CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices

@article{Baker2007CFTRRR,
  title={CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices},
  author={Jennifer M Baker and Rhea P. Hudson and Voula Kanelis and Wing-Yiu Choy and Patrick H. Thibodeau and Philip J. Thomas and Julie Deborah Forman-Kay},
  journal={Nature Structural \&Molecular Biology},
  year={2007},
  volume={14},
  pages={738-745}
}
The regulatory (R) region of the cystic fibrosis transmembrane conductance regulator (CFTR) is intrinsically disordered and must be phosphorylated at multiple sites for full CFTR channel activity, with no one specific phosphorylation site required. In addition, nucleotide binding and hydrolysis at the nucleotide-binding domains (NBDs) of CFTR are required for channel gating. We report NMR studies in the absence and presence of NBD1 that provide structural details for the isolated R region and… 
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TLDR
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TLDR
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TLDR
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TLDR
The results provide a structural basis by which phosphorylation of CFTR may affect the channel gating of full‐length CFTR and expand the understanding of the molecular basis of the ΔF508 defect.
Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions
TLDR
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TLDR
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Thermodynamic study of the native and phosphorylated regulatory domain of the CFTR.
Structural Characterization and Interactions of the CFTR Regulatory Region
The intrinsically disordered nonphosphorylated and phosphorylated R region of CFTR and its interactions with NBD1 and SLC26A3 STAS have been characterized at residuespecific resolution, primarily
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References

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TLDR
The principal mechanism by which phosphoserine 768 inhibits WT CFTR is by hastening the termination of open channel bursts, as the open burst duration of S768A CFTR channels was almost double that of WT channels, at both low and high PKA concentrations.
A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution.
TLDR
Phosphorylation of the regulatory (R) domain initiates cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel activity and stimulated activity of CFTR channels lacking this domain, indicating that R8 is functional.
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TLDR
Functional interactions between the R domain and the two nucleotide binding domains were probed by characterizing the gating of severed CFTR channels expressed in Xenopus oocytes, implying that activation of WT CFTR by PKA likely also includes some component unrelated to the Rdomain.
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TLDR
Crystal structures for mouse NBD1 in unliganded, ADP‐ and ATP‐bound states, with and without phosphorylation are determined, consistent with a CFTR mechanism, whereby channel gating occurs through ATP binding in an N BD1–NBD2 nucleotide sandwich that forms upon displacement of NBD 1 regulatory segments.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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