Researchers unveil protein engineering to delete a message that promotes cancer in cells

Researchers unveil protein engineering to delete a message that promotes cancer in cells -

Over a century of research has shone light on the insides of once dark our cells, genes that serve as our "blue" to proteins and other molecules that are cellular our oppressors.

With this basic knowledge, research is underway for the cellular mechanisms that could serve as gateways for new therapies. These could lead to specific treatments for the disease - targeting a specific cellular function or a gene with fewer adverse side effects. Ideally, these effects would also be temporary, the cells to normal operation to return once the underlying condition is treated.

A team of researchers from the University of Washington and the University of Trento in Italy has announced results that could pave the way for these therapies. In an article published July 18 in Nature Chemical Biology , they unveiled a modified protein that they designed to suppress a message promoting specific cancer within cells.

And this approach to the design of the protein could be modified to target other cellular functions and messages, said lead author and UW chemistry professor Gabriele Varani

"What we show here is a testing ground - a process to determine how to make the right changes to proteins, "he said

for their approach, Varani and his team modified a human protein called Rbfox2, happens.. naturally in cells and binds to microRNA. These small RNA molecules well appointed adjust gene expression levels in cells as a dimmer. Varani the group sought to devise Rbfox2 to bind to a specific microRNA miR-21, which is present at high levels in many tumors, increases the expression of genes promoting cancer and decreases suppressor cancer. If a protein as Rbfox2 could bind to miR-21, researchers have expressed the hypothesis, it could suppress the effects of tumor growth of miR-21.

But for this approach to be effective, the protein must bind to miR-21 microRNA and not others. Fortunately, all RNA molecules, including microRNAs have an inherent property that permeates with specificity. They consist of a chain of "letters" each chemical with an order or a single sequence. To date, no other research team has ever successfully modified a protein to bind to microRNA.

"This is because our knowledge of the structure of proteins is much better than our understanding of RNA structure," said Varani. "We historically lacked key information about how RNA folds and how proteins bind RNA at the atomic scale."

UW researchers relied on high-quality data on the structure Rbfox2 of understanding, to single atoms, how it binds to the unique sequence of "letters" in its natural target RNA. Then they predicted how Rbfox2 sequence should change to make it bind to miR -21 instead. Elegantly, affecting only four amino acids is carefully selected Rbfox2 shift its preference for attachment to miR-21, which prevents the microRNA to pass along its tumor-promoting message.

the UW team spent several years to prove it, because they had to test each change individually or in combination. they also had to ensure that the modified protein Rbfox2 strongly bind to miR-21, but no other microRNAs. Since microRNA have many functions in the cells, it would be against-productive to repress miR-21 while blocking other normal mediated microRNA functions.

The researchers also designed a second protein which should clear miR-21 from cells entirely. They did it by grafting the regions that Rbfox2 related to miR-21 on a separate protein called Dicer. Dicer chops normally RNAs into small pieces and generates functional microRNAs. But Rbfox2 Dicer-fusion protein shows specific affinity for slicing miR-21 into oblivion.

Varani and his team believe that Rbfox2 could be redesigned to bind to microRNA targets other than miR-21. There are thousands of microRNAs to choose from, and many were involved in diseases. The key to realizing this potential would be streamlining and automating laborious methods the team used to model the interactions at the atomic level Rbfox2 with RNA.

"This method is based on knowledge of high quality structures," said Varani. "This allowed us to see what changes would change the binding to the target microRNA."

Not only are useful laboratory tools to study the functions of microRNAs, they could - in time. - form the basis for new therapies to treat disease