Molecular structure of the ATP-bound, phosphorylated human CFTR

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 elicite...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-12, Vol.115 (50), p.12757-12762
Main Authors: Zhang, Zhe, Liu, Fangyu, Chen, Jue
Format: Article
Language:English
Subjects:
ABC transporters
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - metabolism
Animals
ATP
Biological Sciences
Cell Line
Channel gating
Conductance
Cryoelectron Microscopy - methods
Cyclic AMP-Dependent Protein Kinases - chemistry
Cyclic AMP-Dependent Protein Kinases - metabolism
Cystic fibrosis
Cystic Fibrosis - metabolism
Cystic Fibrosis Transmembrane Conductance Regulator - chemistry
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
HEK293 Cells
Humans
Intestine
Ion Channel Gating - physiology
Ion channels
Ion Transport - physiology
Lungs
Molecular Structure
Mutation
Mutation - genetics
Pancreas
Phosphorylation
Protein kinase A
Proteins
Structure-function relationships
Zebrafish
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Summary: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 cryoelectronmicroscopy 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1815287115