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Cystic Fibrosis: Channel, Catalytic, and Folding Properties of the CFTR Protein

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Abstract

The identification and characterization of the CFTR gene and protein have provided not only a major impetus to the dissection of the molecular pathophysiology of cystic fibrosis (CF) but also a new perspective on the structure and function of the large supeifamily of membrane transport proteins to which it belongs. While the mechanism of the active vectorial translocation of many hydrophobic substrates by several of these transporters remains nearly as perplexing as it has for several decades, considerable insight has been gained into the control of the bi-directional permeation of chloride ions through a single CFTR channel by the phosphorylation of the R-domain and ATP interactions at the two nucleotide binding domains. However, details of these catalytic and allosteric mechanisms remain to be elucidated and await the replacement of two-dimensional conceptualizations with three dimensional structure information. Secondary and tertiary structure determination is required both for the understanding of the mechanism of action of the molecule and to enable a more complete appreciation of the misfolding and misprocessing of mutant CFTR molecules. This is the primary cause of the disease in the majority of the patients and hence understanding the details of the cotranslational interactions with multiple molecular chaperones, the ubiquitin-proteasome pathway and other components of the quality control machinery at the endoplasmic reticulum could provide a basis for the development of new therapeutic interventions.

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REFERENCES

  • Akabas, M. H., Kaufmann, C., Cook, T. A., and Archdeacon, P. (1994). “Amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 269, 14865–14868.

    Google Scholar 

  • Anderson, M. P., Rich, D. P., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1991a). “Generation of cAMP-activated chloride currents by expression of CFTR,” Science 257, 679–682.

    Google Scholar 

  • Anderson, M. P., Gregory, R. J., Thompson, S., Souza, D. W., Paul, S., Mulligan, R. C., Smith, A. E., and Welsh, M. J. (1991b). “Demonstration that CFTR is a chloride channel by alteration of its anion selectivity,” Science 253, 202–205.

    Google Scholar 

  • Anderson, M. P., Berger, H. A., Rich, D. P., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1991c). “Nucleoside triphosphates are required to open the CFTR chloride channel,” Cell 67, 775–784.

    Google Scholar 

  • Anderson, M. P., and Welsh, M. J. (1992). Regulation by ATP and ADP of CFTR chloride channels that contain mutant nucleotide-binding domains,” Science 257, 1701–1704.

    Google Scholar 

  • Bear, C. E., Duguay, F., Naismith, A. L., Kartner, N., Hanrahan, J. W., and Riordan, J. R. (1991). “Cl-channel activity in Xenopus oocytes expressing the cystic fibrosis gene,” J. Biol. Chem. 266, 19142–19145.

    Google Scholar 

  • Bear, C. E., Li, C. H., Kartner, N., Bridges, R. J., Jensen, T. J., Ramjeesingh, M., and Riordan, J. R. (1992). “Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR),” Cell 68, 809–818.

    Google Scholar 

  • Becq, F., Fanjul, M., Merten, M., Figarella, C., Hollande, E., and Gola, M. (1993). “Possible regulation of CFTR-chloride channels by membrane-bound phosphatases in pancreatic duct cells,” FEBS Lett. 327, 337–342.

    Google Scholar 

  • Bell, C. L., and Quinton, P. M. (1993). “Regulation of CFTR Cl− conductance in secretion by cellular energy levels,” Am. J. Physiol. 264, C925–931.

    Google Scholar 

  • Berger, H. A., Travis, S. M., and Welsh, M. J. (1993). “Regulation of the cystic fibrosis transmembrane conductance regulator Cl− channel by specific protein kinases and protein phosphatases,” J. Biol. Chem. 268, 2037–2047.

    Google Scholar 

  • Birrer, P. (1995). “Proteases and antiproteases in cystic fibrosis: pathogenetic considerations and therapeutic strategies,” Respiration 1, 25–28.

    Google Scholar 

  • Boat, T. F., Welsh, M. J., and Beaudet, A. L. (1989). Cystic Fibrosis, in The Metabolic Basis of Inherited Disease (Jeffers, J.D.,and Gavert, G., Eds.) McGraw-Hill, New York, pp. 2649–2680.

    Google Scholar 

  • Brown, C. R., Hong-Brown, L. Q., Biwersi, J., Verkman, A. S., and Welch, W. J. (1996). “Chemical chaperones correct the mutant phenotype of the Δ508 cystic fibrosis transmembrane conductance regulator protein,” Cell Stress Chap. 1, 117–125.

    Google Scholar 

  • Carroll, T. P., Morales, M. M., Fulmer, S. B., Allen, S. S., Flotte, T. R., Cutting, G. R., and Guggino, W. B. (1995). “Alternate translation initiation codons can create functional forms of cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 270, 11941–11946.

    Google Scholar 

  • Carson, M. R., Winter, M. C., Travis, S. M., and Welsh, M. J. (1995a). “Pyrophosphate stimulates wild-type and mutant cystic fibrosis transmembrane conductance regulator Cl− channels,” J. Biol. Chem. 270, 20466–20472.

    Google Scholar 

  • Carson, M. R., Travis, S. M., and Welsh, M. J. (1995b). “The two nucleotide-binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) have distinct functions in controlling channel activity,” J. Biol. Chem. 270, 1711–1717.

    Google Scholar 

  • Champigny, G., Imler, J. L., Puchelle, E., Dalemans, W., Gribkoff, V., Hinnrasky, J., Dott, K., Barbry, P., Pavirani, A., and Lazdunski, M. (1995). “A change in gating mode leading to increased intrinsic Cl− channel activity compensates for defective processing in a cystic fibrosis mutant corresponding to a mild form of the disease,” Embo J. 14, 2417–2423.

    Google Scholar 

  • Chang, X. B., Tabcharani, J. A., Hou, Y. X., Jensen, T. J., Kartner, N., Alon, N., Hanrahan, J. W., and Riordan, J. R. (1993). “Protein kinase A (PKA) still activates CFTR chloride channel after mutagenesis of all 10 PKA consensus phosphorylation sites,” J. Biol. Chem. 268, 11304–11311.

    Google Scholar 

  • Chang, X. B., Hou, Y. X., Jensen, T. J., and Riordan, J. R. (1994). “Mapping of cystic fibrosis transmembrane conductance regulator membrane topology by glycosylation site insertion,” J. Biol. Chem. 269, 18572–18575.

    Google Scholar 

  • Chang, X.-B., Hou, Y. X., Jensen, T. J., and Riordan, J. R. (1995). “Oligosaccharide addition and removal at N-linked glycosylation sites in CFTR,” Ped. Pulm. S12, 185.

    Google Scholar 

  • Chen, M., and Zhang, J. T. (1996). “Membrane insertion, processing, and topology of CFTR in microsomal membranes,” Mol. Membr. Biol. 13, 33–40.

    Google Scholar 

  • Cheng, S. H., Gregory, R. J., Marshall, J., Paul, S., Souza, D. W, White, G. A., O'Riordan, C. R., and Smith, A. E. (1990). “Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis,” Cell 63, 827–834.

    Google Scholar 

  • Cheng, S. H., Fang, S. L., Zabner, J., Marshall, J., Piraino, S., Schiavi, S. C., Jefferson, D. M., Welsh, M. J., and Smith, A. E. (1995). “Functional activation of the cystic fibrosis trafficking mutant ΔF508-CFTR by overexpression,” Am. J. Physiol. 268, L615–L624.

    Google Scholar 

  • Cheung, M., and Akabas, M. H. (1996). “Identification of cystic fibrosis transmembrane conductance regulator channel-lining residues in and flanking the M6 membrane-spanning segment,” Biophys. J. 70, 2688–2695.

    Google Scholar 

  • Cliff, W. H., and Frizzell, R. A. (1990). “Separate Cl− conductances activated by cAMP and Ca2+ in Cl(−)-secreting epithelial cells,” Proc. Natl. Acad. Sci. USA 87, 4956–4960.

    Google Scholar 

  • Cotten, J. F., Ostedgaard, L. S., Carson, M. R., and Welsh, M. J. (1996). “Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 271, 21279–21284.

    Google Scholar 

  • Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Dott, K., Dreyer, D., Crystal, R. G., Pavirani, A., Lecocq, J. P., and Lazdunski, M. (1991). “Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation,” Nature 354, 526–528.

    Google Scholar 

  • Davis, P. B., and di Sant'Agnese, P. A. (1980). “A review. Cystic fibrosis at forty—quo vadis?” Pediatr. Res. 14, 83–87.

    Google Scholar 

  • Dechecchi, M. C., Tamanini, A., Berton, G., and Cabrini, G. (1993). “Protein kinase C activates chloride conductance in C127 cells stably expressing the cystic fibrosis gene,” J. Biol. Chem. 268, 11321–11325.

    Google Scholar 

  • Denning, G. M., Ostedgaard, L. S., and Welsh, M. J. (1992a). “Abnormal localization of cystic fibrosis transmembrane conductance regulator in primary cultures of cystic fibrosis airway epithelia,” J. Cell. Biol. 118, 551–559.

    Google Scholar 

  • Denning, G. M., Anderson, M. P., Amara, J. F., Marshall, J., Smith, A. E., and Welsh, M. J. (1992b). “Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive,” Nature 358, 761–764.

    Google Scholar 

  • Doige, C. A., and Ames, G. F. (1993). “ATP-dependent transport systems in bacteria and humans: relevance to cystic fibrosis and multidrug resistance,” Ann. Rev. Microbiol. 47, 291–319.

    Google Scholar 

  • Dork, T., Wulbrand, U., Richter, T., Neumann, T., Wolfes, H., Wulf, B., Maass, G., and Tummler, B. (1991). “Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene,” Hum. Genet. 87, 441–446.

    Google Scholar 

  • Drumm, M. L., Pope, H. A., Cliff, W. H., Rommens, J. M., Marvin, S. A., Tsui, L. C., Collins, F. S., Frizzell, R. A., and Wilson, J. M. (1990). “Correction of the cystic fibrosis defect in vitro by retrovirus mediated gene transfer,” Cell 62, 1227–1233.

    Google Scholar 

  • Drumm, M. L., Wilkinson, D. J., Smit, L. S., Worrell, R. T., Strong, T. V., Frizzell, R. A., Dawson, D. C., and Collins, F. S. (1991). “Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes,” Science 254, 1797–1799.

    Google Scholar 

  • Dulhanty, A. M., and Riordan, J. R. (1994a). “Phosphorylation by cAMP-dependent protein kinase causes a conformational change in the R domain of the cystic fibrosis transmembrane conductance regulator,” Biochemistry 33, 4072–4079.

    Google Scholar 

  • Egan, M., Flotte, T., Afione, S., Solow, R., Zeitlin, P. L., Carter, B. J., and Guggino, W. B. (1992). “Defective regulation of outwardly rectifying Cl− channels by protein kinase A corrected by insertion of CFTR,” Nature 358, 581–584.

    Google Scholar 

  • Fischer, H., Illek, B., and Machen, T. E. (1995). “CFTR's activation, steady-state activity, and inactivation are controlled by distinct phosphatases,” Ped. Pulm. S12, 186.

    Google Scholar 

  • Fischer, H., and Machen, T. E. (1996). “The tyrosine kinase p60c-arc regulates the fast gate of the cystic fibrosis transmembrane conductance regulator chloride channel,” Biophys. J. 71, 3073–3082.

    Google Scholar 

  • French, P. J., Bijman, J., Edixhoven, M., Vaandrager, A. B., Scholte, B. J., Lohmann, S. M., Nairn, A. C., and de Jonge, H. R. (1995). “Isotype-specific activation of cystic fibrosis transmembrane conductance regulator-chloride channels by cGMP-dependent protein kinase II,” J. Biol. Chem. 270, 26626–26631.

    Google Scholar 

  • Gadsby, D. C., and Nairn, A. C. (1994). “Regulation of CFTR channel gating,” Trends Biochem. Sci. 19, 513–518.

    Google Scholar 

  • Gray, M. A., Plant, S., and Argent, B. E. (1993). “cAMP-regulated whole-cell chloride currents in pancreatic duct cells,” Am J Physiol 264, C591–C602.

    Google Scholar 

  • Gregory, R. J., Cheng, S. H., Rich, D. P., Marshall, J., Paul, S., Hehir, K., Ostedgaard, L., Klinger, K. W., Welsh, M. J., and Smith, A. E. (1990). “Expression and characterization of the cystic fibrosis transmembrane conductance regulator,” Nature 347, 382–386.

    Google Scholar 

  • Gregory, R. J., Rich, D. P., Cheng, S. H., Souza, D. W., Paul, S., Manavalan, P., Anderson, M. P., Welsh, M. J., and Smith, A. E. (1991). “Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2,” Mol. Cell Biol. 11, 3886–3893.

    Google Scholar 

  • Gruis, D., Riley, C., and Price, E. (1996). “Role of phosphorylation on domain-domain interactions in CFTR,” Ped. Pulm. S13, 222.

    Google Scholar 

  • Gunderson, K. L., and Kopito, R. R. (1994). “Effects of pyrophosphate and nucleotide analogs suggest a role for ATP hydrolysis in cystic fibrosis transmembrane regulator channel gating,” J. Biol. Chem. 269, 19349–19353.

    Google Scholar 

  • Hamosh, A., Trapnell, B. C., Zeitlin, B. C., Montrose-Rafizadeh, C., Rosenstein, B. J., Crystal, R. G., and Cutting, G. R. (1991). “Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis,” J. Clin. Invest. 88, 1880–1885.

    Google Scholar 

  • Hanrahan, J. W., Tabcharani, J. A., Chang, X.-B., and Riordan, J. R. (1994). “A secretory chloride channel from epithelial cells studied in heterologous expression systems, in Advances in Comparative and Environmental Physiology, Vol. 19, Springer Verlag, Berlin, pp. 193–220.

    Google Scholar 

  • Hartman, J., Huang, Z., Rado, T. A., Peng, S., Jilling, T., Muccio, C. D., and Sorscher, E. J. (1992). “Recombinant synthesis, purification, and nucleotide binding characteristics of the first nucleotide binding domain of the cystic fibrosis gene product,” J. Biol. Chem. 267, 6455–6458.

    Google Scholar 

  • Haws, C., Krouse, M. E., Xia, Y., Gruenert, D. C., and Wine, J. J. (1992). “CFTR channels in immortalized human airway cells,” Am. J. Physiol. 26, L692–L707.

    Google Scholar 

  • Hipper, A., Mall, M., Greger, R., and Kunzelmann, K. (1995). “Mutations in the putative pore-forming domain of CFTR do not change anion selectivity of the cAMP activated Cl− conductance;” FEBS Lett. 374, 312–316.

    Google Scholar 

  • Hwang, T. C., Horie, M., and Gadsby, D. C. (1993). “Functionally distinct phospho-forms underlie incremental activation of protein kinase-regulated Cl− conductance in mammalian heart,” J. Gen. Physiol. 101, 629–650.

    Google Scholar 

  • Hwang, T. C., Nagel, G., Nairn, A. C., and Gadsby, D. C. (1994). “Regulation of the gating of cystic fibrosis transmembrane conductance regulator Cl channels by phosphorylation and ATP hydrolysis,” Proc. Natl. Acad. Sci. USA 91, 4698–4702.

    Google Scholar 

  • Ismailov, I. I., Awayda, M. S., Jovov, B., Berdiev, B. K., Fuller, C. M., Dedman, J. R., Kaetzel, M., and Benos, D. J. (1996). “Regulation of epithelial sodium channels by the cystic fibrosis transmembrane conductance regulator,”J. Biol. Chem. 271, 4725–4732.

    Google Scholar 

  • Jensen, T. J., Loo, M. A., Pind, S., Williams, D. B., Goldberg, A. L., and Riordan, J. R. (1995). “Multiple proteolytic systems, including the proteasome, contribute to CFTR processing,” Cell 83, 129–135.

    Google Scholar 

  • Jia, Y., Mathews, C. J., and Hanrahan, J. W. (1997). “Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A,” J. Biol. Chem. 272, 4978–4984.

    Google Scholar 

  • Johnson, L. G., Olsen, J. C., Sarkadi, B., Moore, K. L., Swanstrom, R., and Boucher, R. C. (1992). Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nature Genet. 2, 21–25.

    Google Scholar 

  • Kartner, N., Hanrahan, J. W., Jensen, T. J., Naismith, A. L., Sun, S. Z., Ackerley, C. A., Reyes, E. F., Tsui, L. C., Rommens, J. M., Bear, C. E., and Riordan, J. R. (1991). “Expression of the cystic fibrosis gene in non-epithelial invertebrate cells produces a regulated anion conductance,” Cell 64, 681–691.

    Google Scholar 

  • Kartner, N., Augustinas, O., Jensen, T. J., Naismith, A. L., and Riordan, J. R. (1992). “Mislocalization of delta F508 CFTR in cystic fibrosis sweat gland,” Nature Genet. 1, 321–327.

    Google Scholar 

  • Kennelly, P. J., and Krebs, E. G. (1991). “Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases,” J. Biol. Chem. 266, 15555–15558.

    Google Scholar 

  • Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., and Tsui, L. C. (1989). “Identification of the cystic fibrosis gene: genetic analysis,” Science 245, 1073–1080.

    Google Scholar 

  • Klausner, R. D., and Sitia, R. (1990). “Protein degradation in the endoplasmic reticulum,” Cell 62, 611–614.

    Google Scholar 

  • Ko, Y. H., and Pedersen, P. L. (1995). “The first nucleotide binding fold of the cystic fibrosis transmembrane conductance regulator can function as an active ATPase,” J. Biol. Chem. 270, 22093–22096.

    Google Scholar 

  • Ko, Y. H., Thomas, P. J., Delannoy, M. R., and Pedersen, P. L. (1993) The cystic fibrosis transmembrane conductance regulator. Overexpression, purification, and characterization of wild type and delta F508 mutant forms of the first nucleotide binding fold in fusion with the maltose-binding protein,” J. Biol. Chem. 268, 24330–24338.

    Google Scholar 

  • Ko, Y. H., Thomas, P. J., and Pedersen, P. L. (1994). “The cystic fibrosis transmembrane conductance regulator. Nucleotide binding to a synthetic peptide segment from the second predicted nucleotide binding fold,” J. Biol. Chem. 269, 14584–14588.

    Google Scholar 

  • Li, C., Ramjeesingh, M., Reyes, E., Jensen, T., Chang, X., Rommens, J. M., and Bear, C. E. (1993). “The cystic fibrosis mutation (delta F508) does not influence the chloride channel activity of CFTR,” Nature Genet. 3, 311–316.

    Google Scholar 

  • Li, C., Ramjeesingh, M., Wang, W., Garami, E, Hewryk, M., Lee, D., Rommens, J. M., Galley, K., and Bear, C. E. (1996). “ATPase activity of the cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 271, 28563–28468.

    Google Scholar 

  • Linsdell, P., and Hanrahan, J. W. (1996a). “Disulphonic stilbene block of cystic fibrosis transmembrane conductance regulator chloride channels expressed in a mammalian cell line and its regulation by a critical pore residue,” J. Physiol. 496, 687–693.

    Google Scholar 

  • Linsdell, P., and Hanrahan, J. W. (1996b). “Flickery block of single CFTR chloride channels by intracellular anions and osmolytes,” Am. J. Physiol. 271, C628–C634.

    Google Scholar 

  • Loo, T. W., and Clarke, D. M. (1996a). “The minimum functional unit of human P-glycoprotein appears to be a monocomer,” J. Biol. Chem. 271, 27488–27492.

    Google Scholar 

  • Loo, T. W., and Clarke, D. M. (1996b). “Inhibition of oxidative cross-linking between engineered cysteine residues at positions 332 in predicted transmembrane segments (TM) 6 and 975 in predicted TM12 of human P-glycoprotein by drug substrates,” J. Biol. Chem. 271, 27482–27487.

    Google Scholar 

  • Loo, T. W., and Clarke, D. M. (1997). “Correction of defective protein kinesis of human P-glycoprotein mutants by substrates and modulators,” J. Biol. Chem. 272, 709–712.

    Google Scholar 

  • Loussouarn, G., Demolombe, S., Mohammad-Panah, R., Escande, D., and Baro, I. (1996). “Expression of CFTR controls cAMP-dependent activation of epithelial potassium currents,” Am. J. Physiol. 271, C1565–C1573.

    Google Scholar 

  • Lukacs, G. L., Chang, X. B., Bear, C., Kartner, N., Mohamed, A., Riordan, J. R., and Grinstein, S. (1993). “The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells,” J. Biol. Chem. 268, 21592–21598.

    Google Scholar 

  • Lukacs, G. L., Mohamed, A., Kartner, N., Chang, X. B., Riordan, J. R., and Grinstein, S. (1994). “Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP,” Embo J. 13, 6076–6086.

    Google Scholar 

  • Ma, J., Tasch, J. E., Tao, T., Zhao, J., Xie, J., Drumm, M. L., and Davis, P. B. (1996). “Phosphorylation-dependent block of cystic fibrosis transmembrane conductance regulator chloride channel by exogenous R domain protein,” J. Biol. Chem. 271, 7351–7356.

    Google Scholar 

  • Mall, M., Kunzelmann, K., Hipper, A., Busch, A. E., and Greger, R. (1996). “cAMP stimulation of CFTR-expressing Xenopus oocytes activates a chromanol-inhibitable K+ conductance,” Pflugers Arch. 432, 516–522.

    Google Scholar 

  • Marshall, J., Fang, S., Ostedgaard, L. S., O'Riordan, C. R., Ferrara, D., Amara, J. F., Hoppe, H. t., Scheule, R. K., Welsh, M. J., Smith, A. E., and Cheng, S. H. (1994). “Stoichiometry of recombinant cystic fibrosis transmembrane conductance regulator in epithelial cells and its functional reconstitution into cells in vitro,” J. Biol. Chem. 269, 2987–2995.

    Google Scholar 

  • Mathews, C. J., Tabcharani, J. A., Chang, X.-B., Riordan, J. R., and Hanrahan, J. W. (1997). “Phosphyorylation-dependent regulation of CFTR by nucleotides,” submitted for publication.

  • McDonough, S., Davidson, N., Lester, H. A., and McCarthy, N. A. (1994). “Novel pore-lining residues in CFTR that govern permeation and open-channel block,” Neuron 13, 623–634.

    Google Scholar 

  • McNicholas, C. M., Guggino, W. B., Schwiebert, E. M., Hebert, S. C., Giebisch, G., and Egan, M. E. (1996). “Sensitivity of a renal K+ channel (ROMK2) to the inhibitory sulfonylurea compound glibenclamide is enhanced by coexpression with the ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator,” Proc. Natl. Acad. Sci. USA 93, 8083–8088.

    Google Scholar 

  • Morales, M. M., Carroll, T. P., Morita, T., Schwiebert, E. M., Devuyst, O., Wilson, P. D., Lopes, A. G., Stanton, B. A., Dietz, H. C., Cutting, G. R., and Guggino, W. B. (1996). “Both the wild type and a functional isoform of CFTR are expressed in kidney,” Am. J. Physiol. 270, F1038–1048.

    Google Scholar 

  • Ostedgaard, L. S., Rich, D. P., DeBerg, L. G., and Welsh, M. J. (1997). “Association of domains within the cystic fibrosis transmembrane conductance regulator,” Biochemistry 36, 1287–1294.

    Google Scholar 

  • Pasyk, E. A., and Foskett, J. K. (1995). “Mutant (delta F508) cystic fibrosis transmembrane conductance regulator Cl+ channel is functional when retained in endoplasmic reticulum of mammalian cells,” J. Biol. Chem. 270, 12347–12350.

    Google Scholar 

  • Penketh, A. R., Wise, A., Mearns, M. B., Hodson, M. E., and Batten, J. C. (1987). “Cystic fibrosis in adolescents and adults,” Thorax 42, 526–532.

    Google Scholar 

  • Picciotto, M. R., Cohn, J. A., Bertuzzi, G., Greengard, P., and Nairn, A. C. (1992). “Phosphorylation of the cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 267, 46–0500.

    Google Scholar 

  • Pind, S., Riordan, J. R., and Williams, D. B. (1994). “Participation of the endoplasmic reticulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 269, 12784–12788.

    Google Scholar 

  • Pind, S., Mohamed, A., Chang, X.-B., Hou, Y. X., Jensen, T. J., and Riordan, J. R. (1995). “Multiple initiation sites are used during translation of the mRNA encoding CFTR,” Ped. Pulm. S12, 180.

    Google Scholar 

  • Price, M. P., Ishihara, H., Sheppard, D. N., and Welsh, M. J. (1996). “Function of Xenopus cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels and use of human-Xenopus chimeras to investigate the pore properties of CFTR,” J. Biol. Chem. 271, 25184–25191.

    Google Scholar 

  • Qu, B. H., and Thomas, P. J. (1996). “Alteration of the cystic fibrosis transmembrane conductance regulator folding pathway,” J. Biol. Chem. 271, 7261–7264.

    Google Scholar 

  • Quinton, P. M. (1990). “Cystic fibrosis: a disease in electrolyte transport,” Faseb J. 4, 2709–2717.

    Google Scholar 

  • Quinton, P. M., and Reddy, M. M. (1992). “Control of CFTR chloride conductance by ATP levels through non-hydrolytic binding,” Nature 360, 79–81.

    Google Scholar 

  • Racker, E. (1985). Reconstitution of Transporters, Receptors, and Pathological States, Academic Press, Orlando, Florida, p. 37.

    Google Scholar 

  • Randak, C., Roscher, A. A., Hadorn, H. B., Assfalg-Machleidt, I., Auerswald, E. A., and Machleidt, W. (1995). “Expression and functional properties of the second predicted nucleotide binding fold of the cystic fibrosis transmembrane conductance regulator fused to glutathione-S-transferase,” FEBS Lett. 363, 189–194.

    Google Scholar 

  • Reddy, M. M., and Quinton, P. M. (1996a). “Deactivation of CFTR chloride conductance by endogenous phosphatases in the native sweat duct,” Am. J. Physiol. 270, C474–480.

    Google Scholar 

  • Reddy, M. M., and Quinton, P. M. (1996b). “Hydrolytic and nonhydrolytic interactions in the ATP regulation of CFTR chloride conductance,” Am. J. Physiol. 271, C35–42.

    Google Scholar 

  • Rich, D. P., Anderson, M. P., Gregory, R. J., Cheng, S. H., Paul, S., Jefferson, D. M., McCann, J. D., Klinger, K. W., Smith, A. E., and Welsh, M. J. (1990). “Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells,” Nature 347, 358–363.

    Google Scholar 

  • Rich, D. P., Gregory, R. J., Anderson, M. P., Manavalan, P., Smith, A. E., and Welsh, M. J. (1991). “Effect of deleting the R domain on CFTR-generated chloride channels,” Science 253, 205–207.

    Google Scholar 

  • Rich, D. P., Berger, H. A., Cheng, S. H., Travis, S. M., Saxena, M., Smith, A. E., and Welsh, M. J. (1993). “Regulation of the cystic fibrosis transmembrane conductance regulator Cl− channel by negative charge in the R domain,” J. Biol. Chem. 268, 20259–20267.

    Google Scholar 

  • Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M. L., Iannuzzi, M. C., Collins, F. S., and Tsui, L.-C. (1989). “Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA,” Science 245, 1066–1073.

    Google Scholar 

  • Rommens, J. M., Iannuzzi, M. C., Kerem, B., Drumm, M. L., Melmer, G., Dean, M., Rozmahel, R., Cole, J. L, Kennedy, D., Hidaka, N., Zsiga, M., Buchwald, M., Riordan, J. R., Tsui, L.-C., and Collins, F. S. (1989). Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059–1065.

    Google Scholar 

  • Sato, S., Ward, C. L., Krouse, M. E., Wine, J. J., and Kopito, R. R. (1996). “Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation,” J. Biol. Chem. 271, 635–638.

    Google Scholar 

  • Schultz, B. D., DeRoos, A. D. G., Venglarik, C. J., Singh, A. K., Frizzell, R. A., and Bridges, R. J. (1996a). “Glibenclamide blockade of CFTR chloride channels,” Am. J. Physiol. 271, L192–L200.

    Google Scholar 

  • Schultz, B. D., Bridges, R. J., and Frizzell, R. A. (1996b). “Lack of conventional ATPase properties in CFTR chloride channel gating,” J. Membr. Biol. 151, 63–75.

    Google Scholar 

  • Schwiebert, E. M., Egan, M. E., Hwang, T. H., Fulmer, S. B., Allen, S. S., Cutting, G. R., and Guggino, W. B. (1995). “CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP,” Cell 81, 1063–1073.

    Google Scholar 

  • Seibert, F. S., Tabcharani, J. A., Chang, X.-B., Dulhanty, A. M., Mathews, C., Hanrahan, J. W., and Riordan, J. R. (1995). “cAMP-dependent protein kinase-mediated phosphorylation of cystic fibrosis transmembrane conductance regulator residue Ser-753 and its role in channel activation,” J. Biol. Chem. 270, 2158–2162.

    Google Scholar 

  • Seibert, F. S., Linsdell, P., Loo, T. W., Hanrahan, J. W., Riordan, J. R., and Clarke, D. M. (1996a). “Cytoplasmic loop three of cystic fibrosis transmembrane conductance regulator contributes to regulation of chloride channel activity,” J. Biol. Chem. 271, 27493–27499.

    Google Scholar 

  • Seibert, F. S., Linsdell, P., Loo, T. W., Hanrahan, J. W., Clarke, D. M., and Riordan, J. R. (1996b). “Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity,” J. Biol. Chem. 271, 15139–15145.

    Google Scholar 

  • Sferra, T. J., and Collins, F. S. (1993). “The molecular biology of cystic fibrosis,” Annu. Rev. Med. 44, 133–144.

    Google Scholar 

  • Sharom, F., Xiaohong, Y. J. C., and Doige, C. A. (1995). Biochem. J. 308, 381–390.

    Google Scholar 

  • Sheppard, D. N., and Welsh, M. J. (1992). “Effect of ATP-sensitive potassium channel regulators in cystic fibrosis transmembrane conductance regulator currents,” J. Gen. Physiol. 100, 573–591.

    Google Scholar 

  • Sheppard, D. N., Rich, D. P., Ostedgaard, L. S., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1993). “Mutations in CFTR associated with mild-disease-form Cl− channels with altered pore properties,” Nature 362, 160–164.

    Google Scholar 

  • Sheppard, D. N., Ostedgaard, L. S., Rich, D. P., and Welsh, M. J. (1994). “The amino-terminal portion of CFTR forms a regulated Cl− channel,” Cell 76, 1091–1098.

    Google Scholar 

  • Sheppard, D. N., Ostedgaard, L. S., Winter, M. C., and Welsh, M. J. (1995). “Mechanism of dysfunction of two nucleotide binding domain mutations in cystic fibrosis transmembrane conductance regulator that are associated with pancreatic sufficiency,” Embo J. 14, 876–883.

    Google Scholar 

  • Smit, L. S., Wilkinson, D. J., Mansoura, M. K., Collins, F. S., and Dawson, D. C. (1993). “Functional roles of the nucleotide-binding folds in the activation of the cystic fibrosis transmembrane conductance regulator,” Proc. Natl. Acad. Sci. USA 90, 9963–9967.

    Google Scholar 

  • Stutts, M. J., Canessa, C. M., Olsen, J. C., Hamrick, M., Cohn, J. A., Rossier, B. C., and Boucher, R. C. (1995). “CFTR as a cAMP-dependent regulator of sodium channels,” Science 269, 847–850.

    Google Scholar 

  • Sugden, P. H., Holladay, L. A., Reimann, E. M., and Corbin, J. D. (1976). “Purification and characterization of the catalytic subunit of adenosine 3′, 5′-cyclic monophosphate-dependent protein kinase from bovine liver,” Biochem. J. 159, 409–422.

    Google Scholar 

  • Tabcharini, J. A., Low, W., Elie, D., and Hanrahan, J. W. (1990). “Low-conductance chloride channel activated by cAMP in the epithelial cell line T84,” FEBS Lett. 270, 157–164.

    Google Scholar 

  • Tabcharani, J. A., Chang, X. B., Riordan, J. R., and Hanrahan, J. W. (1991). “Phosphorylation-regulated Cl− channel in CHO cells stably expressing the cystic fibrosis gene,” Nature 352, 628–631.

    Google Scholar 

  • Tabcharani, J. A., Chang, X. B., Riordan, J. R., and Hanrahan, J. W. (1992). “The cystic fibrosis transmembrane conductance regulator chloride channel. Iodide block and permeation,” Biophys. J. 62, 1–4.

    Google Scholar 

  • Tabcharani, J. A., Rommens, J. M., Hou, Y. X., Chang, X. B., Tsui, L. C., Riordan, J. R., and Hanrahan, J. W. (1993). “Multiion pore behaviour in the CFTR chloride channel,” Nature 366, 79–82.

    Google Scholar 

  • Tao, T., Xie, J., Drumm, M. L., Zhao, J., Davis, P. B., and Ma, J. (1996). “Slow conversions among subconductance states of cystic fibrosis transmembrane conductance regulator chloride channel,” Biophys. J. 70, 743–753.

    Google Scholar 

  • Teem, J. L., Berger, H. A., Ostedgaard, L. S., Rich, D. P., Tsui, L. C., and Welsh, M. J. (1993). “Identification of revertants for the cystic fibrosis delta F508 mutation using STE6-CFTR chimeras in yeast.” Cell 73, 335–346.

    Google Scholar 

  • Thomas, P. J., Shenbagamurthi, P., Ysern, X., and Pedersen, P. L. (1991). “Cystic fibrosis transmembrane conductance regulator: nucleotide binding to a synthetic peptide,” Science 251, 555–557.

    Google Scholar 

  • Thomas, P. J., Shenbagamurthi, P., Sondek, J., Hullihen, J. M., and Pedersen, P. L. (1992). “The cystic fibrosis transmembrane conductance regulator. Effects of the most common cystic fibrosis-causing mutation on the secondary structure and stability of a synthetic peptide,” J. Biol. Chem. 267, 5727–2730.

    Google Scholar 

  • Thomas, P. J., and Pedersen, P. L. (1993). “Effects of the delta F508 mutation on the structure, function, and folding of the first nucleotide-binding domain of CFTR,” J. Bioenerg. Biomembr. 25, 11–19.

    Google Scholar 

  • Thomas, P. J., Qu, B. H., and Pedersen, P. L. (1995). “Defective protein folding as a basis of human disease,” Trends Biochem. Sci. 20, 456–459.

    Google Scholar 

  • Travis, S. M., Carson, M. R., Ries, D. R., and Welsh, M. J. (1993). “Interaction of nucleotides with membrane-associated cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 268, 15336–15339.

    Google Scholar 

  • Tsui, L.-C. (1997). CF Genetic Analysis Consortium. http: // 199.0.26.114/.

  • Vaandrager, A. B., Tilly, B. C., Smolenski, A., Schneider-Rasp, S., Bot, A. G. M., Edixhoven, M., Scholte, B. J., Jarchau, T., Walter, U., Lohmann, S. M., Poller, W. C., and de Jonge, H. R. (1997). “cGMP stimulation of cystic fibrosis transmembrane conductance regulator chloride channels co-expressed with cGMP-dependent protein kinase type II but not type Iβ,” J. Biol. Chem. 272, 4195–4200.

    Google Scholar 

  • Venglarik, C. J., Schultz, B. D., Frizzell, R. A., and Bridges, R. J. (1994). “ATP alters current fluctuations of cystic fibrosis transmembrane conductance regulator: evidence for a three-state activation mechanism,” J. Gen. Physiol. 104, 123–146.

    Google Scholar 

  • Venglarik, C. J., Schultz, B. D., DeRoos, A. D. G., Singh, A. K., and Bridges, R. J. (1996). “Tolbutamide causes open channel blockade of cystic fibrosis transmembrane conductance regulator chloride channels,” Biophys. J. 70, 2696–2703.

    Google Scholar 

  • Walker, J. E., Saraste, M., Runswick, M. J., and Gay, N. J. (1982). “Distantly related sequences in the alpha-and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold,” Embo J. 1, 945–951.

    Google Scholar 

  • Ward, C. L., and Kopito, R. R. (1994). “Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins,” J. Biol. Chem. 269, 25710–25718.

    Google Scholar 

  • Ward, C. L., Omura, S., and Kopito, R. R. (1995). “Degradation of CFTR by the ubiquitin-proteasome pathway,” Cell 83, 121–127.

    Google Scholar 

  • Welch, W. J., and Brown, C. R. (1996). “Influence of molecular and chemical chaperones on protein folding,” Cell Stress and Chap. 1, 109–115.

    Google Scholar 

  • Wilkinson, D. J., Mansoura, M. K., Watson, P. Y., Smit, L. S., Collins, F. S., and Dawson, D. C. (1996). “CFTR: the nucleotide binding folds regulate the accessibility and stability of the activated state,” J. Gen. Physiol. 107, 103–119.

    Google Scholar 

  • Williamson, J. R., and Corkey, B. E. (1969). in Methods Enzymol. 13, 434–513.

    Google Scholar 

  • Winter, M. C., Sheppard, D. N., Carson, M. R., and Welsh, M. J. (1994). “Effect of ATP concentration on CFTR Cl− channels: a kinetic analysis of channel regulation,” Biophys. J. 66, 1398–1403.

    Google Scholar 

  • Xie, J., Drumm, M. L., Ma, J., and Davis, P. B. (1995).“Intracellular loop between transmembrane segments IV and V of cystic fibrosis transmembrane conductance regulator is involved in regulation of chloride channel conductance state,” J. Biol. Chem. 270, 28084–28091.

    Google Scholar 

  • Xie, J., Drumm, M. L., Zhao, J., Ma, J., and Davies, P. B. (1996). “Human epithelial cystic fibrosis transmembrane conductance regulator exon 5 maintains partial chloride channel function in intracellular membranes,” Biophys. J. 71, 3148–3156.

    Google Scholar 

  • Yang, Y., Janich, S., Cohn, J. A., and Wilson, J. M. (1993). “The common variant of cystic fibrosis transmembrane conductance regulator is recognized by hsp70 and degraded in a pre-Golgi nonlysosomal compartment,” Proc. Natl. Acad. Sci. USA 90, 9480–9484.

    Google Scholar 

  • Zhang, Y., Yankaskas J., Wilson, J., and Engelhardt, J. F. (1996). “In vivo analysis of fluid transport in cystic fibrosis epithelia of bronchial xenografts,” Am. J. Physiol. 270, C1326–1335.

    Google Scholar 

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Authors and Affiliations

  1. Mayo Graduate School of Medicine and Department of Biochemistry and Molecular Biology, S. C, Johnson Medical Research Center, Mayo Clinic, Scottsdale, Arizona, 85259

    John R. Riordan

  2. Medical Research Council Group in Membrane Biology, Departments of Medicine and Biochemistry, University of Toronto, Toronto, Ontario, Canada, M5S 1A8

    Fabian S. Seibert, Tip W. Loo & David M. Clarke

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  2. Tip W. Loo
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Seibert, F.S., Loo, T.W., Clarke, D.M. et al. Cystic Fibrosis: Channel, Catalytic, and Folding Properties of the CFTR Protein. J Bioenerg Biomembr 29, 429–442 (1997). https://doi.org/10.1023/A:1022478822214

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