Advertisement

Cellular and Molecular Life Sciences

, Volume 75, Issue 20, pp 3829–3855 | Cite as

Combining theoretical and experimental data to decipher CFTR 3D structures and functions

  • Brice Hoffmann
  • Ahmad Elbahnsi
  • Pierre Lehn
  • Jean-Luc Décout
  • Fabio Pietrucci
  • Jean-Paul Mornon
  • Isabelle Callebaut
Original Article

Abstract

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.

Keywords

CFTR ABC exporter Filamin Comparative modeling Metadynamics Cryo-electron microscopy 

Notes

Acknowledgements

This work was funded by the French Association Vaincre La Mucoviscidose (Paris). It was granted access to the HPC resources of IDRIS/CINES under the allocations 2014-077206, 2015-077206, 2016-077206, and 0020707206 made by GENCI.

Supplementary material

18_2018_2835_MOESM1_ESM.pdf (6 mb)
Supplementary material 1 (PDF 6175 kb)

References

  1. 1.
    Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA, O’Riordan CR, Smith AE (1990) Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63:827–834CrossRefGoogle Scholar
  2. 2.
    Gadsby DC (2009) Ion channels versus ion pumps: the principal difference, in principle. Nat Rev Mol Cell Biol 10:344–352CrossRefGoogle Scholar
  3. 3.
    Aleksandrov LA, Jensen TJ, Cui L, Kousouros JN, He L, Aleksandrov AA, Riordan JR (2015) Thermal stability of purified and reconstituted CFTR in a locked open channel conformation. Protein Expr Purif 116:159–166CrossRefGoogle Scholar
  4. 4.
    Bozoky Z, Krzeminski M, Chong P, Forman-Kay JD (2013) Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions. FEBS J 280:4407–4416CrossRefGoogle Scholar
  5. 5.
    Callebaut I, Hoffmann B, Mornon J-P (2017) The implications of CFTR structural studies for cystic fibrosis drug development. Curr Opin Pharmacol 34:112–118CrossRefGoogle Scholar
  6. 6.
    Zhang Z, Chen J (2016) Atomic structure of the cystic fibrosis transmembrane conductance regulator. Cell 167:1586–1597CrossRefGoogle Scholar
  7. 7.
    Liu F, Zhang Z, Csanády L, Gadsby DC, Chen J (2017) Molecular structure of the human CFTR ion channel. Cell 169:85–95CrossRefGoogle Scholar
  8. 8.
    Zhang Z, Liu F, Chen J (2017) Conformational changes of CFTR upon phosphorylation and ATP binding. Cell 170:483–491CrossRefGoogle Scholar
  9. 9.
    Tordai H, Leveles I, Hegedus T (2017) Molecular dynamics of the cryo-EM CFTR structure. Biochem Biophys Res Commun 491:986–993CrossRefGoogle Scholar
  10. 10.
    Corradi V, Gu R-X, Vergani P, Tieleman D (2018) Structure of transmembrane helix 8 and possible membrane defects in CFTR. Biophys J 114:1751–1754CrossRefGoogle Scholar
  11. 11.
    Callebaut I, Hoffmann B, Lehn P, Mornon J-P (2017) Molecular modelling and molecular dynamics of CFTR. Cell Mol Life Sci 74:3–22CrossRefGoogle Scholar
  12. 12.
    Dalton J, Kalid O, Schushan M, Ben-Tal N, Villà-Freixa J (2012) New model of cystic fibrosis transmembrane conductance regulator proposes active channel-like conformation. J Chem Inf Model 52:1842–1853CrossRefGoogle Scholar
  13. 13.
    Norimatsu Y, Ivetac A, Alexander C, O’Donnell N, Frye L, Sansom MS, Dawson DC (2012) Locating a plausible binding site for an open-channel blocker, GlyH-101, in the pore of the cystic fibrosis transmembrane conductance regulator. Mol Pharmacol 82:1042–1055CrossRefGoogle Scholar
  14. 14.
    Mornon J-P, Hoffmann B, Jonic S, Lehn P, Callebaut I (2015) Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics. Cell Mol Life Sci 72:1377–1403CrossRefGoogle Scholar
  15. 15.
    Corradi V, Vergani P, Tieleman DP (2015) Cystic fibrosis transmembrane conductance regulator (CFTR): closed and open state channel models. J Biol Chem 290:22891–22906CrossRefGoogle Scholar
  16. 16.
    Das J, Aleksandrov AA, Cui L, He L, Riordan JR, Dokholyan NV (2017) Transmembrane helical interactions in the CFTR channel pore. PLoS Comput Biol 13:e1005594CrossRefGoogle Scholar
  17. 17.
    Linsdell P (2014) Functional architecture of the CFTR chloride channel. Mol Membr Biol 31:1–16CrossRefGoogle Scholar
  18. 18.
    Cui G, Freeman CS, Knotts T, Prince CZ, Kuang C, McCarty NA (2013) Two salts bridges differentially contribute to the maintenance of cystic fibrosis transmembrane conductance regulator (CFTR) channel function. J Biol Chem 288:20758–20767CrossRefGoogle Scholar
  19. 19.
    Cui G, Zhang ZR, O’Brien AR, Song B, McCarty NA (2008) Mutation at arginine 352 alters the pore architecture of CFTR. J Membr Biol 222:91–106CrossRefGoogle Scholar
  20. 20.
    Cotten JF, Welsh MJ (1999) Cystic fibrosis-associated mutations at arginine 347 alter the pore architecture of CFTR. Evidence for disruption of a salt bridge. J Biol Chem 274:5429–5435CrossRefGoogle Scholar
  21. 21.
    El Hiani Y, Linsdell P (2015) Functional architecture of the cytoplasmic entrance to the cystic fibrosis transmembrane conductance regulator chloride channel pore. J Biol Chem 290:15855–15865CrossRefGoogle Scholar
  22. 22.
    El Hiani Y, Negoda A, Linsdell P (2016) Cytoplasmic pathway followed by chloride ions to enter the CFTR channel pore. Cell Mol Life Sci 73:1917–1925CrossRefGoogle Scholar
  23. 23.
    Gao X, Hwang TC (2015) Localizing a gate in CFTR. Proc Natl Acad Sci USA 112:2461–2466CrossRefGoogle Scholar
  24. 24.
    Negoda A, El Hiani Y, Cowley EA, Linsdell P (2017) Contribution of a leucine residue in the first transmembrane segment to the selectivity filter region in the CFTR chloride channel. Biochem Biophys Acta 1859:1049–1058CrossRefGoogle Scholar
  25. 25.
    Marti-Renom MA, Stuart A, Fiser A, Sánchez R, Melo F, Sali A (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29:291–325CrossRefGoogle Scholar
  26. 26.
    Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S et al (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614CrossRefGoogle Scholar
  27. 27.
    Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem 29:1859–1865CrossRefGoogle Scholar
  28. 28.
    Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, Wei S, Buckner J, Jeong JC, Yl Qi (2016) CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J Chem Theory Comput 12:405–413CrossRefGoogle Scholar
  29. 29.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935CrossRefGoogle Scholar
  30. 30.
    Lamoureux G, Roux B (2006) Absolute hydration free energy scale for alkali and halide ions established from simulations with a polarizable force field. J Phys Chem B 110:3308–3322CrossRefGoogle Scholar
  31. 31.
    Beglov D, Roux B (1994) Finite representation of an infinite bulk system: solvent boundary potential for computer simulations. J Chem Phys 100:9050–9063CrossRefGoogle Scholar
  32. 32.
    Hart K, Foloppe N, Baker CM, Denning EJ, Nilsson L, Mackerell AD (2012) Optimization of the CHARMM additive force field for DNA: improved treatment of the BI/BII conformational equilibrium. J Chem Theory Comput 8:348–362CrossRefGoogle Scholar
  33. 33.
    Mackerell AD (2004) Empirical force fields for biological macromolecules: overview and issues. J Comput Chem 25:1584–1604CrossRefGoogle Scholar
  34. 34.
    Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K (2005) scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802CrossRefGoogle Scholar
  35. 35.
    Fletcher R (ed) (2000) Practical methods of optimization: fletcher/practical methods of optimization. Wiley, ChichesterGoogle Scholar
  36. 36.
    Feller SE, Zhang Y, Pastor RW, Brooks BR (1995) Constant pressure molecular dynamics simulation: the Langevin piston method. J Chem Phys 103:4613–4621CrossRefGoogle Scholar
  37. 37.
    Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092CrossRefGoogle Scholar
  38. 38.
    Laio A, Parrinello M (2002) Escaping free-energy minima. Proc Natl Acad Sci 99(99):12562–12566CrossRefGoogle Scholar
  39. 39.
    Tribello GA, Bonomi M, Branduardi D, Camilloni C, Bussi G (2014) PLUMED 2: new feathers for an old bird. Comput Phys Commun 185:604–613CrossRefGoogle Scholar
  40. 40.
    Pietrucci F (2017) Strategies for the exploration of free energy landscapes: unity in diversity and challenges ahead. Rev Phys 2:32–45CrossRefGoogle Scholar
  41. 41.
    Branduardi D, Gervasio FL, Parrinello M (2007) From A to B in free energy space. J Chem Phys 126:054103CrossRefGoogle Scholar
  42. 42.
    Crespo Y, Marinelli F, Pietrucci F, Laio A (2010) Metadynamics convergence law in a multidimensional system. Phys Rev E Stat Nonlinear Soft Matter Phys 81:055701CrossRefGoogle Scholar
  43. 43.
    Johansson MU, Zoete V, Michielin O, Guex N (2012) Defining and searching for structural motifs using DeepView/Swiss-PdbViewer. BMC Bioinform 13:173CrossRefGoogle Scholar
  44. 44.
    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612CrossRefGoogle Scholar
  45. 45.
    Harrisson CB, Schulten K (2012) Quantum and classical dynamics simulations of ATP hydrolysis in solution. J Chem Theory Comput 8:2328–2335CrossRefGoogle Scholar
  46. 46.
    de Meis L (1989) Role of water in the energy of hydrolysis of phosphate compounds—energy transduction in biological membranes. Biochem Biophys Acta 973:333–349PubMedGoogle Scholar
  47. 47.
    George P, Witonsky RJ, Trachtman M, Wu C, Dorwart W, Richman L, Richman W, Shurayh F, Lentz B (1970) “Squiggle-H2O”. An enquiry into the importance of solvation effects in phosphate ester and anhydride reactions. Biochem Biophys Acta 223:1–15PubMedGoogle Scholar
  48. 48.
    Vergani P, Nair AC, Gadsby D (2003) On the machanism of MgATP-dependent gating of CFTR Cl channels. J Gen Physiol 121:17–36CrossRefGoogle Scholar
  49. 49.
    Fay JF, Aleksandrov LA, Jensen TJ, Cui LL, Kousouros JN, He L, Aleksandrov AA, Gingerich DS, Riordan J, Chen JZ (2018) Cryo-EM visualization of an active high open probability CFTR ion channel. bioRxiv 274316Google Scholar
  50. 50.
    Alam A, Küng R, Kowal J, McLeod R, Tremp N, Broude E, Roninson I, Stahlberg H, Locher K (2018) Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1. Proc Natl Acad Sci USA 115:E1973–E1982CrossRefGoogle Scholar
  51. 51.
    Kim Y, Chen J (2018) Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science 359:915–919CrossRefGoogle Scholar
  52. 52.
    Johnson ZL, Chen J (2017) Structural basis of substrate recognition by the multidrug resistance protein MRP1. Cell 68:1075–1085CrossRefGoogle Scholar
  53. 53.
    Hohl M, Hürlimann LM, Böhm S, Schöppe J, Grütter MG, Bordignon E, Seeger MA (2014) Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter. Proc Natl Acad Sci USA 111:11025–11030CrossRefGoogle Scholar
  54. 54.
    Cooley RB, Arp DJ, Karplus PA (2010) Evolutionary origin of secondary structures: π-helices as cryptic but widespread insertional variations of α-helices that enhance protein functionality. J Mol Biol 404:232–246CrossRefGoogle Scholar
  55. 55.
    Riek RP, Graham RM (2011) The elusive π-helix. J Struct Biol 173:153–160CrossRefGoogle Scholar
  56. 56.
    Li M, Cowley E, El Hiani Y, Linsdell P (2018) Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore. J Biol Chem 293:5649–5658CrossRefGoogle Scholar
  57. 57.
    Barreto-Ojeda E, Corradi V, Gu RX, Tieleman DP (2018) Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein. J Gen Physiol.  https://doi.org/10.1085/jgp.201711907 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443:180–185CrossRefGoogle Scholar
  59. 59.
    Ward A, Reyes CL, Yu J, Roth CB, Chang G (2007) Flexibility in the ABC transporter MsbA: alternating access with a twist. Proc Natl Acad Sci USA 104:19005–19010CrossRefGoogle Scholar
  60. 60.
    Katzmann D, Epping E, Moye-Rowley W (1999) Mutational disruption of plasma membrane trafficking of Saccharomyces cerevisiae Yor1p, a homologue of mammalian multidrug resistance protein. Mol Cell Biol 19:2998–3009CrossRefGoogle Scholar
  61. 61.
    Göddeke H, Timachi M, Hutter C, Galazzo L, Seeger M, Karttunen M, Bordignon E, Schäfer L (2018) Atomistic mechanism of large-scale conformational transition in a heterodimeric ABC exporter. J Am Chem Soc 140:4543–4551CrossRefGoogle Scholar
  62. 62.
    Locher KP (2016) Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat Struct Mol Biol 23:487–493CrossRefGoogle Scholar
  63. 63.
    Karpowich N, Martsinkevich O, Millen L, Yuan YR, Dai PL, MacVey K, Thomas PJ, Hunt JF (2001) Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. Structure 9:571–586CrossRefGoogle Scholar
  64. 64.
    Naoe Y, Nakamura N, Doi A, Sawabe M, Nakamura H, Shiro Y, Sugimoto H (2016) Crystal structure of bacterial haem importer complex in the inward-facing conformation. Nat Commun 7:13411CrossRefGoogle Scholar
  65. 65.
    Woo J, Zeltina A, Goetz B, Locher K (2012) X-ray structure of the Yersinia pestis heme transporter HmuUV. Nat Struct Mol Biol 19:1310–1315CrossRefGoogle Scholar
  66. 66.
    Wang C, Karpowich N, Hunt J, Rance M, Palmer A (2004) Dynamics of ATP-binding cassette contribute to allosteric control, nucleotide binding and energy transduction in ABC transporters. J Mol Biol 342:525–537CrossRefGoogle Scholar
  67. 67.
    Li N, Wu JX, Ding D, Cheng J, Gao N, Chen L (2017) Structure of a pancreatic ATP-sensitive potassium channel. Cell 168:101–110CrossRefGoogle Scholar
  68. 68.
    Martin GM, Yoshioka C, Rex EA, Fay JF, Xie Q, Whorton MR, Chen JZ, Shyng SL (2017) Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. Elife 6:e24149CrossRefGoogle Scholar
  69. 69.
    Thelin WR, Chen Y, Gentzsch M, Kreda SM, Sallee JL, Scarlett CO, Borchers CH, Jacobson K, Stutts MJ, Milgram SL (2007) Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Investig 117:364–374CrossRefGoogle Scholar
  70. 70.
    Feng Y, Walsh CA (2004) The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034–1038CrossRefGoogle Scholar
  71. 71.
    Nakamura F, Stossel TP, Hartwig JH (2011) The filamins. Cell Adhes Migr 5:160–169CrossRefGoogle Scholar
  72. 72.
    Playford MP, Nurminen E, Pentikäinen OT, Milgram SL, Hartwig JH, Stossel TP, Nakamura F (2010) Cystic fibrosis transmembrane conductance regulator interacts with multiple immunoglobulin domains of filamin A. J Biol Chem 285:17156–17165CrossRefGoogle Scholar
  73. 73.
    Smith L, Page RC, Xu Z, Kohli E, Litman P, Nix J, Ithychanda SS, Liu J, Qin J, Misra S et al (2010) Biochemical basis of the interaction between cystic fibrosis transmembrane conductance regulator and immunoglobulin-like repeats of filamin. J Biol Chem 285:17166–17176CrossRefGoogle Scholar
  74. 74.
    Light S, Sagit R, Ithychanda SS, Qin J, Elofsson A (2015) The evolution of filamin-a protein domain repeat perspective. J Struct Biol 179:289–298CrossRefGoogle Scholar
  75. 75.
    Sampson LJ, Leyland ML, Dart C (2003) Direct interaction between the actin-binding protein filamin-A and the inwardly rectifying potassium channel, Kir2.1. J Biol Chem 278:41988–41997CrossRefGoogle Scholar
  76. 76.
    Sethi R, Seppälä J, Tossavainen H, Ylilauri M, Ruskamo S, Pentikäinen OT, Pentikäinen U, Permi P, Ylänne J (2014) A novel structural unit in the N-terminal region of filamins. J Biol Chem 289:8588–8598CrossRefGoogle Scholar
  77. 77.
    Gaboriaud C, Bissery V, Benchetrit T, Mornon JP (1987) Hydrophobic cluster analysis: an efficient new way to compare and analyse amino acid sequences. FEBS Lett 224:149–155CrossRefGoogle Scholar
  78. 78.
    Callebaut I, Labesse G, Durand P, Poupon A, Canard L, Chomilier J, Henrissat B, Mornon J-P (1997) Deciphering protein sequence information through hydrophobic cluster analysis (HCA): current status and perspectives. Cell Mol Life Sci 53:621–645CrossRefGoogle Scholar
  79. 79.
    Bitard-Feildel T, Callebaut I (2017) Exploring the dark foldable proteome by considering hydrophobic amino acids topology. Sci Rep 7:41425CrossRefGoogle Scholar
  80. 80.
    Eudes R, Le Tuan K, Delettré J, Mornon J-P, Callebaut I (2007) A generalized analysis of hydrophobic and loop clusters within globular protein sequences. BMC Struct Biol 7:2CrossRefGoogle Scholar
  81. 81.
    Rebehmed J, Quintus F, Mornon J-P, Callebaut I (2016) The respective roles of polar/nonpolar binary patterns and amino acid composition in protein regular secondary structures explored exhaustively using hydrophobic cluster analysis. Proteins 84:624–638CrossRefGoogle Scholar
  82. 82.
    Wang W, He Z, O’Shaughnessy TJ, Rux J, Reenstra WW (2002) Domain-domain associations in cystic fibrosis transmembrane conductance regulator. Am J Physiol Cell Physiol 282:C1170–C1180CrossRefGoogle Scholar
  83. 83.
    Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW, Hong JS, Pollard HB, Guggino WB, Balch WE et al (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424–433CrossRefGoogle Scholar
  84. 84.
    Chang SY, Di A, Naren AP, Palfrey HC, Kirk KL, Nelson DJ (2002) Mechanisms of CFTR regulation by syntaxin 1A and PKA. J Cell Sci 115:783–791PubMedGoogle Scholar
  85. 85.
    Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL (2002) CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex. Proc Natl Acad Sci USA 99:12477–12482CrossRefGoogle Scholar
  86. 86.
    Li C, Roy K, Dandridge K, Naren AP (2004) Molecular assembly of cystic fibrosis transmembrane conductance regulator in plasma membrane. J Biol Chem 279:24673–24684CrossRefGoogle Scholar
  87. 87.
    Ameen N, Silvis M, Bradbury NA (2007) Endocytic trafficking of CFTR in health and disease. J Cyst Fibros 6:1–14CrossRefGoogle Scholar
  88. 88.
    Peters KW, Qi J, Johnson JP, Watkins SC, Frizzell RA (2001) Role of snare proteins in CFTR and ENaC trafficking. Pflugers Arch 443:S65–S69CrossRefGoogle Scholar
  89. 89.
    Ford RC (2016) ABC7/CFTR. In: Goerge A (ed) ABC transporters—40 years on. Springer International Publishing, New York, pp 319–340CrossRefGoogle Scholar
  90. 90.
    Naren AP, Cormet-Boyaka E, Fu J, Villain M, Blalock JE, Quick MW, Kirk KL (1999) CFTR chloride channel regulation by an interdomain interaction. Science 286:544–548CrossRefGoogle Scholar
  91. 91.
    Protasevich I, Yang Z, Wang C, Atwell S, Zhao X, Emtage S, Wetmore D, Hunt J, Brouillette CG (2010) Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1. Protein Sci 19:1917–1931CrossRefGoogle Scholar
  92. 92.
    Wang C, Protasevich I, Yang Z, Seehausen D, Skalak T, Zhao X, Atwell S, Spencer Emtage J, Wetmore DR, Brouillette CG et al (2010) Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis. Protein Sci 19:1932–1947CrossRefGoogle Scholar
  93. 93.
    He L, Aleksandrov AA, An J, Cui L, Yang Z, Brouillette CG, Riordan JR (2015) Restauration of NBD1 thermal stability is necessary and sufficient to correct DF508 CFTR folding and assembly. J Mol Biol 427:106–120CrossRefGoogle Scholar
  94. 94.
    Bakos E, Evers R, Szakács G, Tusnády GE, Welker E, Szabó K, de Haas M, van Deemter L, Borst P, Váradi A et al (1998) Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. J Biol Chem 273:32167–32175CrossRefGoogle Scholar
  95. 95.
    Furini S, Domene C (2016) Computational studies of transport in ion channels using metadynamics. Biochim Biophys Acta 1858:1733–1740CrossRefGoogle Scholar
  96. 96.
    Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ (1993) Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 362:160–164CrossRefGoogle Scholar
  97. 97.
    Yu YC, Sohma Y, Hwang TC (2016) On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol 594:3227–3244CrossRefGoogle Scholar
  98. 98.
    Sorum B, Töröcsik B, Csanády L (2017) Asymmetry of movements in CFTR’s two ATP sites during pore opening serves their distinct functions. Elife 6:e29013CrossRefGoogle Scholar
  99. 99.
    Sorum B, Czégé D, Csanády L (2015) Timing of CFTR pore opening and structure of its transition state. Cell 163:724–733CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Brice Hoffmann
    • 1
    • 4
  • Ahmad Elbahnsi
    • 1
  • Pierre Lehn
    • 2
  • Jean-Luc Décout
    • 3
  • Fabio Pietrucci
    • 1
  • Jean-Paul Mornon
    • 1
  • Isabelle Callebaut
    • 1
  1. 1.Sorbonne Université, Muséum National d’Histoire Naturelle, UMR CNRS 7590, IRD, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMCParisFrance
  2. 2.INSERM U1078, SFR ScInBioS, Université de Bretagne OccidentaleBrestFrance
  3. 3.CNRS UMR5063, Université Grenoble-AlpesGrenobleFrance
  4. 4.IktosParisFrance

Personalised recommendations