Cystic fibrosis transmembrane conductance regulator

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Cystic fibrosis transmembrane conductance regulator ( CFTR ) is a membrane protein and chloride channel in vertebrates encoded by the CFTR genes.

The CFTR gene code for the class ABC transporter ion channel protein performs chloride and thiocyanate ions in the epithelial cell membrane. The mutation of the CFTR gene that affects the function of chloride ion channels causes dysregulation of epithelial fluid transport in the lungs, pancreas and other organs, resulting in cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency that causes malnutrition and diabetes. This condition causes chronic disability and reduced life expectancy. In male patients, progressive obstruction and spermatic cord and epididymal destruction appear as a result of abnormal intraluminal secretion, leading to the absence of congenital vas deferens and male infertility.

Video Cystic fibrosis transmembrane conductance regulator

Gene

The gene encoding human CFTR protein is found on chromosome 7, on the long arm at position q31.2. of base pair 116.907.253 to base pair 117.095.955. CFTR orthologists occur in jawed vertebrates.

The CFTR gene has been used in animals as a marker of nuclear phylogenetic DNA. The large genome sequences of these genes have been used to explore the phylogeny of the main group of mammals, and confirm the clustering of placenta orders into four major clones: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires.

Mutations

Nearly 300 mutations of cystic fibrosis have been described. The most common mutation ,? F508 results from the removal (?) Of the three nucleotides resulting in the loss of amino acid phenylalanine (F) at position 508 on the protein. As a result, proteins do not fold normally and degrade faster. Most mutations are rare. Distribution and frequency of mutations vary among different populations that have implications for genetic screening and counseling.

Mutation consists of replacement, duplication, deletion or shortening in the CFTR gene. It may produce proteins that may not work, work less effectively, degrade faster, or present in inadequate quantities.

It has been hypothesized that mutations in the CFTR gene can provide selective advantages for heterozygous individuals. Cells express the mutant form of CFTR protein resistant to invasion by Salmonella typhi bacteria, typhoid fever agents, and mice carrying a single copy of a mutant-resistant CFTR that is resistant to diarrhea caused by cholera toxin.

List of common mutations

The most common mutations among the Caucasians are:

• ? F508
• G542X
• G551D
• N1303K
• W1282X

Maps Cystic fibrosis transmembrane conductance regulator

Structure

The CFTR gene has a length of about 189 kb, with 27 exons and 26 introns. CFTR is a glycoprotein with 1480 amino acids. Proteins consist of five domains. There are two transmembrane domains, each with six alpha-helical ranges. These are each connected to the nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by the domain "R" regulator which is a unique feature of CFTR, not in any other ABC transporter. The ion channel is only open when its R-domain has been phosphorylated by PKA and ATP is bound to NBD. The carboxyl terminal of the protein is anchored to the cytoskeleton by a domain that interacts with PDZ. Caveat : The crystal structure included at the top is not a full CFTR channel (cartoon version is OK). The correct GDP accession figure for the channel structure is 5UAK. The structure shown (PDB # 1XMI) shows the muted NBD1 homopentameric assembly, the first nucleotide binding domain (NBD1) of the transporter.

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Location and function

CFTR functions as an anion channel of ATP-gated, increasing the conductance for certain anions (eg Cl ^- ) to flow down their electrochemical gradients. The ATP-driven conformation changes in CFTR open and close the gates to allow anion transmembrane flow beneath their electrochemical gradients. This is in contrast to other ABC proteins, where ATP-driven conformational changes trigger substrate transports ascending across cellular membranes. Essentially, CFTRs are ion channels that evolve as broken 'leaked' ABC transports when in open conformation.

CFTRs have two transmembrane domains, each of which has a nucleotide-binding domain attached to it. CFTR also contains another domain called the regulatory domain, which consists of the two parts mentioned above. Another issoform of the ABC ion channel is involved in the absorption of nutrients in prokaryotes. The CFTRs have an evolutionary design to transfer the hydrolysis-free energy of ATP to anion movement rising across the cell membrane. The ion channel has two main conformations, one where the binding sites face inward (ATP bound), and one where it is facing out (ATP free). ATP binds to each individual nucleotide binding domain, which results in the subsequent hydrolysis of ATP, leading to a rearrangement of transmembrane helices and transmembrane domains. This changes the accessibility of cargo binding sites to inward positions. This ATP binding and irreversible hydrolysis, promotes an alternative exposure of CFTR, ensuring anion-line transport down the electrochemical gradient.

CFTR is found in the epithelial cells of many organs including the lungs, liver, pancreas, gastrointestinal tract, and reproductive tract. In the skin, CFTR is strongly expressed in the sebaceous and eccrine sweat glands. In the eccrine gland, CFTR is located in the apical membrane of epithelial cells that form the channel of this sweat gland.

Typically, proteins remove chloride ions and thiocyanates (with negative charges) out of epithelial cells into the covering mucus. Positively charged sodium ions follow passively, increasing the total electrolyte concentration in the mucus, producing a movement of water out of the cell through osmosis.

In epithelial cells with motile cilia lining the bronchus and fallopian tubes, CFTR is located in the cell membrane but not in the cilia. In contrast, the ENaC (epithelial sodium channel) lies along the length of the cilia.

In sweat glands, faulty CFTR results reduce the transport of sodium chloride and sodium thiocyanate in reabsorptive channels and therefore sweat is more salty. This is the basis of a clinically important sweat test for cystic fibrosis that is often used diagnostically by genetic screening.

Interactions

Cystic fibrosis transmembrane regulator conductance has been shown to interact with:

This is inhibited by the anti-diarrhea drug crofelemer.

src: www.pnas.org

Related conditions

• Indirect loss of congenital vas deferens: Men with a bilateral inherent presence of vas deferens most commonly have mild mutations (changes that permit partial function of the gene) in one copy of the CFTR gene and cystic fibrosis-cause mutations in other CFTR copies.
• Cystic fibrosis: Over 1,800 mutations in the CFTR gene have been found but most have not been associated with cystic fibrosis. Most of these mutations replace one amino acid (protein building block) for another amino acid in a CFTR protein or remove a small amount of DNA in the CFTR gene. The most common mutation, called? F508, is the removal (?) Of one amino acid (phenylalanine) at position 508 on CFTR protein. This modified protein never reaches the cell membrane because it is degraded immediately after it is made. All disease-causing mutations in the CFTR gene prevent the channel from functioning properly, leading to clogging of the movement of salt and water into and out of cells. As a result of this blockage, the cells lining the streets of the lungs, pancreas, and other organs produce a very thick, sticky mucus. This mucus blocks the airways and glands, causing the typical signs and symptoms of cystic fibrosis. In addition, only thin mucus can be removed with cilia; thick mucus can not, so trap bacteria that cause chronic infection.
• Cholera: ADP-ribosylation caused by cholera toxin results in an increased production of cyclic AMP which in turn opens the CFTR channel leading to oversecretion from Cl ^- . Na and H ₂ O follow Cl ^- into the small intestine, resulting in dehydration and loss of electrolytes.

src: err.ersjournals.com

Drug target

CFTR has been a drug target in the search for treatments for related conditions. Ivacaftor (trade name Kalydeco , developed as VX-770 ) is an FDA-approved drug in 2012 for people with cystic fibrosis who have a specific Ivlebaftor CFTR mutation developed by Vertex Drugs along with the Cystic Fibrosis Foundation and is the first drug to treat underlying causes rather than symptoms of the disease. Called "the most important new drug of 2012", and "miracle drug" it is one of the most expensive drugs, costing more than US $ 300,000 per year, which has led to Vertex criticism at high cost.

src: thorax.bmj.com

References

src: www.pnas.org

Further reading

src: erj.ersjournals.com

External links

• GeneReviews/NCBI/NIH/UW entries on CFTR-Related Disorders - Cystic Fibrosis (CF, Mucoviscidosis) and Kongenital Vas Deferens Disease (CAVD)
• Cystic Fibrosis Transmembrane Conductance Protein Regulator
• Human Gen Human Mutation Database - CFTR Note
• Cystic Fibrosis Database Mutation
• Oak Ridge National CFTR Laboratory Information
• CFTR at OMIM (National Biotechnology Information Center)

Source of the article : Wikipedia