Journal
CELL
Volume 169, Issue 1, Pages 85-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.02.024
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Funding
- Rockefeller University
- Howard Hughes Medical Institute
- MTA-Momentum [LP2012-39/2012]
- Cystic Fibrosis Foundation [CSANAD15G0]
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The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP- binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 angstrom structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo- EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. Fromcomparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix- loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function.
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