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)
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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
- 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