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Stabilizing rescued delF508 CFTR at the plasma membrane by potentiation of its interaction with Na+/H+ exchanger regulatory factor 1
Author(s) -
Arora Kavisha,
Moon Chang Suk,
Zhang Weiqiang,
Ren Aixia,
Yarlagadda Sunitha,
Sinha Chandrima,
Naren Anjaparavanda P.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.553.4
Subject(s) - cystic fibrosis transmembrane conductance regulator , cystic fibrosis , ivacaftor , chemistry , δf508 , mutant , membrane protein , microbiology and biotechnology , mutant protein , mutation , membrane , biophysics , medicine , biology , biochemistry , gene
Cystic fibrosis (CF) is a lethal genetic disease and warrants effective therapeutic interventions. Preclinical studies screened CF‐correctors based on their ability to partially correct the processing defects of ΔF508 mutation of cystic fibrosis transmembrane conductance regulator (CFTR), the most common CF causing mutation. The CF‐corrector VX‐809 underwent Phase II trials in combination with VX‐770 or Ivacaftor and was shown to significantly improve lung function in CF patients. In this study, we demonstrate the significance of protein‐protein interaction in enhancing the stability of mutant channel protein at the plasma membrane. We show that VX‐809 partially stabilizes ΔF508‐CFTR interaction with scaffolding protein Na + /H + exchanger regulatory factor 1 (NHERF1) at the plasma membrane. We demonstrate in cystic fibrosis bronchial epithelial cells that VX‐809 increases half‐life of ΔF508 CFTR at the plasma membrane by potentiating its otherwise weak interaction with NHERF1. Single particle tracking analysis further strengthens our observation as VX‐809 restricts the mobility of ΔF508‐CFTR at the plasma membrane while the effect is mitigated in ΔF508 CFTR His10 (lacks the PDZ motif and hence the ability to interact with NHERF1). Therefore, our studies demonstrate the importance of macromolecular complex in rescuing mutant CFTR to the plasma membrane and will further help device newer generation of more effective CF‐correctors.