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Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
09:59

Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein

Published on: March 9, 2015

12.7K

Combination of Correctors Rescues CFTR Transmembrane-Domain Mutants by Mitigating their Interactions with

Miquéias Lopes-Pacheco, Clément Boinot, Inna Sabirzhanova

    Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
    |April 28, 2017
    PubMed
    Abstract

    Insights

    Cystic fibrosis transmembrane conductance regulator (CFTR) mutations cause CF. Correctors C4 and C18 partially restored function for some CFTR mutants by altering protein interactions, but not all mutants responded.

    Area of Science:

    • Molecular biology
    • Genetics
    • Biochemistry

    Background:

    • Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to premature protein degradation.
    • Many CFTR mutants remain uncharacterized, and the efficacy of novel therapeutics is unclear for these variants.

    Purpose of the Study:

    • To characterize four CFTR transmembrane-domain mutants (G85E, E92K, L1077P, M1101K) regarding their expression, stability, and degradation pathways.
    • To evaluate the potential of therapeutic correctors in rescuing these CFTR mutants.
    • To investigate how correctors influence CFTR interactions with proteostasis machinery.

    Main Methods:

    • Utilized cells expressing wild-type CFTR and four CFTR mutants (G85E, E92K, L1077P, M1101K).
    • Assessed protein expression, thermal stability, and degradation routes (proteasomal and aggresomal).
    • Evaluated corrector efficacy (C4, C18) on mutant CFTR maturation and cell surface localization, and analyzed CFTR-proteostasis component interactions.

    Main Results:

    • All four CFTR mutants showed reduced protein expression and were degraded via proteasomes and aggresomes.
    • Low-temperature treatment enhanced maturation for L1077P and M1101K mutants.
    • Co-administration of C4 and C18 partially restored functional expression and stability for E92K, L1077P, and M1101K mutants, but not G85E.
    • Correctors reduced endoplasmic reticulum retention and ubiquitination by altering CFTR interactions with proteostasis components.

    Conclusions:

    • The combination of correctors C4 and C18 demonstrated efficacy in rescuing specific CFTR transmembrane-domain mutants.
    • These correctors function by remodeling the CFTR interactome, thereby mitigating protein misfolding and degradation.
    • Further research is needed to develop effective therapies for all CFTR mutants, particularly G85E.
    Keywords:
    CFTR mutantsCystic fibrosisElectrophysiologyHeat shock proteinIntracellular traffickingMembrane-spanningPrecision medicineProtein foldingProteostasis network

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