Researchers from Hebrew University of Jerusalem and several American institutions have unveiled the mechanisms behind nuclear pore complexes (NPCs), tiny gateways in human cells that regulate the movement of molecules into and out of the cell nucleus. This breakthrough could enhance our understanding of diseases such as cancer, Alzheimer”s, and amyotrophic lateral sclerosis (ALS), as announced on October 23, 2023.
The collaborative effort involved scientists from the Quantitative Biosciences Institute at the University of California, San Francisco, The Rockefeller University, and Albert Einstein College of Medicine. Their findings suggest that these microscopic structures, which are roughly one five-hundredth the width of a human hair, utilize a dynamic protein network and specialized molecular “passports” for efficient transport.
According to the study”s lead author, Dr. Barak Raveh, the model developed by the team functions as a “virtual microscope,” allowing them to visualize the operations of NPCs at a molecular level. “By integrating numerous independent experiments with computer simulations, we can observe how this gate functions in real-time,” he stated.
Dr. Raveh likened NPCs to advanced security checkpoints, emphasizing their efficiency. “Each checkpoint is minuscule, yet they permit millions of molecules to pass every minute while maintaining a high degree of selectivity,” he noted.
For many years, the duality of speed and selectivity in NPCs remained a mystery, largely due to their size, which made direct observation challenging. Previous theories proposed either rigid gates or sponge-like barriers but failed to clarify how large molecules could efficiently traverse these structures while smaller ones were excluded.
The new model merges experimental insights with computational analysis, revealing the molecular interactions occurring within NPCs in milliseconds. The interior of an NPC is filled with a dense array of protein chains known as FG repeats, which create a congested space that naturally hinders unaccompanied molecules while allowing smaller ones to pass. Large molecules can navigate through NPCs, but only when escorted by nuclear transport receptors—these receptors serve as molecular passports that interact with the FG chains to facilitate transport.
Professor Michael Rout from The Rockefeller University elaborated on this mechanism, stating, “The transport resembles a constantly shifting dance across a bridge. Only those with the appropriate partners, the receptors, can cross. Others are turned away.” This insight resolves a long-standing question about how NPCs can permit large molecular complexes while blocking smaller entities.
Professor Andrej Sali of the Quantitative Biosciences Institute remarked, “Our model offers the first clear explanation of the remarkable selectivity exhibited by NPCs. This discovery paves the way for new advancements in medicine and biotechnology.”
Furthermore, Professor David Cowburn from Albert Einstein College of Medicine emphasized the implications of these findings for diseases related to nuclear transport disruptions. The knowledge gained may inform the development of drugs designed to manipulate molecular traffic within cells or the creation of synthetic nanopores that replicate NPC functions, directly targeting the nucleus for treatment delivery.
The research has successfully predicted transport behaviors that had not been previously observed and demonstrated that brief interactions between receptors and FG chains enhance the system”s efficiency. This built-in redundancy contributes to the reliability of NPCs, explaining their evolutionary success. The full study is published in the peer-reviewed journal Proceedings of the National Academy of Sciences.
