ABCMdb

ABCC7 p.Phe508Trp

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Publications

PMID: 15619636 [PubMed] Thibodeau PH et al: "Side chain and backbone contributions of Phe508 to CFTR folding."

No. Sentence Comment

28 With the exception of F508W, all measured NBD1 proteins were capable of folding at 4 °C at near-100% efficiency as measured by the production of soluble conformers that were quantified by tryptophan fluorescence intensity or western blotting.In addition,all of the domains exhibited a temperature-dependence of refolding efficiency where overall yield in the soluble fraction decreased as temperature increased. Login to comment
38 However, when the F508W mutation was introduced onto the background of W496F, folding of the NBD1 was partially restored and the protein was capable of refolding with higher efficiency (>90% soluble) at 4 °C (Fig.1b). Login to comment
46 How does the isolated NBD accommodate such Temperature (ºC) 4 10 16 22 Fractionalyield 0.0 0.5 1.0 Temperature (ºC) 4 10 16 22 Temperature (ºC) 4 10 16 22 Wild type ∆F508 Wild type ∆F508 ̄ F508A ̄ F508M F508P F508W ͷ F508W W496F Wild type ∆F508 F508Q F508R F508D F508S a b c Figure 1 NBD1 folding efficiency as a function of folding temperature. Login to comment
52 (b) The F508W mutant, the only mutant that deviated markedly from the wild type, was rescued by the introduction of a second missense mutation, W496F. Login to comment
92 The known polymorphism F508C and the non-CF-causing variant F508S both showed measurable quantities of band C at steady-state levels, as would be expected for non-CF-causingsubstitutions.Thehydrophobicaminoacidsubstitutions F508I,F508W and F508Y did not produce substantial steady-state levels of band C as measured by western blotting, nor did the ionizable amino acid substitutions F508D, F508E, F508K, F508H or F508R. Login to comment
101 Notably, missense mutations other than F508W had little effect on either the folding or stability of the isolated NBD, suggesting that the peptide backbone at this locus is critical to NBD1 folding efficiency, whereas the side chain character is largely unimportant. Login to comment
104 The structures of NBD1 proteins also suggest a potential mechanism for the deleterious effects of the F508W substitution,as the phenylalanine side chain, although partially surface-exposed and accessible, interacts with surrounding residues.The nearest atom distances from both Trp496 and Met498 to Phe508 are ~4 Å.The additional physical size of the tryptophan side chain thus may not be accommodated by the local protein structure.However,when a second substitution,W496F,was introduced, the folding of the domain was rescued.Given the close proximity of both residues,theW496F substitution probably resolves a steric clash between the substituted tryptophan at position 508 and other local residues,consistent with the refolded protein reaching a native or near-native-state structure in vitro. Login to comment
113 W ild type ∆∆F508 F508 F508D F508K F508E F508R F508H F508S F508T F508N F508Q C B Charged Polar F508A F508C F508I F508L ∆F508 F508 W ild type C B F508W F508Y F508G F508P Hydrophobic F508M F508V ̅̆ ̆ ̅ Figure 3 Maturation of full-length CFTR mutants. Login to comment

PMID: 26149808 [PubMed] Chong PA et al: "Deletion of Phenylalanine 508 in the First Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator Increases Conformational Exchange and Inhibits Dimerization."

No. Sentence Comment

336 Collectively, the data indicate that F508del reduces the ability of NBD1 èc;RIèc;RE to homodimerize, probably by disrupting the Phe-508/Trp-496 side chain interaction that stabilizes the Q-loop. Login to comment