Box 113 Biochemistry In Medicine

A Defective Ion Channel in Cystic Fibrosis

Cystic fibrosis (CF) is a serious and relatively common hereditary disease of humans. About 5% of white Americans are carriers, having one defective and one normal copy of the gene. Only individuals with two defective copies show the severe symptoms of the disease: obstruction of the gastrointestinal and respiratory tracts, commonly leading to bacterial infection of the airways and death due to respiratory insufficiency before the age of 30. In CF, the thin layer of mucus that normally coats the internal surfaces of the lungs is abnormally thick, obstructing air flow and providing a haven for pathogenic bacteria, particularly Staphylococcus aureus and Pseudomonas aeruginosa.

The defective gene in CF patients was discovered in 1989. It encodes a membrane protein called cystic fibrosis transmembrane conductance regula-

FIGURE 1 Topology of the cystic fibrosis transmembrane conductance regulator, CFTR. It has 12 transmembrane helices, and three functionally significant domains extend from the cytoplasmic surface: NBD1 and NBD2 are nucleotide-binding domains to which ATP binds, and a regulatory domain (R domain) is the site of phos-phorylation by cAMP-dependent protein kinase. Oligosaccharide chains are attached to several residues on the outer surface of the segment between helices 7 and 8. The most commonly occurring mutation leading to CF is the deletion of Phe508, in the NBD1 domain. The structure of CFTR is very similar to that of the multidrug transporter of tumors, described in the text.

tor, or CFTR. Hydropathy analysis predicted that CFTR has 12 transmembrane helices and is structurally related to the multidrug (MDR1) transporters of drug-resistant tumors (Fig. 1). The normal CFTR protein proved to be an ion channel specific for Cl" ions. The Cl" channel activity increases greatly when phosphoryl groups are transferred from ATP to several side chains of the protein, catalyzed by cAMP-dependent protein kinase (Chapter 12). The mutation responsible for CF in 70% of cases results in deletion of a Phe residue at position 508, with the effect that the mutant protein is not correctly folded and inserted in the plasma membrane. Other mutations yield a protein that is inserted properly but cannot be activated by phosphorylation. In each case, the fundamental problem is a nonfunctional Cl" channel in the epithelial cells that line the airways (Fig. 2), the digestive tract, and exocrine glands (pancreas, sweat glands, bile ducts, and vas deferens).

Normally, epithelial cells that line the inner surface of the lungs secrete a substance that traps and kills bacteria, and the cilia on the epithelial cells constantly sweep away the resulting debris. When CFTR is defective or missing, this process is less efficient, and frequent infections by bacteria such as S. aureus and P. aeruginosa progressively damage the lungs and reduce respiratory efficiency.

FIGURE 2 Mucus lining the surface of the lungs traps bacteria. In healthy lungs, these bacteria are killed and swept away by the action of cilia. In CF, the bactericidal activity is impaired, resulting in recurring infections and progressive damage to the lungs.

FIGURE 1 Topology of the cystic fibrosis transmembrane conductance regulator, CFTR. It has 12 transmembrane helices, and three functionally significant domains extend from the cytoplasmic surface: NBD1 and NBD2 are nucleotide-binding domains to which ATP binds, and a regulatory domain (R domain) is the site of phos-phorylation by cAMP-dependent protein kinase. Oligosaccharide chains are attached to several residues on the outer surface of the segment between helices 7 and 8. The most commonly occurring mutation leading to CF is the deletion of Phe508, in the NBD1 domain. The structure of CFTR is very similar to that of the multidrug transporter of tumors, described in the text.

systems that couple the spontaneous, downhill flow of these ions to the simultaneous uphill pumping of another ion, sugar, or amino acid (Table 11-5). The lactose transporter (lactose permease) of E. coli is the well-studied prototype for proton-driven cotrans-porters. This protein consists of a single polypeptide chain (417 residues) that functions as a monomer to transport one proton and one lactose molecule into the

TABLE 11-5 Cotransport Systems Driven by Gradients of Na+ or H+

Organism/tissue/cell type

Transported solute (moving against its gradient)

Cotransported solute (moving down its gradient)

Type of transport

E. coli

Lactose

H +

Symport

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