AGO2

Ago2, also known as Argonaute-2, is a protein encoded by the AGO2 gene in humans. It is a core component of the RNA-induced silencing complex (RISC) and plays a central role in RNA interference and microRNA (miRNA)-mediated gene silencing. Among human Argonaute proteins, Ago2 is unique for retaining slicer or endonuclease activity, enabling direct cleavage of target RNA in cases of near-perfect complementarity with a guiding small RNA.

Structurally, Ago2 contains conserved domains essential for small RNA binding and catalytic function, including PAZ, MID, and PIWI domains. The PAZ domain binds the 3′ end of the small RNA, the MID domain anchors the 5′ phosphate, and the PIWI domain provides the RNase H–like catalytic activity that can cleave target mRNAs. After loading a small RNA (siRNA or miRNA), Ago2 guides the RISC to complementary messenger RNA; if the pairing is sufficiently perfect, the PIWI domain cleaves the mRNA, leading to gene silencing. In many contexts, Ago2 also participates in silencing pathways that repress translation or promote mRNA deadenylation without direct cleavage, often in conjunction with other proteins such as GW182/TNRC6.

Ago2 is broadly expressed and essential for efficient RNA interference in mammals. While miRNA-mediated silencing frequently occurs without Ago2-mediated slicing, Ago2 remains the primary catalytic Argonaute in contexts requiring endonucleolytic cleavage. Dysregulation of Ago2 and the RNAi pathway has been investigated in various diseases, including cancer, and Ago2 is a key focus in research on therapeutic RNAi approaches.