Skip to main content
SpringerLink
Log in

CFTR: Domains, Structure, and Function

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) (Collins, 1992). Over 500 naturally occurring mutations have been identified in CF gene which are located in all of the domains of the protein (Kerem et al., 1990; Mercier et al., 1993; Ghanem et al., 1994; Fanen et al., 1992; Ferec et al., 1992; Cutting et al., 1990). Early studies by several investigators characterized CFTR as a chloride channel (Anderson et al.; 1991b,c; Bear et al., 1991). The complex secondary structure of the protein suggested that CFTR might possess other functions in addition to being a chloride channel. Studies have established that the CFTR functions not only as a chloride channel but is indeed a regulator of sodium channels (Stutts et al., 1995), outwardly rectifying chloride channels (ORCC) (Gray et al., 1989; Garber et al., 1992; Egan et al., 1992; Hwang et al., 1989; Schwiebert et al., 1995) and also the transport of ATP (Schwiebert et al., 1995; Reisin et al., 1994). This mini-review deals with the studies which elucidate the functions of the various domains of CFTR, namely the transmembrane domains, TMD1 and TMD2, the two cytoplasmic nucleotide binding domains, NBD1 and NBD2, and the regulatory, R, domain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

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 

  • Ames, G. F. L., Mimura, C. S., and Shyamala, V. (1990). “Bacterial periplasmic permeases belong to a family of transport proteins operating from Escherichia coli to human traffic ATPases,” FEMS Microbiol. Rev. 75, 429–446.

    Google Scholar 

  • Anderson, M. P., Berger, H. A., Rich, D. P., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1991). “Nucleotide triphosphates are required to open the CFTR chloride channel,” Cell 87, 775–784.

    Google Scholar 

  • Anderson, M. P., Rich, D. P., Gregory, R. J., Smith, A. E., and Welsh, M. J. (1991b). “Generation of cAMP-activated chloride currents by expression of CFTR,” Science 251, 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. (1991c). “Demonstration that CFTR is a chloride channel by alteration of its anion selectivity,” Science 253, 202–205.

    Google Scholar 

  • Bear, C. E., Duguay, F., Naismath, 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., 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 

  • Berger, H. A., Travis, S. M., and Welsh, M. J. (1993). “Regulation of the cystic fibrosis transmembrane conductance regulator by specific protein kinases and protein phosphatases,” J. Biol. Chem. 268, 22037–2047.

    Google Scholar 

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

    Google Scholar 

  • Carroll, T. P., McIntosh, I., Egan, M. E., Zeitlin, P. L., Cutting, G. R., and Guggino, W. B. (1995b). “Transmembrane mutations alter the channel characteristics of the cystic fibrosis transmembrane conductance regulator expressed in Xenopus Oocytes,” Cell Physiol. Biochem. 362, 160–164.

    Google Scholar 

  • Carson, M. R., Travis, S. M., and Welsh, M. J. (1995). “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 

  • 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., Rich, D. P., Marshall, J., Gregory, R. J., Welsh, M. J., and Smith, A. E. (1991). “Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel,” Cell 66, 1027–1036.

    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 

  • Collins, F. S. (1992). “Cystic fibrosis: molecular biology and therapeutic implications,” Science 256, 774–779.

    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 the cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 271, 21279–21284.

    Google Scholar 

  • Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L. C., Antonarakis, S. E., and Kazazian, H. H. J. (1990). “A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein,” Nature 346, 366–369.

    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 ΔF508 cystic fibrosis mutation,” Nature (London) 354, 526–528.

    Google Scholar 

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

    Google Scholar 

  • Deversen, E. V., Gow, I. R., Coadwell, W. J., Monaco, J. J., Butcher, G. W., and Howard, J. C. (1990). “MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters,” Nature (London) 348, 738–741.

    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 ΔF508 and other mutant CFTRs in Xenopus oocytes,” Science 254, 1797–1799.

    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 (London) 358, 781–584.

    Google Scholar 

  • Fanen, P., Ghanem, N., Vidaud, M., Besmond, C., Martin, J., Costyes, B., Plassa, F., and Goossens, M. (1992). “Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions,” Genomics 13, 770–776.

    Google Scholar 

  • Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Querec, I., and Verlingue, C. (1992). “Detection of over 98% cystic fibrosis mutations in a Celtic population,” Nature Genet. 1, 188–191.

    Google Scholar 

  • Garber, S. S. (1992). “Outwardly rectifying chloride channels in lymphocytes,” J. Membr. Biol. 127, 49–56.

    Google Scholar 

  • Ghanem, N., Costes, B., Giorodon, E., Martin, J., Fanen, P., and Goossens, M. (1994). “Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene,” Genomics 21, 434–436.

    Google Scholar 

  • Gray, M. A., Harris, A., Coleman, L., Greenwell, J. R., and Argent, B. E. (1989). “Two types of chloride channels on duct cells cultured from human fetal pancreas,” Am. J. Physiol. 257, C240–C251.

    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 the cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2,” Mol. Cell. Biol. 11, 3886–3893.

    Google Scholar 

  • Higgins, C. F., Hiles, I. D., Salmond, G. P. C., Gill, D. R., Downie, J. A., Evans, I. J., Holland, I. B., Buckel, S. D., Bell, A. W., and Hermondson, M. A. (1986). “A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria,” Nature (London) 323, 448–450.

    Google Scholar 

  • Hwang, T. C., Lu, L., Zeitlin, P. L., Gruenert, D. C., Huganir, R., and Guggino, W. B. (1989). “Chloride channels in CF: Lack of activation by protein kinase C and cAMP-dependent protein kinase,” Science 244, 1351–1353.

    Google Scholar 

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

    Google Scholar 

  • Hyde, S. C., Emsley, P., Hartshorn, M. J., Mimmack, M. M., Gileadi, U., Pearce, S. R., Gallagher, M. P., Gill, D. R., Hubbard, R. E., and Higgins, C. F. (1990). “Structural model of ATP binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport,” Nature (London) 346, 362–365.

    Google Scholar 

  • Kerem, B. S., Zielenski, J., Markiewiz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., and Rommens, J. M. (1990). “Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene,” Proc. Natl. Acad. Sci. USA 87, 8447–8451.

    Google Scholar 

  • Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N., and Sheng, M. (1995). “Clustering of the Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases,” Nature 378, 85–88.

    Google Scholar 

  • Kim, E., Cho, K. O., Rothschild, A., and Sheng, M. (1996). “Hetero-multimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins,” Neuron 17, 103–113.

    Google Scholar 

  • McCarty, N. A., McDonough, S., Cohen, B. N., Riordan, J. R., Davidson, N., and Lester, H. A. (1993). “Voltage-dependent block of the cystic fibrosis transmembrane conductance regulator channel by two closely related arylaminobenzoates,” J. Gen. Physiol. 102, 1–23.

    Google Scholar 

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

    Google Scholar 

  • Mercier, B., Lissens, W., Novelli, G., Kalaydjiev, L., DeArce, M., Kapranov, N., Canki-Klain, N., Lenoir, G., Chauveau, P., Lenaerts, C., Rault, S., Cashman, S., Sanguiolo, F., Audrezet, M. P., Dallapiccola, B., Guillermit, H., Bonduelle, M., Liebaers, I., Quere, I., Verlingue, C., and Ferec, C. (1993). “ Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene,” Genomics 16, 296–297.

    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 the kidney,” Am. J. Physiol. 270, F1038–F1048.

    Google Scholar 

  • Moser, J. A., Douar, A. M., Sarde, C. O., Kioschis, P., Feil, R., Moser, H., Poustka, A. M., Mandel, J. L., and Aubourg, P. (1993). “Putative X-linked adrenoleukodystropy gene shares unexpected homology with ABC transporters,” Nature (London) 361, 726–730.

    Google Scholar 

  • Picciotto, M. R., Cohn, J. A., Bertuzzi, G., Greengard, P., and Nairn, A. C. (1992). “Phosphorylation of cystic fibrosis transmembrane conductance regulator,” J. Biol. Chem. 267, 12742–12752.

    Google Scholar 

  • Reisin, I. L., Prat, A. G., Abraham, E. H., Amara, J. F., Gregory, R. J., Ausiello, D. A., and Cantiello, H. F. (1994). “The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel,” J. Biol. Chem. 269, 20584–20591.

    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 

  • Riordan, J. M., Rommens, J. M., Kerem, B. S., Alon, N., Rozmahel, R., Grzelvzak, Z., Zeilenski, 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 

  • Savov, A., Mercier, B., Kalaydjieva, L., and Ferec, C. (1994). “Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty-seven exons and exon/intron boundaries using DGGE and direct DNA sequencing,” Hum. Mol. Genet. 3, 57–60.

    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 currents through an autocrine mechanism involving ATP,” Cell 81, 1063–1073.

    Google Scholar 

  • Sheng, M. (1996). “PDZs and receptor/channel clustering: Rounding up the latest suspects,” Neuron 17, 575–578.

    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 for Cl− channels with altered pore properties,” Nature (London) 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 

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

    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, 847–849.

    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., 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 (London) 352, 628–631.

    Google Scholar 

  • Valle, D., and Gartner, J. (1993). “Penetrating the peroxisome,” Nature (London) 361, 682–683.

    Google Scholar 

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

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205

    Sreenivas Devidas & William B. Guggino

Authors
  1. Sreenivas Devidas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William B. Guggino
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Devidas, S., Guggino, W.B. CFTR: Domains, Structure, and Function. J Bioenerg Biomembr 29, 443–451 (1997). https://doi.org/10.1023/A:1022430906284

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022430906284

Search

Navigation