Nuclear pore complexes (NPCs) serve as essential gatekeepers that regulate the exchange of materials between a cell”s nucleus and its cytoplasm by swiftly selecting which molecules to transport across the nuclear membrane. Their importance is underscored by their involvement in critical cellular processes, with malfunctions in this transport system being linked to various diseases, particularly neurodegenerative disorders. The mechanisms by which NPCs make rapid decisions regarding molecular passage have long been a subject of scientific intrigue. Researchers from The Rockefeller University, in collaboration with an international team led by the Hebrew University of Jerusalem, have now presented the most comprehensive understanding of macromolecular transport through NPCs to date. This research, published in Proceedings of the National Academy of Sciences (PNAS), paves the way for potential medical and biotechnological advancements.
According to Michael P. Rout, head of the Laboratory of Cellular and Structural Biology at The Rockefeller University, “We can now model genetic or pharmacological perturbations and then experimentally test the most promising ones.” This progress enables the exploration of the molecular underpinnings of various NPC-related genetic disorders and the evaluation of therapeutics aimed at NPCs. Barak Raveh, the lead author from the Hebrew University of Jerusalem, notes that while each NPC is remarkably small—about one five-hundredth the width of a human hair—it facilitates millions of molecular transports per minute while effectively filtering out non-essential molecules.
The longstanding question of how NPCs rapidly distinguish between molecules of different sizes, purposes, and complexities has remained largely unanswered, primarily due to the challenges associated with observing these diminutive structures directly. Previous models conceptualized NPCs as mechanical gates or cohesive hydrogels with fixed pore sizes. However, these interpretations failed to align with the NPC”s intricate composition and architecture, as well as its capabilities for rapid, adaptable, and reversible transport, including the passage of large molecular entities.
In their study, the researchers integrated years of fragmented experimental findings and theoretical insights into a cohesive computational framework, elucidating molecular events occurring at timescales as brief as a few thousandths of a second. This comprehensive approach revealed ten essential molecular features that collectively enhance the NPC”s efficiency and resilience. A pivotal aspect of this mechanism is a dense array of flexible protein chains known as FG repeats that populate the pore”s interior. These dynamic structures create openings that fluctuate rapidly, allowing smaller molecules to traverse the pore while larger molecules gain entry only when escorted by specific nuclear transport receptors. These specialized carriers navigate smoothly through the crowded protein landscape, enabling the transport of their cargo.
The model”s redundancy and heightened sensitivity contribute to its robustness and fine-tuning capabilities. As Rout explains, “The transport mechanism can be imagined as a vast, ever-shifting dance across a bridge.” The FG repeats form a lively crowd that permits only those with suitable partners—the nuclear transport receptors—to cross. Without these escorts, larger molecules remain stranded, unable to proceed.
This computational model has been validated against multiple independent datasets, accurately predicting previously unobserved transport behaviors. It has also demonstrated how transient interactions between transport receptors and FG repeats significantly enhance transport efficiency, facilitating the movement of substantial cargoes like ribosomal subunits or viral particles. The implications of this model extend beyond basic science; it offers insights into diseases such as cancer, Alzheimer”s, and amyotrophic lateral sclerosis (ALS), which arise from failures in this transport system. Moreover, it could serve as a foundational design for artificial nanopores—synthetic analogs of NPCs—offering transformative possibilities in biotechnology, including targeted drug delivery and biosensing technologies.
Rout concludes, “Because NPCs are situated at the intersection of crucial cellular systems like transcription, translation, and the cell cycle, we can now start to model how these systems interact, potentially leading to whole-cell modeling.” However, he emphasizes that this marks just the beginning, as significant unknowns about the molecular intricacies of nuclear transport remain, prompting further investigation into the specific roles of different FG nucleoporins and the precise pathways for cargo transport.
