Suppressive interactions between mutations located in the two nucleotide binding domains of CFTR

The S1235R locus in CFTR was studied in combination with alleles found at t he 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 o n a V470 background) was characterized by an open probability significantly higher than V470-wildtype CFTR, M470, which on its own increases CFTR chlo ride transport activity when compared to V470-wildtype CFTR, suppressed the activity of R1235 in such a way that a protein with an open probability no t significantly different from V470-wildtype CFTR was obtained. While R628- V CFTR had similar current densities as V470-wildtype CFTR in Xenopus laevi s oocytes, R1235-V resulted in current densities that were more than twofol d higher than those of V470-wildtype CFTR, However, the current densities g enerated by R1235/R628-V (R1235 and R628 on a V470 background) CFTR were si gnificant lower than R1235-V or R628-V CFTR, (C) 2000 Federation of Europea n Biochemical Societies.