Softer proteins can cross into the nucleus quicker 

A fundamental discovery that the mechanics of a protein control its entry into the cell’s nucleus.

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To perform various tasks, such as instructing the nucleus to turn on or off particular genes, proteins must enter and exit the nucleus, the cell’s control center. These proteins pass through a channel known as the “nuclear pore complex” that is located on the outside of the nucleus. 

Previously, studies have demonstrated that the size and makeup of these proteins affect their ability to cross. A new survey of the Francis Crick Institute and King’s College London scientists adds to the evidence that mechanical characteristics might affect a protein’s ability to enter a pore.

Scientists found that the softness or rigidity of proteins in certain regions can dictate how fast or slow they enter the nucleus. 

Scientists tracked the movement of proteins in single cells. They found that in proteins of the same size and composition of amino acids (their building blocks), mechanical stability near the protein’s nuclear-localization sequence’ (a particular sequence that allows the protein to enter the nucleus) influenced how fast or slow it could cross. 

They discovered that proteins adjacent to this sequence that possessed a pliable region might enter the nucleus more rapidly. Then, to facilitate the proteins’ easier entry into the nucleus, scientists created a soft tag that could be inserted close to the sequence on stiffer proteins. This was investigated by tagging MRTF, a transcription factor that helps cells migrate throughout the body and activates certain genes. Cell mobility was increased by attaching a soft tag to MRTF, which allowed it to enter the nucleus much more quickly. 

Scientists then engineered a soft tag that could be added near the sequence on stiffer proteins to help them enter the nucleus more easily. 

This was investigated by tagging MRTF, a transcription factor that helps cells migrate throughout the body and activates specific genes. Attaching a soft tag to MRTF increased cell mobility, allowing it to enter the nucleus much more quickly. The scientists think this might be a helpful tool for faster drug delivery to the nucleus or for labeling transcription factors to boost the activity of specific genes. 

Sergi Garcia-Manyes, Group Leader of the Single Molecule Mechanobiology Laboratory at the Francis Crick Institute and Professor of Biophysics at King’s College London, said: “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.” 

Rafael Tapia-Rojo, co-first author, former postdoc at the Crick, and now lecturer in Biological Physics at King’s College London, said“Our findings were rather unanticipated, and it was striking to see how measurements at the single molecule level can be so directly linked to what happens at a cellular level, using a newly designed optomechanical approach.” 

Journal Reference:

  1. Panagaki, F. et al. (2024). Structural anisotropy results in mechano-directional transport of proteins across nuclear pores. Nature Physics. DOI: 10.1038/s41567-024-02438-8

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