Question

Protein-Folding Therapies The Food and Drug Administration recently approved the drug lumacaftor for the treatment of cystic fibrosis in patients with the F508 \(\Delta\) CFTR mutation. This mutation is a genetically encoded deletion of amino acid F508 from the protein. About \(2 / 3\) of cystic fibrosis patients have this mutation, and lumacaftor is one of the first drugs that functions as a pharmacological chaperone to correct a defect in the protein-folding process. However, lumacaftor is not always effective in treating patients who have other CFTR mutations that result in misfolding. Why is lumacaftor able to correct the misfolding of some mutant CFTR proteins and not others?

Short answer

Lumacaftor is designed to stabilize the F508 deletion in CFTR, improving folding for this specific mutation, but other mutations may require different treatments.

Step-by-step solution

Understanding Protein Misfolding

Misfolding occurs when a protein does not assume its functional three-dimensional structure. In cystic fibrosis, the F508 deletion mutation causes the CFTR protein to misfold, leading to its dysfunction.

Role of Lumacaftor

Lumacaftor acts as a pharmacological chaperone. Chaperones assist in the correct folding of proteins, stabilizing them in a conformation that allows them to achieve or maintain their functional state.

Specificity of Lumacaftor

Lumacaftor is particularly designed to assist in the proper folding of the F508 deletion variant of CFTR by binding to and stabilizing this particular mutated protein.

Variable Effectiveness

Even though lumacaftor is effective on the F508 mutation, its efficacy can vary because other CFTR mutations may require different corrections to their folding or stabilization processes. Lumacaftor may not interact effectively with or stabilize other misfolded forms of CFTR.

Key concepts

Cystic Fibrosis

Cystic fibrosis is a genetic condition that affects the respiratory and digestive systems. It is primarily caused by a mutation in the CFTR gene, which is responsible for producing a protein that regulates the movement of salt and water in and out of cells. In cystic fibrosis patients, this protein either does not function properly or is absent altogether.
Cystic fibrosis leads to the buildup of thick and sticky mucus in various organs, most notably the lungs and pancreas. This mucus can cause chronic respiratory infections and digestive issues due to blocked ducts.
Some common symptoms include:

• Persistent cough with thick mucus
• Frequent lung infections
• Poor weight gain despite a good appetite
• Salty-tasting skin

With continuous advancements in medical treatment, patients with cystic fibrosis now have improved life expectancies and quality of life.

Pharmacological Chaperone

Pharmacological chaperones are small molecules that help to stabilize proteins in a way that is conducive to their proper function. They work by binding to the proteins that are prone to misfolding, thereby correcting or preventing their dysfunctional three-dimensional shapes.
For cystic fibrosis, pharmacological chaperones have opened new doors in therapeutic options. These chaperones can target specific mutations within the CFTR gene, potentially restoring the normal function of the CFTR protein.
By doing so:

• They help improve the stability and trafficking of the CFTR protein to the cell surface
• They increase the probability of a correct folding pathway, thus reducing the occurrence of misfolding
• They focus on specific mutations making them tailored therapy options, though this also means they may not work for all mutations

The development of pharmacological chaperones is a significant step toward personalized medicine for genetic disorders like cystic fibrosis.

CFTR Mutation

The CFTR mutation is at the heart of cystic fibrosis, rendering the CFTR protein dysfunctional. The most common CFTR gene mutation causing cystic fibrosis is the F508 deletion, which results in the removal of phenylalanine (F) at position 508 from the CFTR protein sequence.
This deletion prevents the protein from folding into its necessary structure, leading to its eventual degradation rather than being expressed on the cell surface where it should function.
Other mutations can also occur in the CFTR gene, causing variations in disease severity and manifestation. Some mutations cause the protein to reach the cell surface but function improperly, while others entirely block its escape from the cell's internal quality control system.
Understanding the specific type of CFTR mutation is crucial because:

• Treatments can be tailored to target specific folding or functional defects
• It guides the development of personalized treatments using therapies like pharmacological chaperones catered to specific mutations
• The mutation type often correlates with the severity of the disease symptoms and outcomes

Protein Misfolding

Protein misfolding refers to a protein's failure to fold into its intended three-dimensional structure. This process is vital because the protein's shape determines its function. When proteins misfold, they can lose their function and potentially lead to diseases, including cystic fibrosis.
The CFTR protein in cystic fibrosis is an example of protein misfolding. Due to specific mutations such as the F508 deletion, the protein does not achieve its correct form. This misfolding can prevent the protein from reaching its site of action at the cell surface, leading to the impaired function associated with cystic fibrosis symptoms.
Significance of protein misfolding in diseases:

• Misfolded proteins are often targeted for degradation, leading to loss of function
• They can accumulate within cells, causing cellular stress and damage
• Understanding misfolding can lead to treatments that aim to correct these folding errors, as done with pharmacological chaperones

Research into protein misfolding helps guide therapeutic strategies to rescue the function of mutated proteins, improving disease outcomes.