High-speed AFM captures dynamic nature of nuclear pore complexes
Original story from the University of Basel (Switzerland).
Nuclear pore complexes are more dynamic than previously thought, reshaping our understanding of a vital transport process in cells.
An international study led by the University of Basel (Switzerland) has discovered that nuclear pore complexes (NPC) – tiny gateways in the nuclear membrane – are not rigid or gel-like as once thought. Their interiors are dynamically organized, constantly moving and rearranging. The findings reshape our understanding of a vital transport process in cells and have implications for diseases and potential therapies.
Imagine the cell’s nucleus as a bank vault protected by a highly sophisticated security system: the NPC. Only proteins carrying the correct ‘key’ – specialized transport factors – are granted exclusive access. This selective control over what enters and exits the nucleus is essential for ensuring proper communication between the genome protected inside it and the cellular machinery outside.
Infographic: Investigating biomechanics with atomic force microscopy
In this infographic, we dive into how AFM works, the technical features one must consider and how it can be implemented for biomechanical investigation.
Nanoscience leads to new biological insights
Despite its importance, the NPC’s inner workings have remained a mystery. Its transport channel is lined with highly flexible protein ‘threads’ – the FG nucleoporins (FG Nups) – that create a selective barrier whose ultra-fine organization has eluded even the most powerful electron microscopes. Because the FG Nups can form gel-like assemblies outside of cells, older models have compared the NPC’s function to a rigid sieve.
Now, a team led by Argovia Professor for Nanobiology Roderick Lim from the Biozentrum and the Swiss Nanoscience Institute at the University of Basel, has used high-speed atomic force microscopy (AFM) to film never-seen-before nanometer-scale movements with millisecond resolution directly inside the pore.
“The NPC barrier is loosely organized by a mobile central plug, whose identity has long been enigmatic. It turns out to consist of a dynamic mixture of transport factors, cargo molecules, and FG Nups that comingle along the pore’s central axis. This creates a highly adaptable system that reinforces the barrier while ensuring fast selective transport,” explained Lim.
Go with the flow
The team uncovered this dynamic organization while studying NPCs from yeast cells. High-speed AFM movies also revealed highly fluid FG Nup movements that ‘radiated’ towards the central plug inside the pore.
“After prolonged incubation, the central plug of NPCs disappeared but was restored by adding transport factors,” reported Toshiya Kozai, first author of the study. Remarkably, the transport factors also replicated NPC-like barrier function in artificial nanopores, demonstrating the generality of this behavior.
Comparing NPCs and hydrogels
NPCs have often been compared to hydrogels. “This is because FG Nups form hydrogels in vitro – in a test tube – but these assemblies are thousands of times larger than NPCs. Plus, they consist of tangled fiber-like structures that are simply too big to fit inside an NPC, let alone the entire hydrogel body itself,” explained Lim. “When we examined them more closely, we found that the hydrogels were riddled with holes of irregular shapes and sizes – much like a kitchen sponge. Many of these holes were as large as NPCs or even larger, and could potentially mimic NPC-like behavior.”
The self-organizing, dynamic behavior revealed in this study offers a unified view of NPCs that aligns with long-standing structural and biochemical observations – with implications ranging from fundamental cell biology to the design of smart filters and drug delivery systems. Notably, restraining the pore’s dynamic state impeded selective transport into the nucleus, highlighting how essential such behavior is for the cell to function properly.
“The next challenge is to understand how cells fine-tune these remarkable nanomachines in response to changing needs – how the pores adjust to stress, regulate growth, and when they get jammed, contribute to disease,” concluded Michael Rout, Professor at Rockefeller University (NY, USA), who co-led the work.
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