Protein argonaute-2 (AGO2)
The protein contains 859 amino acids for an estimated molecular weight of 97208 Da.
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. Bind (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Epidermal growth factor receptor signaling pathway
Fc-epsilon receptor signaling pathway
Fibroblast growth factor receptor signaling pathway
Gene expression
Gene silencing by RNA
Innate immune response
Intracellular receptor signaling pathway
MiRNA loading onto RISC involved in gene silencing by miRNA
MiRNA mediated inhibition of translation
MiRNA metabolic process
MRNA cleavage involved in gene silencing by miRNA
MRNA cleavage involved in gene silencing by siRNA
Negative regulation of amyloid precursor protein biosynthetic process
Negative regulation of gene expression
Negative regulation of translational initiation
Neurotrophin TRK receptor signaling pathway
Notch signaling pathway
Phosphatidylinositol-mediated signaling
Positive regulation of angiogenesis
Positive regulation of gene expression
Positive regulation of miRNA mediated inhibition of translation
Positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay
Positive regulation of nuclear-transcribed mRNA poly(A) tail shortening
Positive regulation of transcription by RNA polymerase II
Positive regulation of translation, ncRNA-mediated
Positive regulation of trophoblast cell migration
Post-embryonic development
Post-transcriptional gene silencing by RNA
Posttranscriptional gene silencing
Pre-miRNA processing
Production of miRNAs involved in gene silencing by miRNA
Production of siRNA involved in RNA interference
Regulation of gene silencing by miRNA
Regulation of transcription, DNA-templated
RNA phosphodiester bond hydrolysis, endonucleolytic
RNA secondary structure unwinding
SiRNA loading onto RISC involved in RNA interference
Transcription, DNA-templated
Translation
Translational initiation
Wnt signaling pathway, calcium modulating pathway
Cellular Component
Cell junction
Cytoplasm
Cytoplasmic ribonucleoprotein granule
Cytosol
Dendrite
Extracellular exosome
Intracellular ribonucleoprotein complex
Membrane
Micro-ribonucleoprotein complex
MRNA cap binding complex
Nucleoplasm
Nucleus
P-body
Polysome
Ribonucleoprotein complex
RISC complex
RISC-loading complex
Molecular Function
Core promoter binding
Core promoter sequence-specific DNA binding
Double-stranded RNA binding
Endoribonuclease activity
Endoribonuclease activity, cleaving miRNA-paired mRNA
Endoribonuclease activity, cleaving siRNA-paired mRNA
Metal ion binding
MiRNA binding
MRNA binding
MRNA cap binding
Poly(A) RNA binding
Pre-miRNA binding
Protein C-terminus binding
RNA 7-methylguanosine cap binding
RNA binding
RNA polymerase II complex binding
Single-stranded RNA binding
SiRNA binding
Translation initiation factor activity
The reference OMIM entry for this protein is 606229
Eukaryotic translation initiation factor 2c, subunit 2; eif2c2
Argonaute 2; ago2
DESCRIPTION
Binding of microRNA (miRNA) to mRNA within the RNA-induced silencing complex (RISC) leads to either translational inhibition or destruction of the target mRNA. EIF2C2, or Argonaute-2, is a core RISC component that has both mRNA inhibition and degradation functions (summary by O'Carroll et al., 2007).CLONING
In the course of cloning EIF2C1 (606228), Koesters et al. (1999) isolated a crosshybridizing cDNA that represented EIF2C2, a gene very similar to EIF2C1. The EIF2C2 gene encodes a protein of 833 amino acids. EIF2C2 and EIF2C1 share 85% amino acid identity. Northern blot analysis detected an mRNA of 11 to 12 kb. Kiriakidou et al. (2007) reported that human AGO2 contains 859 amino acids and has an N-terminal PAZ domain, a middle (MID) domain, and a large C-terminal PIWI domain. The PIWI domain is predicted to adopt an RNase H fold and catalyze miRNA-directed mRNA degradation. Kiriakidou et al. (2007) found that a portion of the MID domain, which they called the MC domain, shares significant similarity with the 7-methylguanosine (m7G) cap-binding domain of EIF4E (133440). The MC domain is conserved in all mammalian Ago proteins and in some Agos from lower vertebrates and invertebrates, including Drosophila Ago1 (EIF2C1), but not Drosophila Ago2.GENE FUNCTION
GEMIN3 (DDX20; 606168) is a DEAD box RNA helicase that binds to the SMN (600354) protein and is a component of the SMN complex, which also contains GEMIN2 (602595), GEMIN4 (606969), GEMIN5 (607005), and GEMIN6 (607006). Mourelatos et al. (2002) reported that GEMIN3 and GEMIN4 are also in a separate complex that contains EIF2C2, a member of the argonaute protein family. This novel complex is a large, approximately 15S RNP that contains numerous microRNAs, a class of small endogenous RNAs. Martinez et al. (2002) demonstrated that a single-stranded small interfering RNA (siRNA) resides in human RISC together with the EIF2C1 and/or EIF2C2 proteins. RISC could be rapidly formed in HeLa cell cytoplasmic extract supplemented with 21-nucleotide siRNA duplexes, but also by adding single-stranded antisense RNAs, which range in size between 19 and 29 nucleotides. RISC-bound small RNA guides the RISC complex to identify and cleave mRNAs with complementary sequences. Rand et al. (2004) showed that Ago2 was the only protein component in the purified functional Drosophila RISC complex. They found an endonuclease V-like domain in Ago2 and identified 3 residues within this domain as potential magnesium-coordinating residues at the catalytic center of Ago2 nuclease. AU-rich elements (AREs) in the 3-prime UTRs of unstable mRNAs dictate their degradation. Using an RNA interference (RNAi)-based screen in Drosophila S2 cells, Jing et al. (2005) found that Dicer-1 (606241), Ago1 (606228), and Ago2, components involved in microRNA (miRNA) processing and function, were required for rapid decay of mRNA containing AREs of tumor necrosis factor-alpha (TNF; 191160). The requirement for Dicer in the instability of ARE-containing mRNA (ARE-RNA) was confirmed in HeLa cells. Jing et al. (2005) showed that miRNA16 (miR16), a human miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, was required for ARE-RNA turnover. The role of miR16 in ARE-RNA decay was sequence-specific and required the ARE-binding protein tristetraprolin (TTP, or ZFP36; 190700). TTP did not directly bind miR16, but interacted through association with Ago/EIF2C family memb ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606229 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed