Research reveals how our bodies keep unwelcome visitors out of cell nuclei
Findings could lead to development of new drugs to protect normal cell functioning
Professor Elena Orlova of Birkbeck’s Department of Biological Sciences has been working with a team of scientists led by UCL, which has uncovered the structure of pores found in cell nuclei and revealed how they work as gate keepers. The pores selectively block certain molecules from entering the nucleus and protect genetic material and normal cell functions. The discovery could lead to the development of new drugs against viruses that target the cell nucleus and new ways of delivering gene therapies, say the scientists behind the study.
At the heart of every cell in our body is a cell nucleus, a dense structure that contains our DNA. For a cell to function normally, it needs to surround its nucleus with a protective membrane but this must open enough to let vital molecules in and out, so the membrane is pierced by hundreds of tiny gateways known as nuclear pores.
The research, published today in Nature Nanotechnology, reports on nuclear pores in frog eggs and reveals how these pores can act like a supercharged sieve, filtering molecules by size but also based on chemical properties.
Professor Orlova said: “This was the first time that we’ve been able to show how pores in the nucleus membrane stop some molecules passing through, while enabling others to pass freely.
“We discovered that in the centre of each pore is a bundel of proteins which form a barrier. This barrier allows small molecultes to pass through, but it also allows larger molecules through, when they are accompanied by a chaperone molecule – a molecule which lubcricates the protein strands and causes the barrier to relax sufficiently for the molecule to go through.
Before now, scientists understood the overall shape of the pores and that protein structures in the middle of them controlled the flow of molecules, but it was not known how they did this. Some theories suggested the pores acted like a brush and others like a sieve. The researchers behind this study say it was hard to determine which was correct because of the small and fragile nature of the pores and the difficulties in locating the proteins in the pores.
The team used a technique known as atomic force microscopy (AFM) to study the pores. Much like people can use their fingers to read braille, feeling the words rather than seeing them, atomic force microscopes move a minuscule needle across the surface of a sample, measuring its shape and hardness. This method was chosen over other techniques because the pores are too small for optical microscopy and too flexible and mobile for X-ray crystallography.
As well as explaining the remarkable properties of nuclear pores, and the role they play in higher life forms, the research may also hold promise for the development of new antiviral drugs and better delivery mechanisms for gene therapy.
Professor Orlova said: “Certain viruses produce their own proteins that tricks the nuclear pore system and enter the cell nucleus and disrupt the cell’s functioning. This new understanding of how the proteins form a barrier means that we may now be able to develop new drugs that prevent viruses from tricking the proteins in this way. We may also be able to improve the mechanisms for delivering therapeutic genes into the cell nucleus in gene therapy.”
Image caption: A sharp AFM tip enters the Nuclear Pore Complex (NPC) central channel from the cytoplasmic side, indenting the nucleoporins that form the selective barrier for transport between the cell nucleus and the cytoplasm. The NPC consists of a rim (turquoise blue, outer diameter ~125 nm) embedded in the nuclear envelope (grey blue), a nuclear basket (red), and eight flexible filaments anchored to the cytoplasmic ring (blue). A supersharp tip (grey, to scale) probes the nucleoporins (yellow) in the central channel of the NPC.