ABCMdb

ABCC7 p.Val232Asn

None has been submitted yet.

Publications

PMID: 24412276 [PubMed] Loo TW et al: "The cystic fibrosis V232D mutation inhibits CFTR maturation by disrupting a hydrophobic pocket rather than formation of aberrant interhelical hydrogen bonds."

No. Sentence Comment

19 The rationale was that a V232N mutation should mimic V232D and a V232D/Q207A mutant should mature if the processing defect was caused by hydrogen bonds. Login to comment
21 The V232N mutation did not mimic V232D as V232N showed 40% maturation compared to 2% for V232D. Login to comment
42 The rationale was that the V232N mutation should be just as effective as V232D to inhibit CFTR maturation and mutation of Gln207 to nonpolar residues should rescue the V232D mutant if the processing defect was caused by Asp232/Gln207 hydrogen bonds. Login to comment
127 Inhibition of CFTR maturation correlates with the polarity of a Val232 mutation If V232D inhibits CFTR maturation by forming a non-native hydrogen bond with Gln207, then it would be expected that V232N and V232Q mutations would also severely inhibit maturation since asparagine and glutamine are structurally similar to aspartate and their amide groups can accept or donate two hydrogen bonds. Login to comment
128 Accordingly, mutants V232N and V232Q were constructed. Login to comment
131 By contrast, the amount of mature protein was about 20-fold higher (about 40%) for mutants V232N and V232Q compared to V232D or V232E (Fig. 3). Login to comment
137 The V232N and V232Q mutations modestly reduced the yield of mature CFTR by about half (80% for wild-type CFTR compared to about 40% for mutants V232N or V232Q) (Fig. 3). Login to comment
138 The V232N and V232Q mutations may have reduced maturation because of a change in polarity or because introduction of a larger side chain caused steric effects that disrupted packing of the TM segments. Login to comment
274 In summary, the results suggest that: (1) the mechanism of how V232D causes protein misfolding is unlikely to involve non-native hydrogen bond interactions with Gln207 because V232N yielded about 20-fold more mature CFTR than V232D; (2) it appears that the mechanism of protein misfolding by V232D mutation involves disruption of a hydrophobic pocket since the hydrophobicity of the substituted amino acid at position 232 correlated with the amount of mature product and the ability to correct the defects with correctors or the V510D suppressor mutation; (3) the V232D mutation traps CFTR as a partially folded intermediate that can be rescued by corrector VX-809 to yield a native structure. Login to comment