Abstract
Deletion of phenylalanine 508 (ΔF508) in the cystic fibrosis transmembrane-conductance regulator (CFTR) prevents the otherwise functional protein from reaching the plasma membrane and is the leading cause of cystic fibrosis. Indirect evidence suggests that the mutant protein, ΔF508 CFTR, is misfolded. We address this issue directly, using comparative limited proteolysis of CFTR at steady state and during biosynthesis in the native microsomal environment. Distinct protease susceptibilities suggest that cytosolic domain conformations of wild type and ΔF508 CFTR differ, not only near F508, but globally. Moreover, ΔF508 CFTR proteolytic cleavage patterns were indistinguishable from those of the early folding intermediate of wild type CFTR. The results suggest that the ΔF508 mutation causes the accumulation of a form of the protein that resembles an intermediate in the biogenesis of the wild type CFTR, rather than induces the production of non-native variant.
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Zhang, F., Kartner, N. & Lukacs, G. Limited proteolysis as a probe for arrested conformational maturation of ΔF508 CFTR. Nat Struct Mol Biol 5, 180–183 (1998). https://doi.org/10.1038/nsb0398-180
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DOI: https://doi.org/10.1038/nsb0398-180
