Nuclear pore complexes (NPCs) serve as crucial gatekeepers that regulate the movement of materials between a cell”s nucleus and cytoplasm, rapidly determining which molecules can pass through the nuclear membrane. Despite their importance in various cellular functions, the mechanisms by which NPCs operate have largely been a mystery. Recently, a team of researchers from The Rockefeller University and the Hebrew University of Jerusalem, among other institutions, have developed the most comprehensive model to date that elucidates how NPCs manage macromolecular transport. Their findings, published in Proceedings of the National Academy of Sciences (PNAS), open new pathways for advancements in medicine and biotechnology.
“We can now model genetic or pharmacological perturbations and then experimentally test the most promising ones,” stated Michael P. Rout, head of Rockefeller”s Laboratory of Cellular and Structural Biology. His team has dedicated decades to studying NPCs. “For instance, we can explore the molecular foundations of various NPC-related genetic disorders and evaluate therapies that target these complexes.”
Researchers have long recognized that the flow of materials facilitated by NPCs is a highly selective and swift process. Each NPC, despite being roughly one five-hundredth the width of a human hair, can permit millions of molecules to pass through each minute while effectively filtering out others. “Understanding how NPCs can rapidly distinguish between molecules of various sizes and functions has been challenging, primarily due to their minuscule size, which makes direct observation difficult,” explained Barak Raveh, the lead author from the Hebrew University of Jerusalem.
Previous models depicted NPCs as mechanical gates or as fixed-size sieves formed by cohesive hydrogels. However, these interpretations failed to account for the NPC”s complex structure and functionality, particularly its speed and adaptability. To address this, the researchers synthesized years of fragmented experimental data and theoretical insights into a cohesive computational framework, mapping out molecular interactions occurring in less than a second.
This integrated method revealed ten critical design features that contribute to the NPC”s remarkable efficiency and resilience. Central to this process is a dense, dynamic arrangement of flexible protein chains known as FG repeats, which fill the interior of the pore. Openings within this lively configuration emerge and vanish rapidly, enabling small molecules to traverse the pore. Conversely, larger molecules can only pass when escorted by nuclear transport receptors, specialized proteins that navigate through the dense protein chains, facilitating the movement of their cargo.
The model demonstrated that the NPC”s transport mechanism resembles a dynamic dance across a bridge, allowing only those accompanied by the right partners—the nuclear transport receptors—to cross. Those that lack these partners are blocked from entry. This computational model, validated against several independent datasets, effectively predicted previously unrecorded transport behaviors and illustrated how transient interactions between transport receptors and FG repeats enhance efficiency, enabling the transport of large structures like ribosomal subunits and viral particles.
Furthermore, the model provides crucial insights into diseases that arise when this transport system fails, such as cancer and neurodegenerative disorders like Alzheimer”s and ALS. It also serves as a potential blueprint for the engineering of synthetic nanopores, which could transform biotechnology applications, including targeted drug delivery and biosensing. “Given that NPCs are pivotal to critical cellular processes such as transcription and translation, we are now positioned to model how these systems interact, potentially paving the way towards comprehensive cellular modeling,” Rout noted. However, he acknowledged that significant unknowns remain regarding the molecular intricacies of nuclear transport, emphasizing the need for further investigation into the specific roles of different FG nucleoporins and cargo pathways.
