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Cryo-EM Visualization of an Active High Open Probability CFTR Anion Channel.

Fay JF, Aleksandrov LA, Jensen TJ, Cui LL, Kousouros JN, He L, Aleksandrov AA, Gingerich DS, Riordan JR, Chen JZ
Biochemistry 57 6234-6246 (2018)
Cited: 21 times
EuropePMC logo PMID: 30281975

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, crucial to epithelial salt and water homeostasis, and defective due to mutations in its gene in patients with cystic fibrosis, is a unique member of the large family of ATP-binding cassette transport proteins. Regulation of CFTR channel activity is stringently controlled by phosphorylation and nucleotide binding. Structural changes that underlie transitions between active and inactive functional states are not yet fully understood. Indeed the first 3D structures of dephosphorylated, ATP-free, and phosphorylated ATP-bound states were only recently reported. Here we have determined the structure of inactive and active states of a thermally stabilized CFTR, the latter with a very high channel open probability, confirmed after reconstitution into proteoliposomes. These structures, obtained at nominal resolution of 4.3 and 6.6 Å, reveal a unique repositioning of the transmembrane helices and regulatory domain density that provide insights into the structural transition between active and inactive functional states of CFTR. Moreover, we observe an extracellular vestibule that may provide anion access to the pore due to the conformation of transmembrane helices 7 and 8 that differs from the previous orthologue CFTR structures. In conclusion, our work contributes detailed structural information on an active, open state of the CFTR anion channel.

Reviews - 6d3s mentioned but not cited (2)

  1. The role of the degenerate nucleotide binding site in type I ABC exporters. Stockner T, Gradisch R, Schmitt L. FEBS Lett 594 3815-3838 (2020)
  2. Recent Strategic Advances in CFTR Drug Discovery: An Overview. Rusnati M, D'Ursi P, Pedemonte N, Urbinati C, Ford RC, Cichero E, Uggeri M, Orro A, Fossa P. Int J Mol Sci 21 E2407 (2020)

Articles - 6d3s mentioned but not cited (2)

  1. Ins and outs of AlphaFold2 transmembrane protein structure predictions. Hegedűs T, Geisler M, Lukács GL, Farkas B. Cell Mol Life Sci 79 73 (2022)
  2. The molecular evolution of function in the CFTR chloride channel. Infield DT, Strickland KM, Gaggar A, McCarty NA. J Gen Physiol 153 e202012625 (2021)


Reviews citing this publication (6)

  1. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Lopes-Pacheco M. Front Pharmacol 10 1662 (2019)
  2. Regulation of CFTR Biogenesis by the Proteostatic Network and Pharmacological Modulators. Estabrooks S, Brodsky JL. Int J Mol Sci 21 E452 (2020)
  3. Multidrug Resistance in Mammals and Fungi-From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms. Khunweeraphong N, Kuchler K. Int J Mol Sci 22 4806 (2021)
  4. Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures. Martin GM, Sung MW, Shyng SL. Mol Cell Endocrinol 502 110667 (2020)
  5. Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy. Farinha CM, Callebaut I. Biosci Rep 42 BSR20212006 (2022)
  6. One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies. Ensinck MM, Carlon MS. Cells 11 1868 (2022)

Articles citing this publication (11)

  1. Discovering the chloride pathway in the CFTR channel. Farkas B, Tordai H, Padányi R, Tordai A, Gera J, Paragi G, Hegedűs T. Cell Mol Life Sci 77 765-778 (2020)
  2. Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory region of ABCC transporters. Bickers SC, Benlekbir S, Rubinstein JL, Kanelis V. Proc Natl Acad Sci U S A 118 e2025853118 (2021)
  3. Contribution of the eighth transmembrane segment to the function of the CFTR chloride channel pore. Negoda A, Hogan MS, Cowley EA, Linsdell P. Cell Mol Life Sci 76 2411-2423 (2019)
  4. NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis. Brandas C, Ludovico A, Parodi A, Moran O, Millo E, Cichero E, Baroni D. Biomolecules 11 1417 (2021)
  5. G551D mutation impairs PKA-dependent activation of CFTR channel that can be restored by novel GOF mutations. Wang W, Fu L, Liu Z, Wen H, Rab A, Hong JS, Kirk KL, Rowe SM. Am J Physiol Lung Cell Mol Physiol 319 L770-L785 (2020)
  6. Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator. Bahia MS, Khazanov N, Zhou Q, Yang Z, Wang C, Hong JS, Rab A, Sorscher EJ, Brouillette CG, Hunt JF, Senderowitz H. J Chem Inf Model 61 1762-1777 (2021)
  7. Molecular dynamics study of Cl- permeation through cystic fibrosis transmembrane conductance regulator (CFTR). Zeng ZW, Linsdell P, Pomès R. Cell Mol Life Sci 80 51 (2023)
  8. Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1. Padányi R, Farkas B, Tordai H, Kiss B, Grubmüller H, Soya N, Lukács GL, Kellermayer M, Hegedűs T. Comput Struct Biotechnol J 20 2587-2599 (2022)
  9. cryoWriter: a blotting free cryo-EM preparation system with a climate jet and cover-slip injector. Rima L, Zimmermann M, Fränkl A, Clairfeuille T, Lauer M, Engel A, Engel HA, Braun T. Faraday Discuss 240 55-66 (2022)
  10. Conformational Variability in Ground-State CFTR Lipoprotein Particle Cryo-EM Ensembles. Aleksandrov LA, Aleksandrov AA, Jensen TJ, Strauss JD, Fay JF. Int J Mol Sci 23 9248 (2022)
  11. Transmembrane Helices 7 and 8 Confer Aggregation Sensitivity to the Cystic Fibrosis Transmembrane Conductance Regulator. Kleizen B, de Mattos E, Papaioannou O, Monti M, Tartaglia GG, van der Sluijs P, Braakman I. Int J Mol Sci 24 15741 (2023)


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