The cystic fibrosis transmembrane conductance regulator (CFTR) protein helps to maintain the balance of salt and water on many surfaces in the body, such as the surface of the lung. When the protein is not working correctly, chloride — a component of salt — becomes trapped in cells. Without the proper movement of chloride, water cannot hydrate the cellular surface. This leads the mucus covering the cells to become thick and sticky, causing many of the symptoms associated with cystic fibrosis.
To understand how mutations in the CFTR gene cause the protein to become dysfunctional, it is important to understand how the protein is normally made, and how it helps to move water and chloride to the cell surface.
What Are Proteins?
Proteins are tiny machines that do specific jobs within a cell. The instructions for building each protein are encoded in DNA. Proteins are assembled from building blocks called amino acids. There are 20 different amino acids. All proteins are made up of chains of these amino acids connected together in different orders, like different words that are written using the same 26 letters of the alphabet. The DNA instructions tell the cell which amino acid to use at each position in the chain to make a specific protein.
The CFTR protein is made up of 1,480 amino acids. Once the CFTR protein chain is made, it is folded into a specific 3-D shape. The CFTR protein is shaped like a tube that goes through the membrane surrounding the cell, like a straw goes through the plastic top on a cup.
What Does the CFTR Protein Do?
The CFTR protein is a particular type of protein called an ion channel. An ion channel moves atoms or molecules that have an electrical charge from inside the cell to outside, or from outside the cell to inside. In the lung, the CFTR ion channel moves chloride ions from inside the cell to outside the cell. To get out of the cell, the chloride ions move through the center of the tube formed by the CFTR protein.
Once the chloride ions are outside the cell, they attract a layer of water. This water layer is important because it allows tiny hairs on the surface of the lung cells, called cilia, to sweep back and forth. This sweeping motion moves mucus up and out of the airways.
How Do Problems With the CFTR Protein Cause CF?
In people with CF, mutations in the CFTR gene can cause the following problems with the CFTR protein:
- It doesn't work well
- It isn't produced in sufficient quantities
- It is not produced at all
When any of these problems occur, the chloride ions are trapped inside the cell, and water is no longer attracted to the space outside the cell. When there is less water outside the cells, the mucus in the airways becomes dehydrated and thickens, causing it to flatten the cilia. The cilia can't sweep properly when thick, sticky mucus weighs them down.
Because the cilia can't move properly, mucus gets stuck in the airways, making it difficult to breathe. In addition, germs caught in the mucus are no longer expelled from the airway, allowing them to multiply and cause infections. Thick mucus in the lungs and frequent airway infections are some of the most common problems people with CF face.
Researchers Are Still Studying the Basic Structure
Researchers are still trying to learn more about the structure of the CFTR protein so that they can find new and better ways to help improve the function of the protein in people with CF.
Because the 3-D shape of CFTR is so complex, it was not until early 2017 that the first high-resolution pictures were developed. These pictures have given researchers important clues about where drugs bind the protein, how they affect its function, and how to develop new CF therapies. In the future, pictures showing the protein in an “open” position, where salt can move through, will be even more helpful to researchers developing new CF therapies.
