eukaryotic initiation factor 2C2; protein argonaute-2; argonaute2; hAgo2; argonaute RISC catalytic component 2; eukaryotic translation initiation factor 2C 2; eIF-2C 2; eIF2C 2; PAZ Piwi domain protein; PPD; protein slicer (AGO2, EIF2C2)

Function: - 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 & 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, & 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 & prevents its association with the 40S ribosomal subunit - inhibition of translational initiation leads to accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur - RISC-mediated translational repression may also be 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 & 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 - endonucleolytic cleavage to 5'-phosphomonoester - hydroxylated - 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity - interacts with DICER1 through its Piwi domain & with TARBP2 during assembly of the RNA-induced silencing complex (RISC) - interacts with 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 & YBX1 - interacts with the P-body components DCP1A & XRN1 - associates with polysomes & messenger ribonucleoproteins (mNRPs) - interacts with RBM4 - interaction is modulated under stress-induced conditions - occurs under both cell proliferation & differentiation conditions & in a RNA- & phosphorylation- independent manner - interacts with LIMD1, WTIP & AJUBA - interacts with TRIM71 - interacts with APOBEC3G in an RNA-dependent manner - interacts with APOBEC3A, APOBEC3C, APOBEC3F & APOBEC3H Inibition: - inhibited by EDTA Kinetic parameters: - KM=1.1 nM for a synthetic 21-nucleotide single-stranded RNA Structure: - the Piwi domain may perform RNA cleavage by a mechanism similar to that of Rnase - however, while Rnase H utilizes atriad of Asp-Asp-Glu for metal ion coordination, this protein appears to utilize a triad of Asp-Asp-His - belongs to the argonaute family, Ago subfamily - contains 1 PAZ domain - contains 1 Piwi domain Compartment: - cytoplasm, P-body, nucleus - translational repression of mRNAs results in their recruitment to P-bodies - translocation to the nucleus requires IMP8 Alternative splicing: named isoforms=2

Properties

SIZE: entity length = 859 aa MW = 97 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: PAZ domain {235-348} Piwi domain {517-818}

Database Correlations

OMIM 606229 UniProt Q9UKV8 PFAM correlations Entrez Gene 27161 Kegg hsa:27161 ENZYME 3.1.26.n2

References

UniProt :accession Q9UKV8