Article abstract
Nature Structural & Molecular Biology 14, 738 - 745 (2007)
Published online: 29 July 2007 | doi:10.1038/nsmb1278
CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices
Jennifer M R Baker1,2, Rhea P Hudson1, Voula Kanelis1, Wing-Yiu Choy2,4, Patrick H Thibodeau3, Philip J Thomas3 & Julie D Forman-Kay1,2
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.
- Program in Molecular Structure and Function, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
- Department of Physiology, 6001 Forest Park Lane, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
- Present address: Department of Biochemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
Correspondence to: Julie D Forman-Kay1,2 e-mail: forman@sickkids.ca
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