VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level

• Type of Material: Article
• Authors: Guiying Cui, Emory University; Brandon B. Stauffer, Emory University; Barry R. Imhoff, Emory University; Andras Rab, Emory University; Jeong Hong, Emory University; Eric Sorscher, Emory University; Nael McCarty, Emory University
• Language: English
• Date: 2019-09-17
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-49921-4
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 13460
• End Page: 13460
• Grant/Funding Information: This work was supported by National Institutes of Health [Grants DK-056481, DK-075016]; the Cystic Fibrosis Foundation [CFF MCCART14GO] and an Emory/Children’s EECRC 2015 seed grant.
• Keywords: DELTA-F508; ATP HYDROLYSIS; Multidisciplinary Sciences; R-DOMAIN; MUTATION; Science & Technology; RESCUE; TRANSMEMBRANE-CONDUCTANCE-REGULATOR; Science & Technology - Other Topics; CHLORIDE CHANNEL; REGION; CYSTIC-FIBROSIS; NUCLEOTIDE-BINDING DOMAIN
• Research Categories: Biology, Genetics

Abstract

VX-770 (ivacaftor) is approved for clinical use in CF patients bearing multiple CFTR mutations. VX-770 potentiated wildtype CFTR and several disease mutants expressed in oocytes in a manner modulated by PKA-mediated phosphorylation. Potentiation of some other mutants, including G551D-CFTR, was less dependent upon the level of phosphorylation, likely related to the severe gating defects in these mutants exhibited in part by a shift in PKA sensitivity to activation, possibly due to an electrostatic interaction of D551 with K1250. Phosphorylation-dependent potentiation of wildtype CFTR and other variants also was observed in epithelial cells. Hence, the efficacy of potentiators may be obscured by a ceiling effect when drug screening is performed under strongly phosphorylating conditions. These results should be considered in campaigns for CFTR potentiator discovery, and may enable the expansion of VX-770 to CF patients bearing ultra-orphan CFTR mutations.