Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
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Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
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Germline Genetics

AGO2 (Q9UKV8) - Overview - Molecular Target Synopsis

Protein


AGO2, Protein argonaute-2
Enzyme Classification 3.1.26.n2
UniProt Q9UKV8

Also Known as AGO2_HUMAN, AGO2, EIF2C2

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. 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, PubMed:24726324). 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).

6RA4
HUMAN ARGONAUTE-2 PAZ DOMAIN (214-347) IN COMPLEX WITH CGUGACUCU
RCSB/PDB
Inspect Structure
See all 3D Structures for AGO2

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: AGO2 is active in the following subcellular-locations: cytoplasm, nucleus, p-body.
GO terms: AGO2 is active in the following subcellular-locations: cell junction, cytoplasm, cytosol, dendrite, extracellular exosome, membrane, micro-ribonucleoprotein complex, mRNA cap binding complex, nucleoplasm, nucleus, P-body, polysome, ribonucleoprotein complex, RISC complex, RISC-loading complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project AGO2 has gain in 17 cell-lines, loss in 2 cell-lines and no signal in 985 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are:

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: MKN-74, WiDr, HT-29

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HSMM, HeLa-S3, SK-N-SH

(see details)

3D Structures


For AGO2 there are:
31 structures (48 chains) solved
27 are solved in complex with at least one small molecule ligand
22 are solved with an approved drug

AGO2 is solved in complex with the approved drug(s):

IPH/PHENOL (4F3T_A, 4OLA_A, 4W5N_A, 4W5O_A, 4W5Q_A, 4W5R_A, 4W5T_A, 4Z4C_A, 4Z4D_A, 4Z4E_A, 4Z4F_A, 4Z4G_A, 4Z4H_A, 4Z4I_A, 5JS1_A, 5JS2_A, 5KI6_A, 5T7B_A, 5WEA_A),
AMP/ADENOSINE PHOSPHATE (3LUD_A, 3LUD_B, 3LUD_C),
TRP/TRYPTOPHAN (4OLB_A, 6CBD_A).

(see details)
Molecular Target 3D Synopsis