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Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):12757-12762. doi: 10.1073/pnas.1815287115. Epub 2018 Nov 20.

Molecular structure of the ATP-bound, phosphorylated human CFTR.

Zhang Z1, Liu F1,2, Chen J3,4.

Author information

1
Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY 10065.
2
Tri-Institutional Training Program in Chemical Biology, The Rockefeller University, New York, NY 10065.
3
Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY 10065; juechen@rockefeller.edu.
4
Howard Hughes Medical Institute, Chevy Chase, MD 20815.

Abstract

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.

KEYWORDS:

ABC transporter; anion channel; cryo-EM; human CFTR

PMID:
30459277
PMCID:
PMC6294961
DOI:
10.1073/pnas.1815287115
[Indexed for MEDLINE]
Free PMC Article

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