Advisory board member Prof. Piton published a new study on the effects of AGO1 mutations in worms with Prof. Ambros & Prof. Zinovyeva. It shows that some Argonaute syndrome mutations affect Argonaute functionality more adversely than the complete loss of Argonaute itself.
Argonaute proteins are essential cofactors to tiny RNAs called microRNAs. Argonautes and microRNAs work together to regulate gene expression. Because Argonautes are central to this critical gene regulatory pathway, they are incredibly well-conserved throughout the evolutionary tree. To understand how Argonaute syndrome-causing mutations might affect the function of an Argonaute protein, Duan, Li, and colleagues took advantage of this conservation. They engineered some of the Argonaute syndrome mutations into an Argonaute protein of an experimental model animal, C. elegans, which allowed them to rapidly assess how these mutations impact the molecular functions of an Argonaute protein (Duan et al., 2023).
One significant new finding from this research is that some Argonaute syndrome mutations affect Argonaute functionality more adversely than the complete loss of Argonaute itself. This adverse impact is due to the mutant Argonautes’ isolation of gene-regulatory microRNAs away from other functional Argonautes. This insight may explain why single nucleotide mutations, rather than loss of Argonaute, have been documented as causative for Argonaute syndromes.
In addition, this work identified several molecular functions of Argonaute proteins differently affected by the modeled mutations. For example, some mutations resulted in mutant Argonautes inappropriately interacting with microRNA strands they do not typically interact with. All modeled mutations affected some aspect of Argonaute interaction with microRNAs or the ability of the protein to perform their essential job of gene repression. The research also identified subregions of the Argonaute protein necessary for its function. This finding can guide the prioritization of future structural studies.
Overall, the modeled mutations broadly disrupted gene expression regulation, with research showing how disruption of gene expression by the Argonaute mutations may lead to disease pathology.