Protein Flexibility Dictates Cell Nucleus Entry Speed

In a study published in Nature Physics, researchers from the Francis Crick Institute and King's College London have uncovered a fascinating link between the mechanical properties of proteins and their ability to enter the cell's nucleus. Their findings reveal that the softness or rigidity of specific regions within proteins can influence how quickly or slowly they cross the nuclear pore complex, a channel that regulates access to the nucleus.

Proteins must enter and exit the nucleus to perform various functions, such as activating or deactivating certain genes. Previous research has focused on the size and composition of proteins as factors affecting their nuclear entry. However, this new study demonstrates that mechanical stability near the protein's "nuclear-localization sequence" (a special sequence that allows entry into the nucleus) plays a crucial role.

By tracking the movement of proteins in single cells, the researchers discovered that proteins with a soft or flexible region adjacent to the nuclear-localization sequence were able to cross into the nucleus more rapidly compared to those with stiffer regions. This finding led them to engineer a "soft tag" that could be added near the sequence on stiffer proteins, facilitating their entry into the nucleus.

To validate their findings, the researchers tagged a transcription factor called MRTF, which regulates cell movement, with the soft tag. Remarkably, the tagged MRTF was able to enter the nucleus much faster, resulting in increased cell motility.

The researchers believe that this discovery could have significant implications for drug delivery and gene regulation. By understanding the mechanics of protein entry into the nucleus, it may be possible to design more targeted drugs or modify transcription factors to enhance the activity of specific genes.

“We’ve made a fundamental discovery that the mechanics of a protein—how soft or stiff it is in the region that leads translocation—control its entry into the cell’s nucleus. Although we only looked at the nuclear pore, this mechanism could regulate entry into other parts of the cell, such as the mitochondria or proteasomes. Knowing that a more flexible protein can enter the nucleus quicker could help us design more targeted drugs,” explains senior author Sergi Garcia-Manyes.