"Cell" The magic molecule that corrects protein misfolding

Protein misfolding may be the culprit behind many degenerative diseases

Now, a new study shows that a drug commonly used to treat cystic fibrosis ensures that the protein has enough time to bend into shape by directly helping the protein folding process bind CFTR

"Understanding how these drugs bind to proteins allows us to develop the theory at a fundamental level of how protein folding correctors work," said first author Karol Fiedorczuk, a postdoctoral fellow in the lab of Jue Chen at The Rockefeller University

Effective treatments for cystic fibrosis did not appear until about 20 years ago

Scientists are well aware of the contours of the disease

If a protein is not folded correctly, it breaks down inside the cell and never reaches the cell surface

Even in healthy people, CFTR is prone to misfolding and can degrade before it can function (though there is still enough protein to keep the body healthy)

"When a patient has a mutation in the CFTR gene, little or no protein reaches the cell surface, or those proteins that do reach the surface are dysfunctional," Chen said

Researchers have long known that CFTR dysfunction is the underlying cause of cystic fibrosis

It was initially unclear how the two drugs work, but there's no denying that both are effective

But how the second drug works, the so-called corrector, has left researchers scratching their heads

Chen and Fiedorczuk have now solved this puzzle with the help of cryo-electron microscopy

The discovery could have wide-ranging ramifications, enabling the development of novel drugs to treat a range of diseases associated with improper protein folding

"CFTR is not the only protein that folds incorrectly," Chen said

Magazine

Cell

DOI

10.