Cells need proteins to be in the right place to work correctly. In diseases like cancer, proteins can end up in the wrong place, helping the disease grow.
The Stanford team from Stafford University, led by Steven Banik, has developed a solution to this problem. They have engineered TRAMs, a molecule that can guide proteins to their rightful destinations. This breakthrough could pave the way for novel treatments for diseases caused by protein misplacement, such as cancer.
Cell proteins must be in the right place to do their jobs, like building molecules or sending signals. Cells are like crowded spaces, with proteins constantly moving around. If proteins are misplaced, they can’t work correctly. Banik and his team are working on returning these “lost” proteins to where they belong to help them function correctly.
In some diseases, proteins get sent to the wrong places because of mutations, like putting the incorrect address on a package. This can stop the protein from working or even make it harmful, like in ALS, where a protein clumps together and kills cells.
Banik and his team developed a particular molecule called TRAM, which acts like a helper. It connects to both the misplaced protein and a shuttle protein, guiding the misplaced protein back to where it belongs in the cell.
The team worked with two types of shuttles: one that moves proteins into the nucleus and one that removes them. Christine Ng, a graduate student, created TRAMs to connect the shuttle and the misplaced protein.
They had to measure the amount of protein in the nucleus to check if it worked. Since there wasn’t an excellent way to do this, Ng developed a new method to track and measure cell proteins.
Ng tested TRAMs, small transport systems, to move proteins in and out of a cell’s nucleus. She found that the TRAMs worked, helping her figure out the rules for how strong they need to be.
Next, she made a TRAM to treat ALS, a disease where a protein called FUS leaves the nucleus and forms harmful clumps. After using the TRAM, the FUS protein returned to the nucleus, reducing toxic clumps and helping cells survive.
Then, the team designed another TRAM to copy a mutation that protects neurons by moving a protein to the end of nerve cells, which helped make cells more resistant to damage.
The team faced a challenge: designing TRAMs to target proteins is difficult because they need to know all the possible molecules that bind to these proteins. They used genetic tools to add sticky tags to the proteins to solve this. They hope to find natural sticky parts on these proteins to make TRAMs into medicines.
They believe this method can work with other cell processes and hope TRAMs can send healthy proteins to new cell areas, creating unknown functions. Banik is excited to learn the rules and discover new biology by moving proteins around in new ways.
Journal reference :
- Ng, C.S.C., Liu, A., Cui, B. et al. Targeted protein relocalization via protein transport coupling. Nature. DOI: 10.1038/s41586-024-07950-8.
