Protecting the headquarters of genetic information within the cell was a mechanism that provided an evolutionary advantage millions of years ago and established the nucleus as the principal organelle for eukaryotic cells. However, this scenario created the problem of how to transport molecules, often very large ones, across the newly evolved rampart. As it always does, evolution found a way through with the creation of the nuclear pore complex (NPC).
Now, researchers at Rockefeller University have uncovered mechanisms for the molecular orchestration that dilates and constricts the nuclear pore complex—adding to the continued efforts to tease apart the dynamics by which this central channel admits specific molecules.
“Prevailing wisdom cast the nuclear pore complex as a rigid conduit. Instead, we have found that it responds to the need for transport, opening and closing in an elegantly simple cycle,” stated Nobel laureate and senior author Gunter Blobel, Ph.D., professor and head of the Laboratory of Cell Biology at Rockefeller University. “Our most recent study reveals how proteins called transport factors, known to chaperone legitimate cargo through the nuclear pore complex, prompt the ring at the middle of the central channel to dilate.”
The findings from this study were published recently in Cell through an article entitled “Allosteric Regulation in Gating the Central Channel of the Nuclear Pore Complex.”
Previously, the researchers found that the diameter of the NPC was determined by two of the complex’s almost 30 nucleoporin proteins, Nup58 and Nup54, which interact to dilate the pore an astonishing 50 nanometers in diameter.
The current study focused on a transport factor known as karyopherin, which the investigators found initiated the dilation of the NPC. Specifically, the scientists measured changes in heat during reactions between the three key components, karyopherin, Nup58, and Nup54. This biophysical data was able to reveal the energy dynamics taking place during these reactions, providing clues to the behavior of the molecules involved. Furthermore, the Rockefeller team mathematically analyzed the data collected at various conditions, which uncovered an unexpected role for a disordered region of Nup58.
“We found that when one karyopherin molecule binds to at least two disordered regions of Nup58, it stabilizes Nup58 in such a way that the dilated conformation—in which the neighboring ordered region of Nup58 links up with Nup54—becomes more favorable. As a result, the more karyopherin molecules are present, the more the ring dilates,” explained Junseock Koh, Ph.D., postdoctoral researcher in Dr. Blobel’s laboratory and lead author on the current study. “Based on these results, we were able to develop a framework for predicting the extent to which a ring will dilate given the amount of transport factors present.”
This current data provides new insight into constructing a detailed view of the NPC and a greater understanding of how vital molecules are shuttled between the nucleus and cytoplasm of the cell.
“While this discovery is a critical step in understanding how the nuclear pore complex opens and closes, its implications go beyond basic cell biology”, said Dr. Blobel. “It is likely that even subtle problems in nuclear pore complex function may over time lead to numerous diseases.”