IBS and Seoul National University reveal how a key gene-regulating protein is activated, offering a new direction for RNA drug design

Kim Vicki Narry, director of the RNA Research Center at the Institute for Basic Science. [IBS]
Kim Vicki Narry, director of the RNA Research Center at the Institute for Basic Science. [IBS]

Korean researchers have uncovered the assembly mechanism behind a protein that regulates gene expression, opening the door to more precise RNA therapies for hard-to-treat conditions — including metabolic diseases and Alzheimer's — caused by the overactivation of specific genes.

The Ministry of Science and ICT announced Wednesday that a joint research team led by Kim Vicki Narry, director of the RNA Research Center at the Institute for Basic Science (IBS), and Noh Sung-hoon, a professor in the Department of Biological Sciences at Seoul National University, has for the first time mapped the activation process of Argonaute, a protein that controls gene expression.

Argonaute is a protein that identifies and eliminates unwanted genetic information inside human cells. It binds to microRNA (miRNA) carrying the target information, then tracks down and degrades the corresponding messenger RNA (mRNA).

The findings, supported by the Ministry of Science and ICT, were published Wednesday in Nature.

Cells contain microRNA, which suppresses excessive gene expression to maintain the body's balance. For miRNA to suppress gene expression inside a cell, it must first bind with Argonaute to form a protein-RNA complex known as RISC.

Until now, however, the process by which miRNA binds with Argonaute and becomes active had never been explained — a gap that had limited progress in RNA drug development.

To directly observe how Argonaute acquires its gene-regulating activity, the research team became the first in the world to isolate and purify an Argonaute complex bound to a chaperone protein. The team then used cryo-electron microscopy to analyze the complex's structure at the atomic level.

The process by which Argonaute acquires its ability to suppress target genes. [IBS]
The process by which Argonaute acquires its ability to suppress target genes. [IBS]

The analysis showed that the chaperone holds Argonaute in a fully open configuration, creating space for miRNA to enter. Once miRNA binds in that space, the chaperone detaches and Argonaute folds into a closed, active form capable of regulating genes.

The team also reproduced the binding process in a test tube to verify the mechanism. The fully assembled Argonaute complex performed normally, accurately cleaving its target mRNA.

The researchers further confirmed that Argonaute functions stably only when double-stranded miRNA — its natural form inside cells — is present. When miRNA was absent or in single-stranded form, the correct structure did not form.

The team established that miRNA is not simply a binding partner for Argonaute but a critical factor that guides the protein into its proper structure. The finding shows that miRNA plays a direct role in protein assembly, beyond its known function of carrying gene-regulatory information.

The results have direct implications for the design of siRNA therapeutics — artificially synthesized miRNA that selectively blocks specific genes to prevent disease-causing proteins from being produced — a field that has long relied heavily on trial and error.

"This provides a molecular and theoretical basis for RNA drug design that has until now depended on trial and error," Kim said. "We expect it can be used to improve the efficiency of next-generation siRNA therapeutic design and applied to the treatment of a wide range of diseases, including genetic metabolic disorders."


nbgkoo@heraldcorp.com