Argonaute Proteins: From Structure to Function in Development and Pathological Cell Fate Determination

Abstract

The highly conserved Argonaute protein family members play a central role in the regulation of gene expression networks, orchestrating the establishment and the maintenance of cell identity throughout the entire life cycle, as well as in several human disorders, including cancers. Four functional Argonaute proteins (AGO1-4), with high structure similarity, have been described in humans and mice. Interestingly, only AGO2 is robustly expressed during human and mouse early development, in contrast to the other AGOs. Consequently, AGO2 is indispensable for early development in vivo and in vitro. Here, we review the roles of Argonaute proteins during early development by focusing on the interplay between specific domains of the protein and their function. Moreover, we report recent works highlighting the importance of AGO posttranslational modifications in cancer.

RNA packaging into extracellular vesicles: An orchestra of RNA‐binding proteins?

“…Argonaute proteins constitute an evolutionarily conserved protein family, including two subclasses: AGO proteins and PIWI proteins. These proteins can bind to small non‐coding RNAs, such as shRNAs, miRNAs, and Piwi‐interacting RNAs (piRNAs), mediating gene‐silencing effects on their RNA targets (Elkayam et al., 2012; Höck & Meister, 2008; Müller et al., 2020). In humans, four AGO proteins (hAGO1 ‐ 4) are highly expressed and share ∼85% of sequence identity with four conserved structural domains: The N‐terminal domain (N), the PIWI/Argonaute/Zwille (PAZ) domain, the MID domain, and the P‐element‐induced wimpy testis (PIWI) domain (Höck & Meister, 2008; Meister, 2013).…”

“…Moreover, AGO proteins can interact with GW182 protein family (also known as TNRC6 proteins), which recruits AGOs to target RNAs (Meister, 2013). At this point, AGO proteins can coordinate the RNA inducing silencing processes by repressing the target mRNA through RNA degradation or translation inhibition (Höck & Meister, 2008; Müller et al., 2020). AGO proteins have also been found involved in alternative splicing and DNA double‐strand break repair mechanisms (Meister, 2013; Müller et al., 2020) in cancer (Ye et al., 2015) or other diseases like diabetes (Florijn et al., 2019).…”

“…confirmed the association of AGO2 with MVBs in colon cancer cells and demonstrated that the activation of KRAS‐dependent MEK‐ERK signalling was able to hamper the sorting of AGO2 and AGO2‐regulated miRNAs inside extracellular vesicles (Gibbings et al., 2009). AGO2 protein is highly subjected to post‐translational modifications, such as phosphorylation, which influences its cellular localization (Müller et al., 2020). McKenzie et al.…”

A computational approach to design potential siRNA molecules as a prospective tool for silencing nucleocapsid phosphoprotein and surface glycoprotein gene of SARS-CoV-2

“…The resultant docking complexes were downloaded from the server and inspected manually to identify best docked complex based on docking score, visual similarity of the complex with 4z4d structural composite and placement of siRNA inside PAZ domain and MID domain of the Ago2. Such criteria were enforced to reduce the spurious results and identify the complex that is most similar to experimental evidence [ 64 ].…”

“…In order to exert the silencing function, the 5′ and 3′ ends of the siRNA need to be anchored in the MID and PAZ domain of the Argonaute protein respectively [ 64 ], although there is a room for flexibility in PAZ domain due to its dynamic nature [ 65 , 66 ]. On the other hand, strong binding of siRNA with Ago2, especially PAZ domain, corresponds to weaker nuclease/RNAi activity [ 67 ].…”