Exploring the RNA‐bound and RNA‐free human Argonaute‐2 by molecular dynamics simulation method

Kong, Ren; Xu, Lei; Piao, Lianhua; Zhang, Dawei; Hou, Tingjun; Chang, Shan

doi:10.1111/cbdd.12997

Cited by 10 publications

(11 citation statements)

References 46 publications

(89 reference statements)

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“…The movements of the PAZ domain and helix-7 towards the opposing AGO2 lobe (MID and PIWI domains) are concerted ( Fig. 4c, gray histogram in the background), corroborating previous suggestions 22,32 .…”

Section: Ago2 Germline Mutations Impair Shrna-mediated Silencingsupporting

confidence: 90%

Germline AGO2 mutations impair RNA interference and human neurological development

et al. 2020

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ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.

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Section: Ago2 Germline Mutations Impair Shrna-mediated Silencingsupporting

confidence: 90%

Germline AGO2 mutations impair RNA interference and human neurological development

et al. 2020

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“…Human Ago2 bonded to miRNA has a bilobed architecture, with the guide miRNA threaded through a central cleft formed by the N-PAZ and MID-PIWI domains. Multitude interactions within this tight binding pocket were identified, involving mainly residues of the MID domain capped on the 5' side by PIWI domain residues (Elkayam et al, 2012;Kong et al, 2017). There, the target mRNA has access to mate with the miRNA and is cleaved by a RNAase H fold comprised by the Asp-Asp-His (DDH) triad in the PIWI domain (Tolia and Joshua-Tor, 2007).…”

Section: Small Rna Binding and Catalytic Amino Acids Conservation In Flagos And Fliwismentioning

confidence: 99%

Lost and Found: Piwi and Argonaute Pathways in Flatworms

Fontenla

Rinaldi

Tort

2021

Front. Cell. Infect. Microbiol.

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Platyhelminthes comprise one of the major phyla of invertebrate animals, inhabiting a wide range of ecosystems, and one of the most successful in adapting to parasitic life. Small non-coding RNAs have been implicated in regulating complex developmental transitions in model parasitic species. Notably, parasitic flatworms have lost Piwi RNA pathways but gained a novel Argonaute gene. Herein, we analyzed, contrasted and compared the conservation of small RNA pathways among several free-living species (a paraphyletic group traditionally known as ‘turbellarians’) and parasitic species (organized in the monophyletic clade Neodermata) to disentangle possible adaptations during the transition to parasitism. Our findings showed that complete miRNA and RNAi pathways are present in all analyzed free-living flatworms. Remarkably, whilst all ‘turbellarians’ have Piwi proteins, these were lost in parasitic Neodermantans. Moreover, two clusters of Piwi class Argonaute genes are present in all ‘turbellarians’. Interestingly, we identified a divergent Piwi class Argonaute in free living flatworms exclusively, which we named ‘Fliwi’. In addition, other key proteins of the Piwi pathways were conserved in ‘turbellarians’, while none of them were detected in Neodermatans. Besides Piwi and the canonical Argonaute proteins, a flatworm-specific class of Argonautes (FL-Ago) was identified in the analyzed species confirming its ancestrallity to all Platyhelminthes. Remarkably, this clade was expanded in parasitic Neodermatans, but not in free-living species. These phyla-specific Argonautes showed lower sequence conservation compared to other Argonaute proteins, suggesting that they might have been subjected to high evolutionary rates. However, key residues involved in the interaction with the small RNA and mRNA cleavage in the canonical Argonautes were more conserved in the FL-Agos than in the Piwi Argonautes. Whether this is related to specialized functions and adaptations to parasitism in Neodermatans remains unclear. In conclusion, differences detected in gene conservation, sequence and structure of the Argonaute family suggest tentative biological and evolutionary diversifications that are unique to Platyhelminthes. The remarkable divergencies in the small RNA pathways between free-living and parasitic flatworms indicate that they may have been involved in the adaptation to parasitism of Neodermatans.

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“…The 5ʹ end of the small RNA binds to the MID domain and its 3ʹ end to the PAZ domain [97,99], the most mobile domain of the protein [100]. Tryptophan-binding pockets in the PIWI domain are the likely recognition sites for GW-motif proteins [98].…”

Section: The Structures Of Argonaute and The Rits Complexmentioning

confidence: 99%

RNA-induced initiation of transcriptional silencing (RITS) complex structure and function

2019

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Heterochromatic regions of the genome are epigenetically regulated to maintain a heritable '"silent state"'. In fission yeast and other organisms, epigenetic silencing is guided by nascent transcripts, which are targeted by the RNA interference pathway. The key effector complex of the RNA interference pathway consists of small interfering RNA molecules (siRNAs) associated with Argonaute, assembled into the RNA-induced transcriptional silencing (RITS) complex. This review focuses on our current understanding of how RITS promotes heterochromatin formation, and in particular on the role of Argonaute-containing complexes in many other functions such as quelling, release of RNA polymerases, cellular quiescence and genome defense.

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Exploring the RNA‐bound and RNA‐free human Argonaute‐2 by molecular dynamics simulation method

Cited by 10 publications

References 46 publications

Germline AGO2 mutations impair RNA interference and human neurological development

Germline AGO2 mutations impair RNA interference and human neurological development

Lost and Found: Piwi and Argonaute Pathways in Flatworms

RNA-induced initiation of transcriptional silencing (RITS) complex structure and function

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