Argonautic proteins

Argonaute proteins, or argonaute proteins for short, is the name of a protein family whose representatives are highly conserved in evolutionary terms. Representatives of this protein family are involved in RNA interference reactions (RNAi), microRNA-induced mRNA degradation and post-transcriptional gene silencing (PTGS). Pathogenic variants in genes encoding two of the Argonaute proteins, AGO1 and AGO2, have been identified as the cause of rare neurodevelopmental disorders characterized by delayed motor development, seizures, language and comprehension problems, and cognitive impairment. AGO3 and AGO4 are associated with cartilage-hair hypoplasia (CHH/ OMIM:250250/Orphanet:ORPHA175).

Argonaute proteins are approximately 100 kDa large, predominantly basic proteins consisting of the subunits PAZ and PIWI. The PAZ domain consists of 130 amino acids and can also be found in the protein Dicer. It binds the targeting si/miRNA and may also serve as a protein-protein interaction domain for the endonuclease Dicer. The C-terminal PIWI domain has the Mn2+ dependent endonuclease activity against the substrate mRNA to be cut. Argonaute proteins are divided into three classes based on similarities in the protein sequence:

• Argonaute-like proteins: similar to the Arabidopsis thaliana protein AGO1
• PIWI-like proteins: similar to PIWI protein from Drosophila melanogaster (AGO2)
• Group 3 Argonaute proteins: recently discovered group of Argonaute proteins in Caenorhabditis elegans

Humans possess four AGO proteins, AGO1, AGO2, AGO3 and AGO4, which are encoded by the genes of the same name(AGO1 gene, AGO2 gene, AGO3 gene, AGO4 gene. The Argonaute proteins show a high degree of sequence identity (Nakanishi K 2022). In Caenorhabditis elegans there are even up to 27 proteins.

It was initially assumed that the 4 argonate proteins work redundantly. In this respect, AGO2 was intensively studied as a human AGO paralog. It is now believed that the other paralogs play a unique role in various biological processes and diseases.

During mRNA silencing of genes, a small RNAi binds to the different Argonaute proteins (Rand TA et al. 2004) and is thus part of the so-called RNA-induced silencing complex(RISC). The small RNA bound to the RISC directs the RISC complex to identify and cleave mRNAs with complementary sequences. There is homology between the PIWI domain of Ago-2 and endonuclease V and identified potential active site amino acid residues within the PIWI domain of Ago-2 (Rand TA et al. 2004).

Depending on the system studied, Argonaute proteins also form complexes with DICER. DICER, TRBP and can also be present as a protein complex of RISC.

An Argonaut is a member of a legendary group of heroes from Greek mythology who sailed on the Argo in search of the golden fleece. The most famous Argonaut is Jason.

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