scholarly journals Conformational Changes in a Pore-lining Helix Coupled to Cystic Fibrosis Transmembrane Conductance Regulator Channel Gating

2007 ◽  
Vol 283 (8) ◽  
pp. 4957-4966 ◽  
Author(s):  
Edward J. Beck ◽  
Yu Yang ◽  
Sirin Yaemsiri ◽  
Viswanathan Raghuram
Keyword(s):  
Cystic Fibrosis ◽  
Conformational Changes ◽  
Channel Gating ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane ◽  
Pore Lining

scholarly journals Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop

2015 ◽  
Vol 291 (4) ◽  
pp. 1854-1865 ◽  
Author(s):  
Annette Ehrhardt ◽  
W. Joon Chung ◽  
Louise C. Pyle ◽  
Wei Wang ◽  
Krzysztof Nowotarski ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Conformational Changes ◽  
Atp Hydrolysis ◽  
Channel Gating ◽  
Secretory Diarrhea ◽  
Chronic Obstructive ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Specific Domain ◽  
Cystic Fibrosis Transmembrane

In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating.

Intracellular Cysteines of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulate Channel Gating

2002 ◽  
Vol 12 (1) ◽  
pp. 1-008 ◽  
Author(s):  
Christian Ketchum ◽  
Hongwen Yue ◽  
Karen Alessi ◽  
Shreenivas Devidas ◽  
William Guggino ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Channel Gating ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

scholarly journals Molecular structure of the ATP-bound, phosphorylated human CFTR

2018 ◽  
Vol 115 (50) ◽  
pp. 12757-12762 ◽  
Author(s):  
Zhe Zhang ◽  
Fangyu Liu ◽  
Jue Chen
Keyword(s):  
Molecular Structure ◽  
Cystic Fibrosis ◽  
Conformational Changes ◽  
Anion Channel ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Common Features ◽  
Proper Functions ◽  
Cystic Fibrosis Transmembrane ◽  
Kinase A

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel important in maintaining proper functions of the lung, pancreas, and intestine. The activity of CFTR is regulated by ATP and protein kinase A-dependent phosphorylation. To understand the conformational changes elicited by phosphorylation and ATP binding, we present here the structure of phosphorylated, ATP-bound human CFTR, determined by cryoelectron microscopy to 3.2-Å resolution. This structure reveals the position of the R domain after phosphorylation. By comparing the structures of human CFTR and zebrafish CFTR determined under the same condition, we identified common features essential to channel gating. The differences in their structures indicate plasticity permitted in evolution to achieve the same function. Finally, the structure of CFTR provides a better understanding of why the G178R, R352Q, L927P, and G970R/D mutations would impede conformational changes of CFTR and lead to cystic fibrosis.

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