| Structural highlights
Function
[CFTR_DANRE] Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis (PubMed:20933420, PubMed:23487313, PubMed:25592226). Mediates the transport of chloride ions across the cell membrane (By similarity). Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer (By similarity). Required for normal fluid homeostasis in the gut (PubMed:20933420). Required for normal volume expansion of Kupffer's vesicle during embryonic development and for normal establishment of left-right body patterning (PubMed:23487313, PubMed:26432887). Required for normal resistance to infection by P.aeruginosa strain PA14 and strain SMC573 (PubMed:20732993).[UniProtKB:P13569][1] [2] [3] [4] [5]
Publication Abstract from PubMed
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from an ATP-binding cassette transporter. CFTR channel gating is strictly coupled to phosphorylation and ATP hydrolysis. Previously, we reported essentially identical structures of zebrafish and human CFTR in the dephosphorylated, ATP-free form. Here, we present the structure of zebrafish CFTR in the phosphorylated, ATP-bound conformation, determined by cryoelectron microscopy to 3.4 A resolution. Comparison of the two conformations shows major structural rearrangements leading to channel opening. The phosphorylated regulatory domain is disengaged from its inhibitory position; the nucleotide-binding domains (NBDs) form a "head-to-tail" dimer upon binding ATP; and the cytoplasmic pathway, found closed off in other ATP-binding cassette transporters, is cracked open, consistent with CFTR's unique channel function. Unexpectedly, the extracellular mouth of the ion pore remains closed, indicating that local movements of the transmembrane helices can control ion access to the pore even in the NBD-dimerized conformation.
Conformational Changes of CFTR upon Phosphorylation and ATP Binding.,Zhang Z, Liu F, Chen J Cell. 2017 Jul 27;170(3):483-491.e8. doi: 10.1016/j.cell.2017.06.041. Epub 2017, Jul 20. PMID:28735752[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Phennicie RT, Sullivan MJ, Singer JT, Yoder JA, Kim CH. Specific resistance to Pseudomonas aeruginosa infection in zebrafish is mediated by the cystic fibrosis transmembrane conductance regulator. Infect Immun. 2010 Nov;78(11):4542-50. doi: 10.1128/IAI.00302-10. Epub 2010 Aug, 23. PMID:20732993 doi:http://dx.doi.org/10.1128/IAI.00302-10
- ↑ Bagnat M, Navis A, Herbstreith S, Brand-Arzamendi K, Curado S, Gabriel S, Mostov K, Huisken J, Stainier DY. Cse1l is a negative regulator of CFTR-dependent fluid secretion. Curr Biol. 2010 Oct 26;20(20):1840-5. doi: 10.1016/j.cub.2010.09.012. Epub 2010, Oct 7. PMID:20933420 doi:http://dx.doi.org/10.1016/j.cub.2010.09.012
- ↑ Navis A, Marjoram L, Bagnat M. Cftr controls lumen expansion and function of Kupffer's vesicle in zebrafish. Development. 2013 Apr;140(8):1703-12. doi: 10.1242/dev.091819. Epub 2013 Mar 13. PMID:23487313 doi:http://dx.doi.org/10.1242/dev.091819
- ↑ Roxo-Rosa M, Jacinto R, Sampaio P, Lopes SS. The zebrafish Kupffer's vesicle as a model system for the molecular mechanisms by which the lack of Polycystin-2 leads to stimulation of CFTR. Biol Open. 2015 Oct 2;4(11):1356-66. doi: 10.1242/bio.014076. PMID:26432887 doi:http://dx.doi.org/10.1242/bio.014076
- ↑ Navis A, Bagnat M. Loss of cftr function leads to pancreatic destruction in larval zebrafish. Dev Biol. 2015 Mar 15;399(2):237-48. doi: 10.1016/j.ydbio.2014.12.034. Epub 2015 , Jan 13. PMID:25592226 doi:http://dx.doi.org/10.1016/j.ydbio.2014.12.034
- ↑ Zhang Z, Liu F, Chen J. Conformational Changes of CFTR upon Phosphorylation and ATP Binding. Cell. 2017 Jul 27;170(3):483-491.e8. doi: 10.1016/j.cell.2017.06.041. Epub 2017, Jul 20. PMID:28735752 doi:http://dx.doi.org/10.1016/j.cell.2017.06.041
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