An important component in the protein that causes cystic fibrosis has been identified by University of Missouri researchers. The discovery may open the door to the development of new medications and improved therapies for the life-threatening disease affecting almost 70,000 people globally.
“We know that cystic fibrosis is caused by mutations in a gene called CFTR, but we don’t know exactly how these mutations affect the function of the CFTR protein.
In fact, there are nearly 2,000 mutations that could occur in the protein. However, our study identified two amino acids in the CFTR protein that serve as a sort of gate. This gate is a key factor in regulating the flow of chloride ions—one of the key ingredients in salt—into and out of the cells through the CFTR protein.”
Salt out of Balance
Those suffering from cystic fibrosis have an imbalance of salt in their bodies caused by the defective CFTR protein.
Since there is too little salt and water on the outside of the cells, the thin layer of mucus that helps keep the lungs free of bacteria get too thick and difficult to expel by coughing.
This thick mucus can clog the airways and lead to dangerous infections.
Even though advances in the understanding and treatment of the condition have allowed many people with the disease to live into their early 40s, the majority of patients with cystic fibrosis die of respiratory failure.
“In many ways, the function of the CFTR protein can be compared to a motion-activated water faucet,” Hwang says. “All of the parts need to be functioning properly in order for the faucet to work. The motion sensor needs to detect your hand movements and send a signal to open the gate, enabling the flow of water.
When the gate in the CFTR protein is defective, the flow of ions across the cell membrane is disrupted. By identifying the amino acids that make up this gate, we now have a clear idea as to why a mutation in either of these two amino acids causes cystic fibrosis.”
For decades, therapies for cystic fibrosis targeted optimizing organ function and staving off organ failure. But they did nothing to address the root causes of the disease.
In 2012, the US Food and Drug Administration approved the drug, ivacaftor, to treat the underlying cause of cystic fibrosis in individuals with a specific mutation. While the drug targets the defective protein, the actual mechanism of how it enhances CFTR function is unknown.
“When your water faucet is broken, you can call a plumber to repair it,” Hwang says. “But if the plumber doesn’t understand how the faucet works, how is he supposed to fix it?”
Earlier research clarified how the drug affects the CFTR protein’s gate. The current study builds upon that knowledge by identifying the exact location of the gate.
The discovery will help researchers further understand not only how the drug works, but also could shed light on where it works and therefore potentially improve its effects.
“By understanding the physical and chemical basis of CFTR function, we, the molecular plumbers, are equipped with the tools to find ways to correct the defective protein’s function, and subsequently boost treatments and ultimately improve the lives of cystic fibrosis patients.”
Xiaolong Gao and Tzyh-Chang Hwang Localizing a gate in CFTR PNAS 2015 112 (8) 2461-2466; published ahead of print February 9, 2015, doi:10.1073/pnas.1420676112