CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices

Jennifer M R Baker, Rhea P. Hudson, Voula Kanelis, Wing Yiu Choy, Patrick H. Thibodeau, Philip J. Thomas, Julie D. Forman-Kay

Research output: Contribution to journalArticle

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Abstract

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 its interaction with NBD1 at residue-level resolution. Several sites in the R region with measured fractional helical propensity mediate interactions with NBD1. Phosphorylation reduces the helicity of many R-region sites and reduces their NBD1 interactions. This evidence for a dynamic complex with NBD1 that transiently engages different sites of the R region suggests a structural explanation for the dependence of CFTR activity on multiple PKA phosphorylation sites.

Original languageEnglish (US)
Pages (from-to)738-745
Number of pages8
JournalNature Structural and Molecular Biology
Volume14
Issue number8
DOIs
StatePublished - Aug 2007

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Cystic Fibrosis Transmembrane Conductance Regulator
Nucleic Acid Regulatory Sequences
Phosphorylation
Nucleotides
Hydrolysis

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Baker, J. M. R., Hudson, R. P., Kanelis, V., Choy, W. Y., Thibodeau, P. H., Thomas, P. J., & Forman-Kay, J. D. (2007). CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nature Structural and Molecular Biology, 14(8), 738-745. https://doi.org/10.1038/nsmb1278

CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. / Baker, Jennifer M R; Hudson, Rhea P.; Kanelis, Voula; Choy, Wing Yiu; Thibodeau, Patrick H.; Thomas, Philip J.; Forman-Kay, Julie D.

In: Nature Structural and Molecular Biology, Vol. 14, No. 8, 08.2007, p. 738-745.

Research output: Contribution to journalArticle

Baker, JMR, Hudson, RP, Kanelis, V, Choy, WY, Thibodeau, PH, Thomas, PJ & Forman-Kay, JD 2007, 'CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices', Nature Structural and Molecular Biology, vol. 14, no. 8, pp. 738-745. https://doi.org/10.1038/nsmb1278
Baker, Jennifer M R ; Hudson, Rhea P. ; Kanelis, Voula ; Choy, Wing Yiu ; Thibodeau, Patrick H. ; Thomas, Philip J. ; Forman-Kay, Julie D. / CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. In: Nature Structural and Molecular Biology. 2007 ; Vol. 14, No. 8. pp. 738-745.
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