The Birth of the Gene Hunter 'Argonaute' Captured... V. Narry Kim's Team First Reveals Activation Principle [Reading Science]

IBS and Seoul National University Unveil, for the First Time, the Activation Principle of a Key Protein in Gene Regulation
Providing Molecular Evidence to Enhance the Precision of RNA Therapeutic Design

Argonaute, the "gene hunter" inside cells, identifies and silences genes responsible for Alzheimer's disease and metabolic disorders. The research team led by V. Narry Kim at the RNA Research Center of the Institute for Basic Science (IBS) was the first in the world to uncover the process by which this protein is formed and activated.

By solving a key piece of the gene regulation mechanism that had remained shrouded in mystery for decades, a new phase is now expected in the development of next-generation RNA therapeutics. RNA therapeutics are new drugs that selectively inhibit the activity of disease-causing genes. They are attracting attention as next-generation treatments for Alzheimer's, rare diseases, and metabolic disorders.

The process through which Argonaute acquires target gene repression function. Argonaute (AGO) is a protein that suppresses the activity of specific genes (mRNA) using microRNA (miRNA). The research team discovered that chaperone proteins maintain Argonaute in an open state, creating space for double-stranded miRNA to enter. After the miRNA binds, the chaperone detaches, activating Argonaute. The activated Argonaute then uses the selected miRNA to locate target genes and suppress their expression. Provided by the research team

On June 11, the Ministry of Science and ICT announced that the joint research team led by V. Narry Kim of the IBS RNA Research Center and Professor Sunghoon Noh of the Department of Biological Sciences at Seoul National University has, for the first time globally, revealed the activation principle of Argonaute, a key protein that regulates gene expression.

This research was published on the same day in the international journal Nature.

Argonaute is the core component of the "RNA-induced silencing complex (RISC)," which binds to microRNA (miRNA) inside cells to suppress the activity of specific genes. It is responsible for removing unnecessary genetic information from the cell or inhibiting the excessive expression of certain genes.

Although a variety of RNA therapeutics currently utilize this mechanism, the processes by which Argonaute is formed and activated had not yet been elucidated. This is why much of the RNA therapeutic development process has relied heavily on trial and error.

To directly observe how Argonaute acquires its function, the researchers were the first in the world to isolate and purify a complex of Argonaute bound to a chaperone protein that aids in its structural formation. They then analyzed its structure at the atomic level using cryo-electron microscopy (Cryo-EM).

The results showed that the chaperone maintains Argonaute in a fully open state, creating space for microRNA to enter. When microRNA binds, the chaperone detaches, and Argonaute is completed in a closed conformation capable of performing gene regulation functions.

The researchers also succeeded in fully reproducing this process in vitro. The completed Argonaute complex accurately located and cleaved the target gene (mRNA).

In particular, the team confirmed that Argonaute assembles stably only in the presence of its original cellular form, "double-stranded" microRNA. Previously, microRNA was thought to serve only as a messenger of gene regulatory information, but this study revealed that it is also a crucial element directly involved in the protein assembly process.

A New Phase for RNA Therapeutics: First Identification of Design Principles

The researchers also systematically analyzed which RNAs are most efficiently loaded onto Argonaute.

They found that the chemical properties of RNA, its double-helical structure, and a length of 20 to 24 nucleotides are essential for the proper assembly and functional expression of Argonaute. They also clarified how the chemical modifications of siRNA therapeutics currently used in clinical settings affect Argonaute formation.

This study is significant in that it provides molecular-level design principles for RNA therapeutic development, which had previously depended on experience and trial and error. It is expected to contribute to improving the efficacy and safety of RNA therapeutics targeting Alzheimer's disease, metabolic disorders, and rare diseases in the future.

V. Narry Kim, Director of the IBS RNA Research Center, said, "This achievement provides molecular and theoretical grounds for the design of RNA therapeutics, which had previously relied on trial and error, and could lead to the development of more efficient and safer siRNA therapeutics."

Professor Sunghoon Noh of Seoul National University commented, "It is significant that we directly observed the process by which the protein acquires its function, rather than just the completed protein structure. By elucidating the principles of protein assembly, we have presented a new perspective on understanding biological phenomena."

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