Reduced protein stability. 1 Publication1
    Mutagenesisi704F → Y: No effect. 1 Publication1
    Mutagenesisi744T → Y: No effect. 1 Publication1
    Mutagenesisi807H → A or R: Abrogates RNA cleavage. 2 Publications1

    Organism-specific databases

    DisGeNETi27161
    OpenTargetsiENSG00000123908
    PharmGKBiPA27694

    Polymorphism and mutation databases

    BioMutaiAGO2
    DMDMi229463006

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001940571 – 859Protein argonaute-2Add BLAST859

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2Nitrated tyrosineUniRule annotationBy similarity1
    Modified residuei387PhosphoserineCombined sources1
    Modified residuei7004-hydroxyprolineUniRule annotation1 Publication1
    Modified residuei828PhosphoserineCombined sources1

    Post-translational modificationi

    Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity.UniRule annotation1 Publication

    Keywords - PTMi

    Hydroxylation, Nitration, Phosphoprotein

    Proteomic databases

    EPDiQ9UKV8
    PaxDbiQ9UKV8
    PeptideAtlasiQ9UKV8
    PRIDEiQ9UKV8
    ProteomicsDBi84894
    84895 [Q9UKV8-2]

    PTM databases

    iPTMnetiQ9UKV8
    PhosphoSitePlusiQ9UKV8
    SwissPalmiQ9UKV8

    Expressioni

    Gene expression databases

    BgeeiENSG00000123908 Expressed in 220 organ(s), highest expression level in forebrain
    CleanExiHS_EIF2C2
    ExpressionAtlasiQ9UKV8 baseline and differential
    GenevisibleiQ9UKV8 HS

    Organism-specific databases

    HPAiCAB019309
    HPA058075

    Interactioni

    Subunit structurei

    Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC). Together, DICER1, 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 AGO2. 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 AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, 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 an RNA- and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71; the interaction increases in presence of RNA (PubMed:23125361). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H. Interacts with DICER1, TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929). Interacts with FMR1 (PubMed:14703574). Interacts with ZFP36 (PubMed:15766526). Found in a complex, composed of AGO2, CHD7 and FAM172A (By similarity). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406). Interacts with SND1 (PubMed:14508492, PubMed:28546213).UniRule annotationBy similarity31 Publications

    Binary interactionsi

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi118041, 103 interactors
    ComplexPortaliCPX-1072 RISC-loading complex, PRKRA variant
    CPX-134 RISC-loading complex, TARBP2 variant
    CORUMiQ9UKV8
    DIPiDIP-29194N
    IntActiQ9UKV8, 197 interactors
    MINTiQ9UKV8
    STRINGi9606.ENSP00000220592

    Structurei

    Secondary structure

    1859
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    DisProtiDP00736
    ProteinModelPortaliQ9UKV8
    SMRiQ9UKV8
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9UKV8

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini235 – 348PAZUniRule annotationAdd BLAST114
    Domaini517 – 818PiwiUniRule annotationAdd BLAST302

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni311 – 316Interaction with guide RNA6
    Regioni524 – 566Interaction with guide RNAAdd BLAST43
    Regioni587 – 590Interaction with GW182 family membersSequence analysis4
    Regioni650 – 660Interaction with GW182 family membersSequence analysisAdd BLAST11
    Regioni709 – 710Interaction with guide RNA2
    Regioni753 – 761Interaction with guide RNA9
    Regioni790 – 812Interaction with guide RNAAdd BLAST23

    Domaini

    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).

    Sequence similaritiesi

    Belongs to the argonaute family. Ago subfamily.UniRule annotation

    Phylogenomic databases

    eggNOGiKOG1041 Eukaryota
    ENOG410XP07 LUCA
    GeneTreeiENSGT00760000119148
    HOGENOMiHOG000116043
    InParanoidiQ9UKV8
    KOiK11593
    OMAiSPDGYYH
    OrthoDBiEOG091G020J
    PhylomeDBiQ9UKV8
    TreeFamiTF101510

    Family and domain databases

    Gene3Di3.30.420.10, 1 hit
    HAMAPiMF_03031 AGO2, 1 hit
    InterProiView protein in InterPro
    IPR028602 AGO2
    IPR014811 ArgoL1
    IPR032472 ArgoL2
    IPR032473 Argonaute_Mid_dom
    IPR032474 Argonaute_N
    IPR003100 PAZ_dom
    IPR036085 PAZ_dom_sf
    IPR003165 Piwi
    IPR012337 RNaseH-like_sf
    IPR036397 RNaseH_sf
    PfamiView protein in Pfam
    PF08699 ArgoL1, 1 hit
    PF16488 ArgoL2, 1 hit
    PF16487 ArgoMid, 1 hit
    PF16486 ArgoN, 1 hit
    PF02170 PAZ, 1 hit
    PF02171 Piwi, 1 hit
    SMARTiView protein in SMART
    SM01163 DUF1785, 1 hit
    SM00949 PAZ, 1 hit
    SM00950 Piwi, 1 hit
    SUPFAMiSSF101690 SSF101690, 1 hit
    SSF53098 SSF53098, 1 hit
    PROSITEiView protein in PROSITE
    PS50821 PAZ, 1 hit
    PS50822 PIWI, 1 hit

    Sequences (2+)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.iShow all

    Isoform 1 (identifier: Q9UKV8-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MYSGAGPALA PPAPPPPIQG YAFKPPPRPD FGTSGRTIKL QANFFEMDIP
    60 70 80 90 100
    KIDIYHYELD IKPEKCPRRV NREIVEHMVQ HFKTQIFGDR KPVFDGRKNL
    110 120 130 140 150
    YTAMPLPIGR DKVELEVTLP GEGKDRIFKV SIKWVSCVSL QALHDALSGR
    160 170 180 190 200
    LPSVPFETIQ ALDVVMRHLP SMRYTPVGRS FFTASEGCSN PLGGGREVWF
    210 220 230 240 250
    GFHQSVRPSL WKMMLNIDVS ATAFYKAQPV IEFVCEVLDF KSIEEQQKPL
    260 270 280 290 300
    TDSQRVKFTK EIKGLKVEIT HCGQMKRKYR VCNVTRRPAS HQTFPLQQES
    310 320 330 340 350
    GQTVECTVAQ YFKDRHKLVL RYPHLPCLQV GQEQKHTYLP LEVCNIVAGQ
    360 370 380 390 400
    RCIKKLTDNQ TSTMIRATAR SAPDRQEEIS KLMRSASFNT DPYVREFGIM
    410 420 430 440 450
    VKDEMTDVTG RVLQPPSILY GGRNKAIATP VQGVWDMRNK QFHTGIEIKV
    460 470 480 490 500
    WAIACFAPQR QCTEVHLKSF TEQLRKISRD AGMPIQGQPC FCKYAQGADS
    510 520 530 540 550
    VEPMFRHLKN TYAGLQLVVV ILPGKTPVYA EVKRVGDTVL GMATQCVQMK
    560 570 580 590 600
    NVQRTTPQTL SNLCLKINVK LGGVNNILLP QGRPPVFQQP VIFLGADVTH
    610 620 630 640 650
    PPAGDGKKPS IAAVVGSMDA HPNRYCATVR VQQHRQEIIQ DLAAMVRELL
    660 670 680 690 700
    IQFYKSTRFK PTRIIFYRDG VSEGQFQQVL HHELLAIREA CIKLEKDYQP
    710 720 730 740 750
    GITFIVVQKR HHTRLFCTDK NERVGKSGNI PAGTTVDTKI THPTEFDFYL
    760 770 780 790 800
    CSHAGIQGTS RPSHYHVLWD DNRFSSDELQ ILTYQLCHTY VRCTRSVSIP
    810 820 830 840 850
    APAYYAHLVA FRARYHLVDK EHDSAEGSHT SGQSNGRDHQ ALAKAVQVHQ

    DTLRTMYFA
    Length:859
    Mass (Da):97,208
    Last modified:May 5, 2009 - v3
    Checksum:i5C8552C43FC81345
    GO
    Isoform 2 (identifier: Q9UKV8-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         724-757: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:825
    Mass (Da):93,620
    Checksum:i464C15B9413608D4
    GO

    Computationally mapped potential isoform sequencesi

    There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    E5RJY2E5RJY2_HUMAN
    Protein argonaute-2
    AGO2
    36Annotation score:
    E5RGG9E5RGG9_HUMAN
    Protein argonaute-2
    AGO2
    73Annotation score:

    Sequence cautioni

    The sequence AAH07633 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
    The sequence AAL76093 differs from that shown. cDNA contains a duplication of an internal sequence at the 5' end.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti564C → W in AAF13034 (PubMed:10534406).Curated1
    Sequence conflicti589Q → E in AAF13034 (PubMed:10534406).Curated1
    Sequence conflicti617S → R in AAF13034 (PubMed:10534406).Curated1
    Sequence conflicti637E → K in AAL76093 (PubMed:11914277).Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_037001724 – 757Missing in isoform 2. 1 PublicationAdd BLAST34

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AC067931 Genomic DNA No translation available.
    AC107375 Genomic DNA No translation available.
    BC007633 mRNA Translation: AAH07633.1 Different initiation.
    BC018727 mRNA Translation: AAH18727.2
    BC125214 mRNA No translation available.
    AY077717 mRNA Translation: AAL76093.1 Sequence problems.
    BT007229 mRNA Translation: AAP35893.1
    AF121255 mRNA Translation: AAF13034.2
    CCDSiCCDS55279.1 [Q9UKV8-2]
    CCDS6380.1 [Q9UKV8-1]
    RefSeqiNP_001158095.1, NM_001164623.2 [Q9UKV8-2]
    NP_036286.2, NM_012154.4 [Q9UKV8-1]
    UniGeneiHs.660189
    Hs.743313

    Genome annotation databases

    EnsembliENST00000220592; ENSP00000220592; ENSG00000123908 [Q9UKV8-1]
    ENST00000519980; ENSP00000430176; ENSG00000123908 [Q9UKV8-2]
    GeneIDi27161
    KEGGihsa:27161
    UCSCiuc003yvm.5 human [Q9UKV8-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Entry informationi

    Entry nameiAGO2_HUMAN
    AccessioniPrimary (citable) accession number: Q9UKV8
    Secondary accession number(s): Q8TCZ5, Q8WV58, Q96ID1
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
    Last sequence update: May 5, 2009
    Last modified: September 12, 2018
    This is version 175 of the entry and version 3 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome
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    Main funding by: National Institutes of Health

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