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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Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions
TLDR
The dynamic conformational sampling and transient binding of the R region to multiple partners enables complex control of CFTR channel activity and trafficking.
NMR spectroscopy to study the dynamics and interactions of CFTR.
TLDR
NMR data are yielding insights into the dynamic properties and interactions that facilitate normal CFTR regulation as well as pathological effects of mutations, including the most common disease mutant, deletion of F508 in NBD1.
Allosteric Coupling between the Intracellular Coupling Helix 4 and Regulatory Sites of the First Nucleotide-binding Domain of CFTR
TLDR
Using a sensitive method for detecting inter-residue correlations between chemical shift changes in NMR spectra, an allosteric network was revealed within NBD1, suggesting a mechanism synthesizing diverse regulatory N BD1 interactions and providing biophysical evidence for the allosterics coupling required for CFTR function.
NMR evidence for differential phosphorylation‐dependent interactions in WT and ΔF508 CFTR
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
Detailed characterizations of phosphorylation-dependent interactions of the regulatory region and structural models of its highly dynamic complexes provide direct insight into the basis of CFTR regulation and the general binding mechanisms of disordered hub proteins.
CFTR gating mechanism: The role of dimerization of nucleotide binding domains
TLDR
It is concluded that signature sequence serves as a switch that transmits the signal of Cd binding to the gate opening of CFTR channels, and that micromolar [Cd] can dramatically increase the activity of G551D-CFTR.
Role of individual R domain phosphorylation sites in CFTR regulation by protein kinase A.
Thermodynamic study of the native and phosphorylated regulatory domain of the CFTR.
Computational studies reveal phosphorylation-dependent changes in the unstructured R domain of 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
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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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