Question

Cystic fibrosis is a relatively common \((1 \text { in } 2000\) live births) genetic disease of Caucasians. Although it affects many organs, pulmonary obstruction is a major problem. CF patients have reduced \(\left.\mathrm{Cl}^{-} \text {permeability and the discase can be diagnosed by elevated [Cl }^{-1}\right]\) in sweat. Genetic mutations lead to defects in cystic fibrosis transmembrane conductance regulator (CFTR) protein which is a cAMP-dependent Cl \(^{-}\) channel. CFTR has structural homology to the superfamily of ATP-binding cassette (ABC) transporters. ATP-binding cassette (ABC) transporters A. have both a membrane-spanning domain that recognizes the substrate and an ATP-binding domain. B. all effect translocation by forming channels. C. are found only in cukaryotes. D. all have two functions: forming a channel and conductance regulation. E. are all P-glycoproteins.

Short answer

A. have both a membrane-spanning domain that recognizes the substrate and an ATP-binding domain.

Step-by-step solution

Analyze statement A

"A. have both a membrane-spanning domain that recognizes the substrate and an ATP-binding domain." This statement is true. ABC transporters, including the CFTR protein, have a membrane-spanning domain that recognizes the substrate and an ATP-binding domain responsible for energy-driven transport across the membrane.

Analyze statement B

"B. all effect translocation by forming channels." This statement is not entirely true. While some ABC transporters form channels for translocation, others function as primary active transporters that bind and move specific substrates across the membrane using ATP hydrolysis. So, not all of them form channels.

Analyze statement C

"C. are found only in eukaryotes." This statement is false. ABC transporters are widely distributed across all domains of life, including bacteria, archaea, and eukaryotes.

Analyze statement D

"D. all have two functions: forming a channel and conductance regulation." This statement is not correct. While the CFTR protein, which is an ABC transporter, has the dual function of forming a channel and regulating conductance, not all ABC transporters share these two functions. Some only function in the transport of substrates without forming channels or regulating conductance.

Analyze statement E

"E. are all P-glycoproteins." This statement is false. P-glycoproteins are one type of ABC transporter, but not all ABC transporters belong to the P-glycoprotein subfamily. They are a large and diverse protein family with various molecular features and functions.

Select the correct statement

The correct statement about ATP-binding cassette (ABC) transporters, based on our analysis, is: A. have both a membrane-spanning domain that recognizes the substrate and an ATP-binding domain.

Key concepts

CFTR Protein Function

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein plays a crucial role in maintaining the balance of salt and water across epithelial membranes in the body. It is predominantly known for regulating the movement of chloride ions (Cl^-) out of cells. When the CFTR protein is functional, it ensures the proper hydration of mucus layers, which is particularly important in the lungs, pancreas, and other organs. The protein operates as a gated ion channel that, upon stimulation by cyclic Adenosine Monophosphate (cAMP), allows Cl^- ions to pass through the cell membrane. This process is critical for maintaining the viscosity of mucus, which helps in clearing bacteria and other pathogens from the respiratory system.

Furthermore, CFTR is involved in the movement of bicarbonate ions, which are crucial for neutralizing acid in the digestive system and for preventing the formation of thick, sticky mucus. In people with cystic fibrosis, mutations in the CFTR gene lead to dysfunction in these processes, resulting in the accumulation of thick mucus and subsequent health issues.

ATP-Binding Cassette (ABC) Transporters

ATP-binding cassette (ABC) transporters makeup a large family of proteins that utilize the energy derived from Adenosine Triphosphate (ATP) hydrolysis to transport various substrates across cellular membranes. These transporters consist of two main components: a membrane-spanning domain (MSD) that identifies and traverses the lipid bilayer with the substrate, and an ATP-binding domain (nucleotide-binding domain, NBD) that provides the necessary energy for the transport process.

Despite their name, not all ABC transporters form channels; some function by changing their conformation in a way that moves the substrate from one side of the membrane to the other. This diversity allows ABC transporters to participate in a wide variety of biological processes, including drug resistance, lipid transport, and the regulation of ion channels, as seen with the CFTR protein in healthy cells. Moreover, they are found not only in eukaryotes but also in prokaryotes, highlighting their essential role in cellular function across different life forms.

Genetic Mutations in Cystic Fibrosis

Cystic fibrosis is caused by genetic mutations in the CFTR gene, which is responsible for encoding the CFTR protein. More than 2,000 different mutations in the CFTR gene have been identified, which can lead to the disease manifesting in various ways. These mutations can be categorized based on how they affect the CFTR protein's production, folding, trafficking, gating, or conductance.

The most common mutation, ΔF508, results in a protein that is misfolded and, therefore, gets degraded by the cell before it can reach the cell membrane to perform its function. Other mutations might allow the CFTR protein to reach the membrane but impair its opening (gating) or reduce its conductance. Understanding these mutations is pivotal for developing targeted therapies that can correct specific dysfunctional aspects of the CFTR protein in cystic fibrosis patients.

Chloride Ion Permeability in Cystic Fibrosis

In cystic fibrosis, the permeability of chloride ions (Cl^-) across the cell membrane is significantly hindered due to the dysfunctional CFTR protein. This reduction in Cl^- permeability leads to a series of clinical manifestations, the most impactful being the thickening of mucus secretions. Normally, Cl^- ions leave the cells, followed by water, which helps to maintain the mucus in a fluid state that can easily transport and clear inhaled particles and pathogens.

However, with impaired Cl^- permeability, less water follows, resulting in dehydrated and sticky mucus. This mucus becomes difficult to clear and can obstruct airways, leading to respiratory infections, inflammation, and reduced lung function. The classic diagnostic sign of cystic fibrosis is increased chloride concentration in the sweat, as the sweat glands are also affected by the same ion transport defect. Treatments aim to improve Cl^- transport and hydration of secretions to alleviate symptoms of the disease.