title: Suppressive interactions between mutations located in the two nucleotide binding domains of CFTR.
abstract: The S1235R locus in CFTR was studied in combination with alleles found at the M470V and G628R loci. While R628 caused a maturational defect, R1235 did not. The impact of R1235 was found to be influenced by the alleles present at the G628R and M470V loci. At the single channel level, R1235-V (R1235 on a V470 background) was characterized by an open probability significantly higher than V470-wildtype CFTR. M470, which on its own increases CFTR chloride transport activity when compared to V470-wildtype CFTR, suppressed the activity of R1235 in such a way that a protein with an open probability not significantly different from V470-wildtype CFTR was obtained. While R628-V CFTR had similar current densities as V470-wildtype CFTR in Xenopus laevis oocytes, R1235-V resulted in current densities that were more than twofold higher than those of V470-wildtype CFTR. However, the current densities generated by R1235/R628-V (R1235 and R628 on a V470 background) CFTR were significant lower than R1235-V or R628-V CFTR.
authors.affiliation: Department of Physiology, University of Leuven, B-3000, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.forename: A
authors.initials: A
authors.lastname: Vankeerberghen
authors.forename: M
authors.initials: M
authors.lastname: Jaspers
authors.forename: J
authors.initials: J
authors.lastname: Cassiman
authors.forename: B
authors.initials: B
authors.lastname: Nilius
authors.forename: H
authors.initials: H
authors.lastname: Cuppens
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D005787:Gene Frequency; D049452:Green Fluorescent Proteins; D006239:Haplotypes; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D018075:RNA, Complementary / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013489:Suppression, Genetic; D014982:Xenopus laevis
chemical_list: C505032:CFTR protein, human; D008164:Luminescent Proteins; D018075:RNA, Complementary; D011993:Recombinant Fusion Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D049452:Green Fluorescent Proteins