Interplay between CFTR Phosphorylation, CFTR-ATPase Activity, and Anion Flux

Zwick, Matthias and Esposito, Cinzia and Hellstern, Manuel and Seelig, Anna. (2016) Interplay between CFTR Phosphorylation, CFTR-ATPase Activity, and Anion Flux. Journal of Biological Chemistry, 291 (28). pp. 14483-14498.

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Official URL: http://edoc.unibas.ch/43564/

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The cystic fibrosis (CF) transmembrane conductance regulator (CFTR, ABCC7), mutations of which cause CF, belongs to the ATP binding cassette (ABC) transporter family and works as a channel for small anions, such as chloride and bicarbonate. Anion channel activity is known to depend on phosphorylation by cAMP-dependent protein kinase A (PKA) and CFTR-ATPase activity. Whereas anion channel activity has been extensively investigated, phosphorylation and CFTR-ATPase activity are still poorly understood. Here, we show that the two processes can be measured in a label-free and non-invasive manner in real time in live cells, stably transfected with CFTR. This study reveals three key findings. (i) The major contribution to the total CFTR-related ATP hydrolysis rate (≥ 90 %) is due to phosphorylation by PKA and the minor contribution (≤ 10 %) to CFTR-ATPase activity. (ii) The mutant CFTR-E1371S which is still conductive, but defective in ATP hydrolysis, is not phosphorylated, suggesting that phosphorylation requires a functional nucleotide binding domain and occurs in the post-hydrolysis transition state. (iii) CFTR-ATPase activity is inversely related to CFTR anion flux. The present data are consistent with a model in which CFTR is in a closed conformation with two ATPs bound. The open conformation is induced by ATP hydrolysis and corresponds to the post hydrolysis transition state which is stabilized by phosphorylation and binding of chloride channel potentiators.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Biochemistry and Molecular Biology
Note:Publication type according to Uni Basel Research Database: Journal article -- The final publication is available at Journal of Biological Chemistry, see DOI link.
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Last Modified:27 Sep 2017 10:13
Deposited On:20 Dec 2016 09:57

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