Limited proteolysis as a probe for arrested conformational maturation of delta F508 CFTR - PubMed (original) (raw)
Limited proteolysis as a probe for arrested conformational maturation of delta F508 CFTR
F Zhang et al. Nat Struct Biol. 1998 Mar.
Abstract
Deletion of phenylalanine 508 (delta F508) 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, delta F508 CFTR, is misfolded. We address this issue directly, using comparative limited proteolysis of CFTR at steady steady state and during biosynthesis in the native microsomal environment. Distinct protease susceptibilities suggest that cytosolic domain conformations of wild type and delta F508 CFTR differ, not only near F508, but globally. Moreover, delta F508 CFTR proteolytic cleavage patterns were indistinguishable from those of the early folding intermediate of wild type CFTR. The results suggest that the delta F508 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.
Comment in
- Cystic fibrosis problem probed by proteolysis.
Welsh MJ, Ostedgaard LS. Welsh MJ, et al. Nat Struct Biol. 1998 Mar;5(3):167-9. doi: 10.1038/nsb0398-167. Nat Struct Biol. 1998. PMID: 9501902 No abstract available.
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