ID AGO2_RAT Reviewed; 860 AA. AC Q9QZ81; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 14-NOV-2003, sequence version 2. DT 23-FEB-2022, entry version 138. DE RecName: Full=Protein argonaute-2 {ECO:0000255|HAMAP-Rule:MF_03031}; DE Short=Argonaute2 {ECO:0000255|HAMAP-Rule:MF_03031}; DE EC=3.1.26.n2 {ECO:0000255|HAMAP-Rule:MF_03031}; DE AltName: Full=Argonaute RISC catalytic component 2; DE AltName: Full=Eukaryotic translation initiation factor 2C 2 {ECO:0000255|HAMAP-Rule:MF_03031}; DE Short=eIF-2C 2 {ECO:0000255|HAMAP-Rule:MF_03031}; DE Short=eIF2C 2 {ECO:0000255|HAMAP-Rule:MF_03031}; DE AltName: Full=Golgi ER protein 95 kDa; DE Short=GERp95; DE AltName: Full=Protein slicer {ECO:0000255|HAMAP-Rule:MF_03031}; GN Name=Ago2; Synonyms=Eif2c2; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=Sprague-Dawley; TISSUE=Hepatoma; RX PubMed=10512872; DOI=10.1091/mbc.10.10.3357; RA Cikaluk D.E., Tahbaz N., Hendricks L.C., DiMattia G.E., Hansen D., RA Pilgrim D., Hobman T.C.; RT "GERp95, a membrane-associated protein that belongs to a family of proteins RT involved in stem cell differentiation."; RL Mol. Biol. Cell 10:3357-3372(1999). RN [2] RP INTERACTION WITH AGO2 AND SND1. RX PubMed=24882364; DOI=10.1016/j.febslet.2014.05.031; RA Milochau A., Lagree V., Benassy M.N., Chaignepain S., Papin J., RA Garcia-Arcos I., Lajoix A., Monterrat C., Coudert L., Schmitter J.M., RA Ochoa B., Lang J.; RT "Synaptotagmin 11 interacts with components of the RNA-induced silencing RT complex RISC in clonal pancreatic beta-cells."; RL FEBS Lett. 588:2217-2222(2014). CC -!- FUNCTION: Required for RNA-mediated gene silencing (RNAi) by the RNA- CC induced silencing complex (RISC). The 'minimal RISC' appears to include CC AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short CC interfering RNA (siRNA). These guide RNAs direct RISC to complementary CC mRNAs that are targets for RISC-mediated gene silencing. The precise CC mechanism of gene silencing depends on the degree of complementarity CC between the miRNA or siRNA and its target. Binding of RISC to a CC perfectly complementary mRNA generally results in silencing due to CC endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of CC RISC to a partially complementary mRNA results in silencing through CC inhibition of translation, and this is independent of endonuclease CC activity. May inhibit translation initiation by binding to the 7- CC methylguanosine cap, thereby preventing the recruitment of the CC translation initiation factor eIF4-E. May also inhibit translation CC initiation via interaction with EIF6, which itself binds to the 60S CC ribosomal 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 (P- CC bodies), where mRNA degradation may subsequently occur. In some cases CC RISC-mediated translational repression is also observed for miRNAs that CC perfectly match the 3' untranslated region (3'-UTR). Can also up- CC regulate the translation of specific mRNAs under certain growth CC conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF- CC alpha) mRNA and up-regulates translation under conditions of serum CC starvation. Also required for transcriptional gene silencing (TGS), in CC which short RNAs known as antigene RNAs or agRNAs direct the CC transcriptional repression of complementary promoter regions. CC {ECO:0000255|HAMAP-Rule:MF_03031}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Endonucleolytic cleavage to 5'-phosphomonoester.; CC EC=3.1.26.n2; Evidence={ECO:0000255|HAMAP-Rule:MF_03031}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250}; CC -!- SUBUNIT: Interacts with DICER1 through its Piwi domain and with TARBP2 CC during assembly of the RNA-induced silencing complex (RISC). Together, CC DICER1, AGO2 and TARBP2 constitute the trimeric RISC loading complex CC (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the CC RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs CC (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound CC to the mature miRNA constitutes the minimal RISC and may subsequently CC dissociate from DICER1 and TARBP2. Note however that the term RISC has CC also been used to describe the trimeric RLC/miRLC. The formation of CC RISC complexes containing siRNAs rather than miRNAs appears to occur CC independently of DICER1. Interacts with AGO1. Also interacts with DDB1, CC DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, ELAVL, FXR1, GEMIN4, CC HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, PABPC1, PRMT5, P4HA1, P4HB, RBM4, CC SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body CC components DCP1A and XRN1. Associates with polysomes and messenger CC ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is CC modulated under stress-induced conditions, occurs under both cell CC proliferation and differentiation conditions and in an RNA- and CC phosphorylation-independent manner. Interacts with LIMD1, WTIP and CC AJUBA. Interacts with TRIM71; the interaction increases in presence of CC RNA. Interacts with APOBEC3G in an RNA-dependent manner. Interacts with CC APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H. Interacts with DICER1, CC TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large CC RNA-induced silencing complex (RISC). Interacts with FMR1. Interacts CC with ZFP36. Interacts with RC3H1; the interaction is RNA independent CC (By similarity). Found in a complex, composed of AGO2, CHD7 and FAM172A CC (By similarity). Interacts with SND1 and SYT11 (PubMed:24882364). CC Interacts with CLNK (By similarity). Interacts with GARRE1 (By CC similarity). {ECO:0000250|UniProtKB:Q8CJG0, CC ECO:0000250|UniProtKB:Q9UKV8, ECO:0000255|HAMAP-Rule:MF_03031, CC ECO:0000269|PubMed:24882364}. CC -!- SUBCELLULAR LOCATION: Cytoplasm, P-body {ECO:0000255|HAMAP- CC Rule:MF_03031}. Nucleus {ECO:0000255|HAMAP-Rule:MF_03031}. CC Note=Translational repression of mRNAs results in their recruitment to CC P-bodies. Translocation to the nucleus requires IMP8. CC {ECO:0000255|HAMAP-Rule:MF_03031}. CC -!- DOMAIN: The Piwi domain may perform RNA cleavage by a mechanism similar CC to that of RNase H. However, while RNase H utilizes a triad of Asp-Asp- CC Glu (DDE) for metal ion coordination, this protein appears to utilize a CC triad of Asp-Asp-His (DDH). {ECO:0000255|HAMAP-Rule:MF_03031}. CC -!- PTM: Hydroxylated. 4-hydroxylation appears to enhance protein stability CC but is not required for miRNA-binding or endonuclease activity. CC {ECO:0000255|HAMAP-Rule:MF_03031}. CC -!- PTM: Ubiquitinated on surface-exposed lysines by a SCF-like E3 CC ubiquitin-protein ligase complex containing ZSWIM8 during target- CC directed microRNA degradation (TDMD), a process that mediates CC degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 CC ubiquitin-protein ligase complex containing ZSWIM8 leads to its CC subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 CC recognizes and binds AGO2 when it is engaged with a TDMD target. CC {ECO:0000250|UniProtKB:Q9UKV8}. CC -!- PTM: Phosphorylation at Ser-388 by AKT3; leads to up-regulate CC translational repression of microRNA target and down-regulate CC endonucleolytic cleavage. {ECO:0000250|UniProtKB:Q9UKV8}. CC -!- PTM: A phosphorylation cycle of C-terminal serine cluster (Ser-825-Ser- CC 835) regulates the release of target mRNAs. Target-binding leads to CC phosphorylation of these residues by CSNK1A1, which reduces the CC affinity of AGO2 for mRNA and enables target release. The ANKRD52-PPP6C CC phosphatase complex dephosphorylates the residues, which primes AGO2 CC for binding a new target. {ECO:0000250|UniProtKB:Q9UKV8}. CC -!- SIMILARITY: Belongs to the argonaute family. Ago subfamily. CC {ECO:0000255|HAMAP-Rule:MF_03031}. CC -!- CAUTION: Was originally thought to be membrane-associated. CC {ECO:0000305|PubMed:10512872}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF12800.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF195534; AAF12800.1; ALT_INIT; mRNA. DR RefSeq; NP_067608.1; NM_021597.1. DR SMR; Q9QZ81; -. DR BioGRID; 248738; 1. DR IntAct; Q9QZ81; 7. DR MINT; Q9QZ81; -. DR STRING; 10116.ENSRNOP00000011898; -. DR iPTMnet; Q9QZ81; -. DR PhosphoSitePlus; Q9QZ81; -. DR jPOST; Q9QZ81; -. DR PaxDb; Q9QZ81; -. DR PeptideAtlas; Q9QZ81; -. DR PRIDE; Q9QZ81; -. DR GeneID; 59117; -. DR UCSC; RGD:621255; rat. DR CTD; 27161; -. DR RGD; 621255; Ago2. DR eggNOG; KOG1041; Eukaryota. DR InParanoid; Q9QZ81; -. DR OrthoDB; 159407at2759; -. DR PhylomeDB; Q9QZ81; -. DR Reactome; R-RNO-203927; MicroRNA (miRNA) biogenesis. DR Reactome; R-RNO-426486; Small interfering RNA (siRNA) biogenesis. DR Reactome; R-RNO-426496; Post-transcriptional silencing by small RNAs. DR Reactome; R-RNO-5578749; Transcriptional regulation by small RNAs. DR PRO; PR:Q9QZ81; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0005737; C:cytoplasm; ISO:RGD. DR GO; GO:0005829; C:cytosol; ISO:RGD. DR GO; GO:0030425; C:dendrite; ISO:RGD. DR GO; GO:0070062; C:extracellular exosome; ISO:RGD. DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL. DR GO; GO:0005845; C:mRNA cap binding complex; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; ISO:RGD. DR GO; GO:0000932; C:P-body; ISO:RGD. DR GO; GO:0005844; C:polysome; ISS:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; ISS:UniProtKB. DR GO; GO:0016442; C:RISC complex; ISS:UniProtKB. DR GO; GO:0070578; C:RISC-loading complex; ISS:UniProtKB. DR GO; GO:0001046; F:core promoter sequence-specific DNA binding; ISO:RGD. DR GO; GO:0003725; F:double-stranded RNA binding; ISO:RGD. DR GO; GO:0004521; F:endoribonuclease activity; ISO:RGD. DR GO; GO:0090624; F:endoribonuclease activity, cleaving miRNA-paired mRNA; ISO:RGD. DR GO; GO:0070551; F:endoribonuclease activity, cleaving siRNA-paired mRNA; ISS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0035198; F:miRNA binding; ISO:RGD. DR GO; GO:0003729; F:mRNA binding; ISO:RGD. DR GO; GO:0098808; F:mRNA cap binding; ISO:RGD. DR GO; GO:0008022; F:protein C-terminus binding; ISO:RGD. DR GO; GO:0000340; F:RNA 7-methylguanosine cap binding; ISS:UniProtKB. DR GO; GO:0003723; F:RNA binding; ISO:RGD. DR GO; GO:0000993; F:RNA polymerase II complex binding; ISO:RGD. DR GO; GO:0003727; F:single-stranded RNA binding; ISO:RGD. DR GO; GO:0035197; F:siRNA binding; ISS:UniProtKB. DR GO; GO:0030154; P:cell differentiation; NAS:RGD. DR GO; GO:0031047; P:gene silencing by RNA; ISS:UniProtKB. DR GO; GO:0035280; P:miRNA loading onto RISC involved in gene silencing by miRNA; ISO:RGD. DR GO; GO:0035278; P:miRNA mediated inhibition of translation; ISS:UniProtKB. DR GO; GO:0010586; P:miRNA metabolic process; ISO:RGD. DR GO; GO:0035279; P:mRNA cleavage involved in gene silencing by miRNA; ISS:UniProtKB. DR GO; GO:0090625; P:mRNA cleavage involved in gene silencing by siRNA; ISO:RGD. DR GO; GO:0042985; P:negative regulation of amyloid precursor protein biosynthetic process; IMP:ARUK-UCL. DR GO; GO:0045947; P:negative regulation of translational initiation; ISS:UniProtKB. DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:RGD. DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD. DR GO; GO:1905618; P:positive regulation of miRNA mediated inhibition of translation; ISO:RGD. 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:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:0045975; P:positive regulation of translation, ncRNA-mediated; ISO:RGD. DR GO; GO:1901165; P:positive regulation of trophoblast cell migration; ISO:RGD. DR GO; GO:0009791; P:post-embryonic development; ISO:RGD. DR GO; GO:0031054; P:pre-miRNA processing; ISS:UniProtKB. DR GO; GO:0035196; P:production of miRNAs involved in gene silencing by miRNA; ISO:RGD. DR GO; GO:0010501; P:RNA secondary structure unwinding; ISO:RGD. DR GO; GO:0035087; P:siRNA loading onto RISC involved in RNA interference; ISO:RGD. DR CDD; cd04657; Piwi_ago-like; 1. DR Gene3D; 3.30.420.10; -; 1. DR HAMAP; MF_03031; AGO2; 1. DR InterPro; IPR028602; AGO2. DR InterPro; IPR014811; ArgoL1. DR InterPro; IPR032472; ArgoL2. DR InterPro; IPR032473; Argonaute_Mid_dom. DR InterPro; IPR032474; Argonaute_N. DR InterPro; IPR003100; PAZ_dom. DR InterPro; IPR036085; PAZ_dom_sf. DR InterPro; IPR003165; Piwi. DR InterPro; IPR045246; Piwi_ago-like. DR InterPro; IPR012337; RNaseH-like_sf. DR InterPro; IPR036397; RNaseH_sf. DR Pfam; PF08699; ArgoL1; 1. DR Pfam; PF16488; ArgoL2; 1. DR Pfam; PF16487; ArgoMid; 1. DR Pfam; PF16486; ArgoN; 1. DR Pfam; PF02170; PAZ; 1. DR Pfam; PF02171; Piwi; 1. DR SMART; SM01163; DUF1785; 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 Cytoplasm; Endonuclease; Hydrolase; Hydroxylation; Magnesium; Manganese; KW Metal-binding; Nitration; Nuclease; Nucleus; Phosphoprotein; KW Reference proteome; Repressor; Ribonucleoprotein; RNA-binding; KW RNA-mediated gene silencing; Transcription; Transcription regulation; KW Translation regulation; Ubl conjugation. FT CHAIN 1..860 FT /note="Protein argonaute-2" FT /id="PRO_0000194060" FT DOMAIN 236..349 FT /note="PAZ" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03031" FT DOMAIN 518..819 FT /note="Piwi" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03031" FT REGION 312..317 FT /note="Interaction with guide RNA" FT /evidence="ECO:0000250" FT REGION 525..567 FT /note="Interaction with guide RNA" FT /evidence="ECO:0000250" FT REGION 588..591 FT /note="Interaction with GW182 family members" FT /evidence="ECO:0000255" FT REGION 651..661 FT /note="Interaction with GW182 family members" FT /evidence="ECO:0000255" FT REGION 710..711 FT /note="Interaction with guide RNA" FT /evidence="ECO:0000250" FT REGION 754..762 FT /note="Interaction with guide RNA" FT /evidence="ECO:0000250" FT REGION 791..813 FT /note="Interaction with guide RNA" FT /evidence="ECO:0000250" FT METAL 598 FT /note="Divalent metal cation" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03031" FT METAL 670 FT /note="Divalent metal cation" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03031" FT METAL 808 FT /note="Divalent metal cation" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03031" FT MOD_RES 2 FT /note="3'-nitrotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q8CJG0, ECO:0000255|HAMAP- FT Rule:MF_03031" FT MOD_RES 388 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9UKV8" FT MOD_RES 701 FT /note="4-hydroxyproline" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03031" FT MOD_RES 825 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9UKV8" FT MOD_RES 829 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9UKV8" FT MOD_RES 832 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9UKV8" FT MOD_RES 835 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9UKV8" SQ SEQUENCE 860 AA; 97318 MW; A5B0798C66481C9C CRC64; MYSGAGPVLA SPAPTTSPIP GYAFKPPPRP DFGTTGRTIK LQANFFEMDI PKIDIYHYEL DIKPEKCPRR VNREIVEHMV QHFKTQIFGD RKPVFDGRKN LYTAMPLPIG RDKVELEVTL PGEGKDRIFK VSIKWVSCVS LQALHDALSG RLPSVPFETI QALDVVMRHL PSMRYTPVGR SFFTASEGCS NPLGGGREVW FGFHQSVRPS LWKMMLNIDV SATAFYKAQP VIEFVCEVLD FKSIEEQQKP LTDSQRVKFT KEIKGLKVEI THCGQMKRKY RVCNVTRRPA SHQTFPLQQE SGQTVECTVA QYFKDRHKLV LRYPHLPCLQ VGQEQKHTYL PLEVCNIVAG QRCIKKLTDN QTSTMIRATA RSAPDRQEEI SKLMRSASFN TDPYVREFGI MVKDEMTDVT GRVLQPPSIL YGGRNKAIAT PVQGVWDMRN KQFHTGIEIK VWAIACFAPQ RQCTEVHLKS FTEQLRKISR DAGMPIQGQP CFCKYAQGAD SVEPMFRHLK NTYAGLQLVV VILPGKTPVY AEVKRVGDTV LGMATQCVQM KNVQRTTPQT LSNLCLKINV KLGGVNNILL PQGRPPVFQQ PVIFLGADVT HPPAGDGKKP SIAAVVGSMD AHPNRYCATV RVQQHRQEII QDLAAMVREL LIQFYKSTRF KPTRIIFYRD GVSEGQFQQV LHHELLAIRE ACIKLEKEYQ PGITFIVVQK RHHTRLFCTD KNERVGKSGN IPAGTTVDTK ITHPTEFDFY LCSHAGIQGT SRPSHYHVLW DDNRFSSDEL QILTYQLCHT YVRCTRSVSI PAPAYYAHLV AFRARYHLVD KEHDSAEGSH TSGQSNGRDH QALAKAVQVH QDTLRTMYFA //