Cystic fibrosis transmembrane conductance regulator CFTR protein

In a patient with cystic fibrosis, the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein folds incorrectly. The patient s cells modify this abnormal protein by attaching ubiquitin molecules to it. What is the fate of this modified CFTR protein ... 

A.B., Aleksandrov, L.A., Riordan, J.R., and Ford, R.C. (2005) Crystallographic and single-particle analyses of native- and nucleotide-bound forms of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Biochemical Society Transactions, 33, 996-999. 

Cystic fibrosis (CF) is a genetic disease caused by mutations to the gene coding the cystic fibrosis transmembrane conductance regulator (CFTR) protein in many epithelial cells and blood cells. It is the most common autosomal recessive disorder in Caucasians and affects approximately 28,000 patients in the United States and approximately 36,000 patients in Europe. An estimated 70,000 people worldwide have CF. The life expectancy of patients with CF has risen steadily over the last 25 years, from a median predicted age of survival of 25 years in 1985 to 37 years in 2011. Since in the United States an orphan disease is defined as an disease afflicting fewer than 100,000 patients, CF is an orphan disease, and ivacaftor (Kalydeco, 1) is an orphan drug. The drug is also known as a personalized medicine because CF affects about only 70,000 people worldwide. 

CF is caused by the absence of a protein called cystic fibrosis transmembrane conductance regulator (CFTR). This protein is required for the transport of chloride ions across cell membranes. On the molecular level, there is a mutation in the gene that encodes for CFTR. As a result, CFTR cannot be processed properly by the cell and is unable to reach the exocrine glands to assume its transport function. 

The cystic fibrosis (c/) gene was first identified in 1989. It codes for a 170 kDa protein, the cystic fibrosis transmembrane conductance regulator (CFTR), which serves as a chloride channel in epithelial cells. Inheritance of a mutant cftr gene from both parents results in the CF phenotype. While various organs are affected, the most severely affected are the respiratory epithelial cells, which have, unsurprisingly, become the focus of attempts at corrective gene therapy. 

A disease that results from a decrease in fluid and salt secretion by a transport protein referred to as the cystic fibrosis transmembrane conductance regulator (CFTR). As a result of this defect, secretion from the pancreas is blocked, and heavy, dehydrated mucus accumulates in the lungs, leading to chronic lung infections. 

The membrane proteins with ATP-binding cassette (ABC) domains are complex ATP-dependent pumps. Each pump includes four major domains two domains span the membrane and two others contain ABC P-loop ATPase structures. The multidrug resistance proteins confer resistance on cancer cells by pumping chemotherapeutic drugs out of a cancer cell before the drugs can exert their effects. Another ABC domain protein is the cystic fibrosis transmembrane conductance regulator (CFTR), an ATP-gated chloride channel. Mutations in CFTR can result in cystic fihrosis. 

Szczypka, M.S., Wemmie, J.A., Moye-Rowley, W.S., and Thiele, D.J. (1994) A yeast metal resistance protein similar to human cystic fibrosis transmembrane conductance regulator (CFTR) and multidrug resistance-associated protein. 

Cystic fibrosis is the most common lethal autosomal recessive disease affecting the Caucasian population. It has a frequency of approximately 1 in 2500 and a carrier frequency of approximately 1 in 25. The protein affected is the cystic fibrosis transmembrane conductance regulator (CFTR), which is a chloride ion channel. There are over 1000 mutations that have been discovered in the CFTR gene and over 80 percent of these mutations lead to disease. The mutations lead to (1) defective or decreased protein production, (2) defective processing of the protein, (3) protein that is defective in the regulation of the chloride channel, or (4) defect in the transport of chloride ions. The most common mutation, a deletion of a phenylalanine residue at amino acid position 508 (AFjog), results in misfolding of the protein it consequently does not traffic to the membrane. 

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