Tiny pores in the cell nucleus play an essential role in healthy aging by protecting and maintaining genetic material. A team from the Department of Theoretical Biophysics at the Max Planck Institute for Biophysics in Frankfurt am Main and the Synthetic Biophysics of the Protein Disorders Group at Johannes Gutenberg University Mainz (JGU) has filled a gap in understanding the structure and function of these elements. nuclear pores.
Scientists have discovered how intrinsically disordered proteins in the center of a pore can form a movable, spaghetti-like barrier that is permeable to important cellular factors but keeps viruses or other pathogens out.
Human cells protect their genetic material within the cell nucleus which is protected by the nuclear membrane. As the control center of the cell, the nucleus must be able to exchange important messenger molecules, metabolites or proteins with the rest of the cell. So about 2,000 pores are built into the nuclear membrane, each made up of about 1,000 proteins.
For decades, researchers have been intrigued by the three-dimensional structure and function of these nuclear pores, which act as guardians of the genome: substances needed to control the cell are let through, while pathogens or other DNA-damaging substances are let through. Banned from entering. Nuclear pores can therefore be thought of as molecular sentinels, each screening several thousand visitors per second. Only those with an entry ticket are allowed to pass.
How do nuclear pores manage such a formidable task? About 300 scaffold-related proteins protrude deeply into the central pore like tentacles. Until now, researchers didn’t know how these sensors are arranged and how they repel intruders. This is because these proteins are intrinsically disordered and lack a defined three-dimensional structure. It is flexible and constantly moving – like spaghetti in boiling water.
A combination of microscopy and computer simulation
Because these intrinsically disordered proteins (IDPs) are constantly changing their structure, it is difficult for scientists to decipher their three-dimensional structure and function. Most of the experimental techniques researchers use to image proteins only work with a specific 3D structure. So far, the central region of the nuclear pore has been represented as a vacuole because it was not possible to determine the organization of IDPs at the opening.
The team led by Gerhard Hammer, Director of the Max Planck Institute for Biophysics, and Eduard Lemke, Professor of Synthetic Biophysics at the Johannes Gutenberg University Mainz and Associate Director at the Institute for Molecular Biology Mainz (IMB) now used a novel combination of synthetic biology, multidimensional fluorescence microscopy and menu simulations. on the computer to study displaced nuclear pores in living cells.
“We used state-of-the-art micro-instruments to mark several spots of spaghetti-like proteins with fluorescent dyes, which we excite with light and visualize under a microscope,” Lemke explained. “Based on the glow patterns and duration, we were able to infer how the proteins are arranged.” Hammer added, “We then used molecular dynamics simulations to calculate how the displaced are organized spatially in the pores, how they interact with each other and how they move. For the first time, we can visualize the gateway to the control center of human cells.”
Dynamic protein network as a barrier to transport
The probes in the transport pores exhibit a completely different behavior compared to what we knew before, because they interact with each other and with the payload. It moves perpetually like the aforementioned spaghetti in boiling water. Therefore, there is no hole in the center of the pore, but a shield of vibrating, spaghetti-like particles.
Viruses or bacteria are too big to pass through this sieve. However, other large cellular molecules required in the nucleus can pass because they carry very specific signals. These particles have an entry ticket, whereas pathogens usually do not. “By unstuffing pores, we are entering a new phase in nuclear transport research,” added Martin Beck, collaborator and fellow at the Max Planck Institute for Biophysics.
“Understanding how pores move or block cargo will help us identify errors. After all, some viruses manage to enter the cell nucleus despite the barrier,” Hammer summed up.
“With our range of methods, we can now study IDPs in greater detail to find out why, despite their fault, they cannot dispense with certain cellular functions. In fact, IDPs are found in almost all species, although they involve On the risks of forming a lump during the aging process which can lead to neurodegenerative diseases such as Alzheimer’s, Lemke said.By learning how IDPs work, researchers aim to develop new drugs or vaccines that prevent viral infections and aid healthy aging.
The paper has been published in the journal nature.
Miao Yu et al, Visualization of the perturbed in situ nuclear transport mechanism, nature (2023). DOI: 10.1038/s41586-023-05990-0
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