Researchers from the Francis Crick Institute and King’s College London have discovered that the mechanical properties of proteins can play a role in determining how fast or slow they enter the nucleus of a cell. Proteins need to enter and exit the nucleus in order to carry out various functions, such as regulating gene expression. The researchers found that proteins with a soft or flexible region near their ‘nuclear-localisation sequence,’ which allows them to enter the nucleus, were able to enter more quickly. This discovery could have implications for drug delivery and gene regulation.
The movement of proteins in and out of the nucleus is controlled by the nuclear pore complex, a channel on the edge of the nucleus. Previous research has shown that the size and composition of proteins can affect how easily they can cross the pore, but this new study revealed that mechanical stability also plays a role. By tracking the movement of proteins in single cells, the researchers were able to observe how mechanical properties near the nuclear-localisation sequence influenced the speed of protein entry.
To confirm their findings, the researchers engineered a soft tag that could be added to stiffer proteins to help them enter the nucleus more easily. They attached this soft tag to a transcription factor called MRTF, which is involved in cell movement. With the soft tag, MRTF was able to enter the nucleus more quickly, leading to an increase in cell movement. This suggests that modifying the mechanical properties of proteins could be a useful tool for enhancing drug delivery or gene regulation.
Sergi Garcia-Manyes, Group Leader at the Francis Crick Institute and Professor of Biophysics at King’s College London, emphasized the potential impact of this discovery on drug development. He pointed out that understanding how the mechanics of a protein can influence its entry into the nucleus could help in designing more targeted drugs. This mechanism could also potentially regulate entry into other parts of the cell, such as the mitochondria or proteasomes.
Rafael Tapia-Rojo, co-first author of the study and now a lecturer in Biological Physics at King’s College London, highlighted the surprising nature of the findings and the direct link between single molecule measurements and cellular behavior. Their newly designed optomechanical approach allowed them to make these connections. The researchers are now further investigating how transcription factors have evolved to contain flexible regions that facilitate their entry into the nucleus. Understanding these mechanisms could provide valuable insights into protein function and cellular processes.
Overall, this research sheds light on a previously unexplored aspect of protein entry into the nucleus and highlights the importance of the mechanical properties of proteins in this process. By demonstrating how modifying the mechanical properties of proteins can influence their entry into the nucleus, the researchers have opened up new possibilities for drug delivery and gene regulation strategies. Further studies on the evolution of flexible regions in transcription factors could provide a deeper understanding of how proteins interact with cellular structures.
