Biochemists Unravel CF at Most Basic Level
In an advance that promises to speed development of new drugs for cystic fibrosis, Johns Hopkins biochemists have discovered what goes awry inside the cells of CF patients at the most basic level.
It's a folding problem that might be familiar to any home-maker.
In a report in this month's "Biochemistry," the scientists describe the key snafu in cystic fibrosis transmembrane conductance regulator (CFTR), a protein that regulates cellular salt levels and helps ward off bacteria in the lungs. They also offer a new way to remedy it.
Much like, when folding a big bed sheet, one little slip can turn the whole thing into a misshapen mess, a similar thing happens in CF patients, deep within their cells. A genetic slip deletes a tiny but essential slice of CFTR.
This deletion -- of a single amino acid along a chain of nearly 1,500 of them -- occurs at a critical juncture in the twisting, turning protein. So instead of folding into an orderly shape, part of the molecule comes undone.
Molecular traffic cops, which act as chaperones, catch the misshapen proteins and keep them from passing onto the cell's surface, where they are to shuttle chloride ions and other essentials into and out of the cell. The broken protein gets flagged, degraded and recycled.
"The deleted amino acid is like a passport," says Young-Hee Ko, Ph.D., who initiated the project. "Without it, the protein can't travel to the cell membrane, where it is critical for killing bacteria, especially in the lungs." Subsequently, CF patients suffer a lifetime of chronic lung infections and an early death.
The key step in the work was isolating a small, manageable section of the
huge CFTR molecule. Because it would have taken years to decode the
structure of the whole protein in the lab, the researchers saved time by
synthesizing a small section, just 26 amino acids long. They also made a
25-amino acid version that was missi
Contact: Brian Vastag
Johns Hopkins Medical Institutions